The 2017 Japan-NIH Joint Symposium · The 2017 Japan-NIH Joint Symposium Office c/o International Exchange Office, Graduate School of Medicine, Tohoku University c/o Research Cooperation

The 2017 Japan-NIH Joint Symposium

on Advances in Biomedical Research and Disease

Program and Abstracts

February 15 (Wed) – 17 (Fri), 2017

Seiryo Auditorium

Seiryo Campus, Tohoku University, Sendai Japan

Contents

Congress Information ……………………………………………………………………………………… 1

Registration and Social Programs ………………………………………………………………………… 2

Floor Plan ………………………………………………………………………………………………… 3

Instructions for Presentation ……………………………………………………………………………… 4

Time Table ………………………………………………………………………………………………… 6

Program …………………………………………………………………………………………………… 7

Abstract and Profiles

Plenary Session ………………………………………………………………………………… 13

Scientific Sessions ……………………………………………………………………………… 23

Concurrent Workshops ………………………………………………………………………… 63

Career Development Workshop ………………………………………………………………… 79

Poster Sessions …………………………………………………………………………………………… 81

Committees and Administrative Office …………………………………………………………………… 108

▼ ▼ The 2017 Japan-NIH Joint Symposium

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February 15 (Wed)-17(Fri), 2017 1

Congress Information

◆Date:Wednesday, February 15th – Friday, February 17th, 2017

◆Venue:Seiryo Auditorium, Seiryo Campus, Tohoku University 2-1 Seiryo-machi, Aobaku, Sendai 980-8574, JapanTel: +81-22-718-5091

◆Main Theme:Advances in Biomedical Research and Disease

◆Official Language:English

◆Mobile Phones:You are prohibited from using your mobile phone during the lectures. Please turn it off or put it in the silent mode.

◆Security:Please keep your eyes on your personal belongings at all times. The symposium organizers will not be responsible for any loss or damage.

◆Filming and Photography:Filming, photography and recording are prohibited. Please refrain from carrying recording devices into the presentation venue.

◆Photographs and Press:Staff of Public Relations Office, Tohoku University Graduate School of Medicine, will take photographs during the Symposium. Tohoku University will use the photographs in Tohoku University-related publications, material and websites.

◆Contact Secretariat:(During the Congress, Thursday, February 16th – Friday, February 17th, 2017)Registration Desk, 2F, Seiryo Auditorium(Except congress period)The 2017 Japan-NIH Joint Symposium Officec/o International Exchange Office, Graduate School of Medicine, Tohoku Universityc/o Research Cooperation Section, Graduate School of Medicine Administration Office, Tohoku University2-1 Seiryo-machi, Aoba-ku Sendai 980-8575, JAPANTEL: +81-22-718-5091e-mail: [email protected]

◆Congress Website:http://www.med.tohoku.ac.jp/english/nih2017/


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2 February 15 (Wed)-17(Fri), 2017

Registration

◆Registration Desk:In front of “Main Hall (Auditorium), 2F, Seiryo Auditorium

◆Open Hours:Thursday, February 16th 8:20 – 19:00Friday, February 17th 8:00 – 17:40

◆Registration Fee:Free

◆Entitlements:Participants’ registration includes:+ A Program and Abstracts Book+ A Name Tag+Coffee Breaks

Social Programs

◆Site Visit for invited NIH Guests:Date & Time: Wednesday, February 15th 8:00 – 14:30Destination: “Ishinomaki City”, the affected areas by the Great East Japan Earthquake and TsunamiLecture: Masaaki Abe, Kuniharu Takahashi, the Japanese Red Cross Ishinomaki Hospital Takeshi Kanno, Tohoku University Hospital

◆Tour of Tohoku Medical Megabank for invited NIH guests Date & Time: Wednesday, February 15th 15:00 – 16:00Tohoku Medical Megabank Project is a national project run by Tohoku University, which constructs 150,000 general residents genome cohort and integrated biobank. The project has completed more than 2,000 whole genome sequencing, and analyzed more than 1,000 comprehensive metabolome of plasma, and these data are open to research community on line. The tour will be guided by researchers of the project, and the facilities are unique and very advanced.


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Floor Plan


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Instructions for Presentation

◆Poster Sessions: 1. Poster size

・ Poster　85 cm width X 180 cm height (20 cm for title)

2. Schedule

・・You must set up your poster during 8:20 am - 9:00 am on Thursday, February 16th.

・・Poster session: 17:00 pm – 19:00 pm Thursday, February 16th

・・ Please do NOT tear down your poster right after your presentation. 　(You can tear down it from 13:30 pm to 16:30 pm on Friday, February 17th.)

3. Presentation

・ All poster presenters are required to present their work in English. (Presentation: 5 minutes, Discussion: 2 minutes)

　Your assigned board will be indicated with your poster presentation number. Please refer to the “Poster Session Map”. Please prepare a label showing the title, author’s name and the affiliations. Adhesive tape for mounting the posters will be available from the Poster Check-in Desk. The organizing committee is not responsible for any loss or mishandling.


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Poster Session Map


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Time Table


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Program

DAY1 Wednesday, February 15th, 2017

Opening Remarks (8:00)

Site Visit to the Great East Japan Earthquake affected areas for invited NIH guests(8:00-14:30)Tour of Tohoku Medical Megabank for invited NIH guests (15:00-16:00)

(in both Japanese and English) (15:00-17:00)Facilitator: Reiko Toyama, Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIHRemarks1 Reiko Toyama, NICHD, NIHRemarks2 Akiyoshi Fukamizu, Life Science Center of Tsukuba Advanced Research Alliance,

University of TsukubaPanel Discussion with NIH Young Researchers Javier Traba Dominguez, NHLBI, NIH Brian Duchez, NIDCR, NIH Tomoko Ikeuchi, NIDCR, NIH Xiaoyi Li, NIDCD, NIH Jaroslawna Meister, NIDDK, NIH Teresa Ramirez, NHGRI, NIH Stephanie Olivier-Van Stichelen, NIDDK, NIH Sumihito Togi, NICHD, NIHBreak Out Sessions and Networking


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DAY2 Thursday, February 16th, 2017Place: Main Hall (Seiryo Auditorium)Registration and Poster Mounting (8:20 - )

Special Session (9:00-9:40)Special Remarks Susumu Satomi, President, Tohoku University Tooru Shimosegawa, Dean Graduate School of Medicine, Tohoku University James F. Battey, Director, NIDCD, NIHRemarks from NIH Japanese Scientist Association Keiko Ozato, Chief, Molecular Genetics of Immunity Section, NICHD, NIH

(Photograph)

Plenary Session-Genome Medicine (9:50-12:00) Chair: Masayuki Yamamoto, Executive Director, Tohoku Medical Megabank Organization PS-1 Genomic Medicine Implementation Projects of the National Human Genome Research Institute Teri A. Manolio, Division of Genomic Medicine, NHGRI, NIHPS-2 Experience as the Public Population-Based Biobank in the Disaster- Stricken Areas in Japan Naoko Minegishi, Department of Biobank, Tohoku Medical Megabank OrganizationPS-3 Strategy of genome-omics analyses in Tohoku Medical Megabank Project Kengo Kinoshita, Department of Integrative Genomics, Tohoku Medical Megabank Organization PS-4 Genetic Susceptibility to Acute Lung Injury: Interaction Between Nuclear and Mitochondrial Genomes Steven Kleeberger, Immunity, Inflammation & Disease Laboratory, NIEHS, NIH

(Lunch Break: 12:00-13:00)

Scientific Session 1- Systems Biology of Immune Responses (13:00 – 15:10) Chair: Kazuhiko Igarashi, Tohoku University Graduate School of MedicineSS1-1 γc Family Cytokines and the Fine-Tuning of Cytokine Signaling Warren J. Leonard, Laboratory of Molecular Immunology, NHLBI, NIHSS1-2 Gene Regulatory Networks Composed by Transcription Factors Orchestrate Plasma Cell Differentiation Kyoko Ochiai, Department of Biochemistry, Tohoku University Graduate School of MedicineSS1-3 IRF Transcription Factors in the Development and Function of Mononuclear Phagocytes Tomohiko Tamura, Department of Immunology, Yokohama City University Graduate School of MedicineSS1-4 Chromatin Regulation of Innate Immunity: BRD4 is Required for Hematopoietic Stem Cell DevelopmentandRegulatesProandAnti-InflammatoryResponsesThroughSuper-enhancers Keiko Ozato, Molecular Genetics of Immunity Section, NICHD, NIH


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Scientific Session 2- Cross-talk between Acquired and Innate Immune Systems (15:10 –16:50) Chair: Kouetsu Ogasawara, Institute of Development, Aging and Cancer, Tohoku University SS2-1 Dectin-Stimulated Dendritic Cells Induce Unique IL-10-Producing T Cells with Regulatory Properties Warren Strober, Mucosal Immunity Section, NIAID, NIHSS2-2 CD11b-CD103- Dermal Dendritic Cells Express RALDH1 and Regulate Skin Fibrosis via Retinoic Acid-Dependent Development of Induced Regulatory T Cells Yoshihide Asano, Department of Dermatology, Graduate School of Medicine, The University of TokyoSS2-3 Neural Control of Gut Homeostasis in Drosophila Immunity Shoichiro Kurata, Department of Molecular Genetics, Graduate School of Pharmaceutical Sciences, Tohoku University

(Coffee break: 16:50-17:00)

Poster Sessions (17:00-19:00)Place: Poster Hall 1, 2 and 3

ModeratorsPoster Session 1: James F. Battey and Kazuhiko IgarashiPoster Session 2: Kim Y. Green and Hitoshi OshitaniPoster Session 3: Warren Strober, Warren J. Leonard and Takanori SoPoster Session 4: Teri A. Manolio and Steven KleebergerPoster Session 5: Matthew P. Hoffman and Kazuhiro Nagata Poster Session 6: Keiko Ozato and Keiko NakayamaPoster Session 7: YoshihikoYamada and Mitsunori FukudaPoster Session 8: Shioko Kimura and Keiichi ItoiPoster Session 9: ReikoToyama and Takashi TakahashiPoster Session 10: Kathleen R. Merikangas and Noriko OsumiPoster Session 11: Jeffrey B. Kopp and Takaaki Abe


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DAY3 Friday, February 17th, 2017Place: Main Hall (Seiryo Auditorium)Registration (8:00 - )

Scientific Session 3- Neuroscience (8:30-10:40) Chair: Noriko Osumi, Tohoku University Graduate School of MedicineSS3-1 A Bright Future for People with Communication Disorders James F. Battey, Director, NIDCD, NIH SS3-2 Rhythms of Motor Activity and Related Homeostatic Systems and Bipolar Disorder: Opportunities for Cross-Species Research Kathleen Ries Merikangas, Genetic Epidemiology Research Branch, NIMH, NIHSS3-3 Endophenotype in the Brain: A Key Concept for Understanding the Relationships Between Genes and Behavior Tsuyoshi Miyakawa, Division of Systems Medical Science, Fujita Health UniversitySS3-4 Multi-Faceted Researches into Mental Health Problems after the Great East Japan Earthquake – Towards Development of Precision Medicine for Affected Communities Hiroaki Tomita, Department of Disaster Psychiatry, International Research of Disaster Science, Tohoku University

(Coffee break: 10:40-10:55)

Scientific Session 4- Developmental Biology and Regenerative Medicine (10:55-13:05) Chair: Koji Tamura, Tohoku University Graduate School of Life SciencesSS4-1 Salivary Gland Morphogenesis Guides Gland Regeneration Matthew P. Hoffman, Matrix and Morphogenesis Section, NIDCR, NIHSS4-2 EpiprofinisaMulti-FunctionalFactorEssentialtoPromoteDentalEpithelialStemCell Commitment to the Ameloblast Lineage and its Proliferation and Differentiation Yoshihiko Yamada, Molecular Biology Section, NIDCR, NIH SS4-3 Regulation of Proteostasis and Calcium Homeostasis in the ER and of Autophagy Kazuhiro Nagata, Laboratory of Molecular and Cellular Biology, Kyoto Sangyo UniversitySS4-4 RolesofRabFamilySmallGTPasesinPolarizedTraffickinginEpithelialCells Mitsunori Fukuda, Department of Developmental Biology and Neurosciences, Tohoku University Graduate School of Life Sciences

(Lunch break: 13:05-14:00)


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Scientific Session 5- Cancer Science (14:00 - 15:40) Chair: Keiko Nakayama, Tohoku University Graduate School of MedicineSS5-1 TTF-1/NKX2-1: An Enigmatic Double-Edged Sword in Lung Adenocarcinoma Takashi Takahashi, Division of Molecular Carcinogenesis, Graduate School of Medicine, Nagoya UniversitySS5-2 Interplay of MYC Oncogene and Ubiquitin-Proteasomal Degradation of a TFIID Component in Proliferation Switch Tadashi Nakagawa, Division of Cell Proliferation, Tohoku University Graduate School of Medicine SS5-3 Stem Cells and Cancer of Thyroid Shioko Kimura, Laboratory of Metabolism, CCR, NCI, NIH

Closing Remarks (15:40-16:00) Sadayoshi Ito, Executive Vice President, Tohoku University

(Poster award and certificate ceremony)(Photograph)


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Concurrent Workshops 1 & 2 (16:00-17:40)

Workshop1: Infectious Diseases (Bldg.6 1F Auditorium) Chair: Hitoshi Oshitani, Tohoku University Graduate School of MedicineCW1-1 The Challenges in Treating Chronic Norovirus Infection Kim Y. Green, Caliciviruses Section, NIAID, NIHCW1-2 IdentificationoftheFunctionalReceptorforMurineNorovirus Kazuhiko Katayama, Laboratory of Viral Infection I, Graduate School of Infection Control Sciences, Kitasato UniversityCW1-3 Genetic Diversity of Norovirus and Sapovirus in Multiple Infection Among Birth Cohort Children Mayuko Saito, Department of Virology, Tohoku University Graduate School of MedicineCW1-4 Norovirus Monitoring in Sewage as a Tool for Detecting Infectious Gastroenteritis and Genotypes Circulating in Human Populations Shinobu Kazama, New Industry Creation Hatchery Center, Tohoku University

Workshop2: Kidney Diseases (Seiryo Auditorium) Chair: Takaaki Abe, Tohoku University Graduate School of Biomedical EngineeringCW2-1 APOL1 Genetic Variants Explain Much of the Increased Kidney Disease Risk Among African Americans Jeffrey B. Kopp, Kidney Disease Section, NIDDK, NIHCW2-2 Mechanism of the Progression from Podocyte Injury to Glomerulosclerosis in Chronic Kidney Disease Katsuhiko Asanuma, Medical Innovation Center, TMK project, Graduate School of Medicine, Kyoto UniversityCW2-3 Development of a Novel Mitochondrial Drug, MA-5 Takaaki Abe, Division of Medical Science, Tohoku University Graduate School of Biomedical Engineering

Plenary Session:

PS : Genome Medicine


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PS-1

Genomic Medicine Implementation Projects of the National Human Genome Research Institute

Teri A. Manolio, M.D., Ph.D.National Human Genome Research Institute, NIH

Increasing knowledge about the influence of genetic variation on human health and growing availability of reliable, cost-effective genetic testing have spurred the implementation of genomic medicine in the clinic. As defined by the National Human Genome Research Institute (NHGRI), genomic medicine uses an individual’s genetic information in his or her clinical care, and has begun to be applied effectively in areas such as cancer genomics, pharmacogenomics, and rare and undiagnosed diseases. In 2011 NHGRI published its strategic vision for the future of genomic research, including an ambitious research agenda to facilitate and promote the implementation of genomic medicine. To realize this agenda, NHGRI is consulting and facilitating collaborations with the external research community through a series of “Genomic Medicine Meetings,” under the guidance and leadership of the National Advisory Council on Human Genome Research. These meetings have identified and begun to address significant obstacles to implementation, such as lack of evidence of efficacy, limited availability of genomics expertise and testing, lack of standards, and difficulties in integrating genomic results into electronic medical records.

The six research and dissemination initiatives comprising NHGRI’s genomic research portfolio are designed to speed the evaluation and incorporation, where appropriate, of genomic technologies and findings into routine clinical care. Actual adoption of successful approaches in clinical care will depend upon the willingness, interest, and energy of professional societies, practitioners, patients, and payers to promote their responsible use and share their experiences in doing so.


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Teri A. Manolio, M.D., Ph.D.

Position and Affiliation: Director, Division of Genomic Medicine, National Human Genome Research Institute, NIH

Research Interest: Genome-wide association studies of complex diseases, ethnic differences in disease risk, integrating genomic research into electronic medical records, and incorporating genomic findings into clinical care.

Biographical Sketch:　Dr. Manolio directs the Division of Genomic Medicine of the National Human Genome Research Institute (NHGRI), where she leads programs to develop and implement genomic applications in clinical care. She came to NHGRI from the National Heart, Lung, and Blood Institute where she was heavily involved in large cohort studies such as the Cardiovascular Health Study, the Framingham Heart Study, and the Multi-Ethnic Study of Atherosclerosis. She moved to NHGRI in 2005 to lead efforts in applying genomic technologies to population research, including the Electronic Medical Records and Genetics (eMERGE) Network, the NHGRI Genome-Wide Association Catalog, and the Clinical Genome (ClinGen) Resource. She continues to practice and teach medicine on the internal medicine service of the Walter Reed National Military Medical Center in Bethesda, and is a professor of medicine at the F. Edward Hebert School of Medicine of the Uniformed Services University of the Health Sciences. She is the author of over 270 original research reports and papers and has research interests in genome-wide association studies of complex diseases, ethnic differences in disease risk, integrating genomic research into electronic medical records, and incorporating genomic findings into clinical care.　Dr. Manolio received her M.D. from the University of Maryland and did her internal medicine residency at Boston City Hospital. She was chief resident of the Georgetown Service at D.C. General Hospital and a fellow in general internal medicine at Johns Hopkins University, where she earned a Master of Health Sciences degree in epidemiology focusing on complications of coronary bypass grafting in older adults. She later returned to Hopkins to complete a Ph.D. in human genetics/genetic epidemiology, focusing on the genetics of B. tropicalis sensitization in asthma.


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PS-2

Experience as the Public Population-Based Biobank in the Disaster- Stricken Areas in Japan

Naoko Minegishi1, the Tohoku Medical Megabank Project Study Group1,2

1Tohoku Medical Megabank Organization, Tohoku University2Iwate Tohoku Medical Megabank Organization, Iwate Medical University

The biobank in the Tohoku Medical Megabank Project (TMM Biobank) is the first major population-based biobank in Japan and has collected more than 2.7 million biospecimens with their health-related data from nearly 150,000 individuals in Miyagi and Iwate prefectures, using the latest biobanking techniques to realize the very low error rate and the high quality specimens for genomics studies.

These specimens and data were obtained from the participants in the cohort studies conducted as part of a reconstruction program after the great earthquake and tsunami in 2011: Community-Based Cohort Study and the BirThree (Birth and Three Generation) Cohort Study. The study results, showing an increased prevalence of mental disorders and the frequent interruption of hypertension treatment among the disaster-stricken people, were quickly provided to health workers as necessary information to improve the community health status. Each participant also received the results of the biological and physiological examinations, with the recommendation to consult doctors when necessary.

TMM biobank started its distribution program in 2015. The participants of these cohort studies gave consent for the future use of their specimens and data, in a broad range of medical research performed by not-otherwise-specified researchers. Researchers can use biospecimens and individual data (after data cleaning) when the review and contracting processes are completed. In addition, the statistical data of whole genome sequences of more than 2,000 people in the TMM biobank (>30× coverage), elucidating the considerable differences in the frequency of single nucleotide variations between the Japanese and Caucasian populations, are publicly available on websites and have been utilized in dozens of studies for variant prioritization.

We hope that public availability of the data and biospecimens in TMM biobank will enhance genome-based research and disaster-medicine in Japan and that the endorsement from researchers and communities will help the sustainability of TMM biobank.


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Naoko Minegishi

Position and Affiliation:Professor, Department of Biobank,Tohoku Medical Megabank Organization,Tohoku University

[Research Interest]1) Biobank management, especially quality management system and sample quality standardization2) Enhancement of research using biospecimens stored in biobank3) Transcriptional regulation of hematopoiesis in cis and trans4) Biology of hematopoietic stem cells and hematopoietic cell differentiation5) Regulation of Erythropoietin production

[Biographical Sketch]Education:Tohoku University School of Medicine (MD in May 1982) Tohoku University Graduated School of Medicine (Ph.D. in March 1989)

Professional Experience: 1989 Research Fellow, Department of Pediatric Heamtology Oncology, Institute of Development, Aging

and Cancer)1995 Assistant professor, Department of Biochemistry, Tohoku University. School of Medicine1997 Lecturer, Institute of Basic Medical Science, University of Tsukuba2001 Associate Professor, Institute of Basic Medical Science, University of Tsukuba2004 Associate Professor, Tohoku University Biomedical Engineering Research Organization2008 Professor, Sendai University2010 Professor, Miyagi University2012- Professor, Tohoku University, Tohoku Medical Megabank Organization


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PS-3

Strategy of genome-omics analyses in Tohoku Medical Megabank Project

Kengo Kinoshita1, the Tohoku Medical Megabank Project Study Group1,2

1Tohoku Medical Megabank Organization, Tohoku University2Iwate Tohoku Medical Megabank Organization, Iwate Medical University

The Tohoku Medical Megabank (TMM) Project has been collecting specimens and their health-related data from nearly 150,000 individuals in Miyagi and Iwate prefectures; those areas were heavily damaged by the great eastern Japan Earthquakes and Tsunami on Mar 11, 2011. As a part of this large project, we are performing systematic genome and omics analyses to construct the basis of personalized healthcare for the next generations in this area to realize constructive regeneration from the disaster.

For the purpose, missing heritability is one of the most important issues to be solved. To overcome this problem, we first designed two types of genome cohort studies; the TMM Community-Based Cohort Study with 80k individuals and the TMM Birth and Three-Generation Cohort Study with 70k individuals. The former cohort will be strong to design case control studies and suitable for genome environment interaction analyses, while the latter will be useful for the improvement of genotype imputations by family-based precise phasing.

As results, we have completed 2,049 whole-genome sequencing with high coverage and identified more than 28 million SNPs for the participants in these cohorts. Based on the SNPs data, we designed a SNP array that is most suitable for Japanese population, called Japonica array, to reduce the cost of genome analyses and to determine the genotypes of all participants in our two types of cohort studies. In addition, we performed metabolome analyses of more than 1000 participants, and whole genome bisulfite sequence analyses of about 100 participants to establish the precise reference state of healthy volunteers by using omics data.

In this presentation, we will introduce our strategy of genome-omics analyses in TMM, the current status of our progress, and discuss the future perspectives.


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Kengo Kinoshita

Position and Affiliation:Professor, Graduate School of Information Sciences, Tohoku University

[Research Interest]The general area of my research concerns understanding biological roles of proteins by computational analyses of large-scale data. In particular, I’m interested in the identification of function of proteins. The term “function of proteins” may need some explanations as it refers to two things: one is the biochemical function, which is the function of individual proteins by itself and it will be tightly coupled with the three-dimensional structure of proteins, while the other is the biological function, which is a global process in which each protein participates, and an interaction network of proteins will be the key to elucidate the function. I have been studying both aspects of protein functions until now.

[Biographical Sketch]1999 -2000: JST Research Fellow, Osaka University2000 -2001: Research associate, RIKEN2001 -2004: Assistant Professor, Yokohama City University2004-2009: Associate Professor, Tokyo University2009-present: Professor, Tohoku University2012-present: Professor, Tohoku Medical Megabank Organization2015-present: Deputy Executive Director, Tohoku Medical Megabank Organization2012: Awarded 8th JSPS Prize for “Prediction of Functions for the Genes with Unknown Functions

Through Bioinformatics”


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PS-4

Genetic susceptibility to acute lung injury: interaction between nuclear and mitochondrial genomes

Steven R. Kleeberger, PhDImmunity, Inflammation & Disease Laboratory National Institute of Environmental Health Sciences, NIH, Research Triangle Park, North Carolina, USA

Reactive oxygen species contribute to the pathogenesis of many acute and chronic pulmonary disorders, including bronchopulmonary dysplasia (BPD), a respiratory condition affecting preterm infants. BPD treatment often involves respiratory support with high O2, and oxidative stress is an adverse effect associated with vascular damage and impaired lung development and function in a subset of infants. Genetic polymorphisms in a few candidate nuclear genes have been associated with BPD susceptibility, however the genetic basis of differential susceptibility remains poorly understood, and the role of the mitochondrial genome has not been investigated. Understanding the role of genetic background in disease susceptibility is critical to improving treatment strategies and reducing oxidant injury in developing lungs. We established a genetic neonatal model of hyperoxic ALI in 32 inbred strains of mice. ALI mimics features of BPD and we used the injury phenotypes for genome-wide association (GWA) mapping to identify QTLs and candidate susceptibility genes that associate with neonatal hyperoxic ALI. Our GWA mapping of ALI phenotypes identified QTLs on chromosomes 1, 2, 4, 6, and 7. We next used comparative mapping of the chromosome 6 QTL for PMNs and identified Chrm2 (cholinergic receptor, muscarinic 2, cardiac) as a candidate susceptibility gene. We found that mouse strains with a nonsynonymous coding SNP in Chrm2 that causes an amino acid substitution (P265L) had significantly reduced hyperoxia-induced inflammation compared to strains without the SNP. Further, hyperoxia-induced ALI was significantly reduced in neonatal mice with targeted deletion of Chrm2, relative to wild-type controls. We then isolated lung DNA from mice exposed to normoxia or hyperoxia, amplified the mitochondrial genome with long range PCR, and used ultra-deep sequencing to identify variants in the mitochondrial genome. A total of 438 bona fide SNPs (~1/37 bases) were identified in 32 inbred strains. Variants were found in the D-loop region with even higher frequency (~1/28 bases). We also identified a total of 398 heteroplasmies and 30 indels. Hyperoxia caused 14 additional SNPs in coding and tRNA genes and had strain-specific effects on the heteroplasmies. Significant interaction between sequence variants in the mitochondrial and nuclear genomes also contributed to differential susceptibility to ALI. Finally, we have also found significant association of mitochondrial genome sequence variants with severe BPD in a population of very low birthweight infants and their parents (case-parent triads). In conclusion, we have identified novel candidate nuclear and mitochondrial susceptibility genes that improve our understanding of neonatal lung injury and development. Future investigations into interactions between mitochondrial and nuclear genomes should provide important insight to pathogenesis of complex diseases.

Supported by the NIEHS intramural research program.


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Steven R. Kleeberger, PhD

Position and Affiliation:Senior InvestigatorImmunity, Inflammation & Disease Laboratory National Institute of Environmental Health SciencesNational Institutes of HealthResearch Triangle Park, North Carolina, USA

Steven Kleeberger received his A.B. degree in zoology from Miami University and a Ph.D. in ecology from Kent State University in 1982. He did his postdoctoral research at Johns Hopkins University and became a full Professor at Hopkins in 2000. He was recruited to the National Institute of Environmental Health Sciences (NIEHS) as Chief of the Laboratory of Respiratory Biology in 2001. Currently, he holds several Adjunct Professorships including Duke University School of Medicine and the University of North Carolina at Chapel Hill School of Medicine. He also directs the Environmental Genetics research group and the Director’s Challenge program in Mechanisms of Susceptibility to Oxidant-stress Induced Disease at NIEHS. He was the Deputy Director of NIEHS from 2009-2011.

The overall goal of his research has been to utilize positional cloning approaches in inbred mice to identify candidate genes that determine susceptibility to environmental lung disease. His lab has developed a number of models of genetic predisposition to inhaled agents including acid-coated particles nitrogen dioxide, ozone, and hyperoxia. The work has led to the identification of significant susceptibility quantitative trait loci (QTLs), and functional characterization of candidate genes for susceptibility to lung injury induced by environmental pollutants and oxidants, including NRF2. His laboratory is also focused on gene-environment interaction and the pathogenesis of disease in human populations. His lab is participating in genetic analysis of acute respiratory distress syndrome (ARDS), bronchopulmonary dysplasia, and susceptibility to respiratory syncytial virus (RSV). His lab is also directing investigation of the role of innate immunity and antioxidant genes in determination of susceptibility to RSV infection and chronic lung disease in infants. Dr. Kleeberger has served on multiple study sections at the National Institutes of Health, international advisory committees on genetic susceptibility for the World Health Organization (WHO) and US Environmental Protection Agency (US EPA), and Clean Air Scientific Advisory Committee (CASAC) Review Panels. He has authored over 170 peer-reviewed manuscripts and two dozen book chapters. He is a reviewer for over 20 journals, and he has held a number of editorial positions. He has given over 150 lectures nationally and internationally.


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------------------ Memo ------------------

Scientific Sessions:

SS-1 : Session 1- Systems Biology of Immune ResponsesSS-2 : Session 2- Cross-talk between Acquired and Innate Immune SystemsSS-3 : Session 3- NeuroscienceSS-4 : Session 4- Developmental Biology and Regenerative MedicineSS-5 : Session 5- Cancer Science


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SS1-1

γc Family Cytokines and the Fine-tuning of Cytokine Signaling

Warren J. Leonard, Peng Li, Suman Mitra, Edwin Wan, Rosanne Spolski, and Jian-Xin LinLaboratory of Molecular Immunology and the Immunology Center, National Heart, Lung, and Blood Institute, NIH, Bethesda, MD 20892-1674

The γc family of cytokines (IL-2, IL-4, IL-7, IL-9 IL-15, and IL-21) together regulate normal development and function of lymphocytes, with dys-regulated signaling by these cytokines resulting in pathologic states including immunodeficiency and autoimmunity. These cytokines substantially signal via STAT proteins and can, for example, in the case of IL-2 and IL-21 have opposing actions as a means of fine tuning biological actions. Moreover, differential utilization of STAT1 versus STAT3 in the case of IL-21 or of STAT5 dimerization versus tetramerization in the case of IL-2 are additional physiological mechanisms by which signaling can be fine-tuned. STAT5 tetramerization is critical for normal proliferation of T cells and maturation and survival of NK cells, with critical regulation of genes involved in cell cycle progression and survival, with, for example, binding of STAT5 tetramers to a superenhancer region in the Il2ra gene as well as to an intronic element in the Bcl2 gene. Additionally, with Chris Garcia’s lab at Stanford, we have created and studied novel IL-2 partial agonists that attenuate receptor heterodimerization thereby acting as receptor signaling clamps, with inhibition of STAT5 activation and global gene expression, correlating with the ability to prolong survival in a model of graft versus host disease as well as blocking proliferation of IL-2-dependent adult T cell leukemia cells. Thus, physiological and pharmacological modes of fine-tuning of γc family cytokines allow STAT protein-based manipulation of the immune system.


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Warren J. Leonard, M.D.

Position and Affiliation:NIH Distinguished Investigator,Chief, Laboratory of Molecular Immunology, andDirector, Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health

[Research Interest]　Dr. Leonard’s group focuses on the biology, signaling, and gene regulation of cytokines of the immune system and their receptors, with studies ranging from normal physiological mechanisms to human disease, also using in vivo animal models as well as basic biochemical and molecular mechanisms of signaling and epigenetic regulation. Dr. Leonard has focused on the IL-2 or common γ chain family of cytokines. He cloned and characterized the IL-2 receptor γ chain, the first receptor component cloned for a type 1 cytokine. He then co-discovered the IL-2 receptorβ chain and in a major breakthrough discovered that mutations in the gene encoding human IL-2Rγ result in X-linked severe combined immunodeficiency (XSCID, also known as the “Bubble Boy Disease”). This led to his predicting and demonstrating that IL-2Rγ was a common γ chain, γc, now known to be shared by the receptors for IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. Leonard’s group also discovered human JAK3-deficient SCID and IL7R-deficient SCID, and he predicted that inhibitors of JAK3 would be immunosuppressive, with such agents now FDA-approved. His group also cloned the receptor for IL-21, elucidating its roles as an anti-cancer agent, in autoimmune disease, and viral infection. He also assisted Harvey Lodish in the cloning of the TSLP receptor and then demonstrated that TSLP is vital to the development of allergic lung inflammation.　Dr. Leonard currently engages in a range of studies of γc family cytokines, STAT proteins, and regulatory processes, combining state-of-the-art methodologies such as ChIP-Seq, RNA-Seq, ATAC-Seq, ChIA-PET, and other molecular techniques with the analysis of human cells as well as transgenic, knock-in, and knockout mouse models to elucidate the biology and mechanisms involved in important in vivo processes. Moreover, his lab also uses next generation sequencing approaches related to the study of select types of immune-related diseases.

[Biographical Sketch]　Dr. Leonard received his A.B. in mathematics, magna cum laude and Phi Beta Kappa, from Princeton University and his M.D. from Stanford University. After completing residency training in medicine at Barnes Hospital and a year of research in biochemistry at Washington University in St. Louis, Dr. Leonard came to the NIH as a postdoctoral fellow in the National Cancer Institute. He began his own laboratory in the National Institute of Child Health and Human Development and then joined the National Heart, Lung, and Blood Institute. Dr. Leonard has authored or co-authored more than 350 articles and book chapters and holds 20 patents. He is an Associate Editor and former Co-Editor of Immunity, on the editorial board of Cytokine, and a contributing member of the Faculty of 1000. He is past-President of the International Cytokine Society, a member of the Board and former Vice President of the Foundation for Advanced Education in the Sciences (FAES), and serves on the Council of the Association of American Physicians. Dr. Leonard is the recipient of


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many honors and awards, including the American Federation for Clinical Research Foundation Outstanding Investigator Award, the Food and Drug Administration Center for Biologics Evaluation and Research Outstanding Service Award, the American Association of Immunologists (AAI)-Huang Foundation Meritorious Career Award, and the Honorary Lifetime Membership Award of the International Cytokine and Interferon Society. He is an elected member of the American Society for Clinical Investigation, the Association of American Physicians, a Fellow of the American Association for the Advancement of Science, and a member of the National Academy of Medicine (formerly the Institute of Medicine), the National Academy of Sciences, and the American Academy of Arts and Sciences.


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SS1-2

Gene regulatory networks composed by transcription factors orchestrate plasma cell differentiation

Kyoko Ochiai, Toru Tamahara, Kazuhiko IgarashiDepartment of Biochemistry, Tohoku University Graduate School of Medicine

The nature of cell differentiation lies on the organization of gene expression in proper manner. During B-to-plasma cell differentiation, cells undergo class switch recombination (CSR) for the affinity maturation of immunoglobulin gene prior to differentiation. However, little is known about how cell transits to differentiation state after occurring CSR. Both CSR and plasma cell (PC) differentiation are ingeniously controlled by transcription factors (TFs). We attempted to reveal the question by focusing on function of two TFs, IRF4 (Interferon regulatory factor-4) and Bach2 (BTB and CNC homologue 2), which commonly regulate the expression of Prdm1, a regulator of PC differentiation. Whereas IRF4 activates Prdm1 expression, Bach2 represses it. Moreover, IRF4 regulates variety of gene sets depending on its protein amount; IRF4lo state promotes CSR, and IRF4hi state induces differentiation respectively. We identified Aicda gene encoding AID, which is an essential enzyme for CSR, as a direct target of IRF4. When AID initiates CSR, cell cycle is arrested at G1 phase for successful immunoglobulin gene rearrangement. Importantly, we found that Bach2 promotes G1 arrest by repressing the expression of Ccnd3 gene encoding G1/S-specific cyclin D3. Furthermore, Bach2 is negatively regulated by mTOR signaling and gradually inactivated upon differentiation stimuli. As a result, Prdm1 expression is de-repressed as well as shifted to activation by IRF4 for promoting terminal differentiation. Thus, we suggest that the functional balance between IRF4 and Bach2 orchestrate PC differentiation accompanied with CSR.


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Kyoko Ochiai

Position and Affiliation:Assistant ProfessorBiochemistry, Tohoku University School of Medicine

[Research Interest]Molecular mechanism of cell differentiationGene regulatory networkRegulation of transcriptional factor under receptor signaling

[Biographical Sketch]Education:March 2002 Hiroshima University, School of Dentistry, D.D.S.January 2007 Hiroshima University Graduate School of Biomedical Sciences, Ph.D. (Medical)Research Career:2007-2011 Post-doctoral fellow, Molecular Genetics and Cell Biology, University of Chicago2011-present Assistant professor, Biochemistry, Tohoku University School of Medicine


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SS1-3

IRF transcription factors in the development and function of mononuclear phagocytes

Tomohiko Tamura Department of Immunology, Yokohama City University Graduate School of Medicine

Differentiation of stem or progenitor cells to mature cells requires appropriate changes in gene expression patterns, i.e., transcriptional control, where transcription factors play essential roles. Mononuclear phagocytes such as monocytes and dendritic cells (DCs) are essential for tissue homeostasis and immunity. These cells develop from hematopoietic stem cells via a common intermediate progenitor population called monocyte−DC progenitors. We have been investigating the mechanism underlying the development of mononuclear phagocytes from a viewpoint of gene expression control by transcription factors. Particularly, interferon regulatory factor-8 (IRF8), the loss of which causes immunodeficiency and chronic myeloid leukemia (CML)-like neutrophilia in mice and humans, promotes the development of monocytes and DCs, while it limits neutrophil differentiation.

Recent studies have pinpointed the stages where IRF8 acts during mononuclear phagocyte differentiation (Kurotaki et al, Nat Commun 2014). Transcription factor networks centered on IRF8 have also been revealed (Kurotaki et al, Blood 2013; Sasaki et al, Blood 2015). More recently, we have analyzed enhancer landscape dynamics during the development of mononuclear phagocytes (Kurotaki et al, submitted). Our data indicate that enhancers specific for monocytes and/or DCs are gradually established at their progenitor stages prior to gene expression. Furthermore, IRF8 was found to be vital for the priming and activation of enhancers in mononuclear phagocyte progenitors, particularly those common to both monocyte and DC lineages. These data illustrate the molecular basis of how the two related but distinct cell lineages are generated from a common progenitor population. Moreover, our results on Irf8–/– progenitors indicate that enhancers, rather than global gene expression patterns, are more representative of the future ability of cells to differentiate.

We will also show our data on the role of another IRF family member, IRF5, in the pathogenesis of the autoimmune disease, systemic lupus erythematosus (Ban et al, Immunity 2016).


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Tomohiko Tamura

Position and Affiliation:ProfessorDepartment of ImmunologyYokohama City University Graduate School of Medicine

[Research Interest]Investigating the molecular mechanisms of myeloid cell development and immune responses with an emphasis on the transcriptional and epigenetic control of gene expression by transcription factors, such as Interferon Regulatory Factors (IRFs). Also developing new therapies for autoimmune diseases and leukemias.

[Biographical Sketch]Professional Experience2009- Professor, Department of Immunology, Yokohama City University Graduate School of

Medicine2007-2009 Associate Professor, Department of Immunology, Graduate School of Medicine, The

University of Tokyo2006-2007 Associate Professor, Department of Physiology, Osaka City University Graduate School of

Medicine1998-2006 Postdoctoral fellow (1998-2001), Staff Scientist (2001-2006), National Institute of Child

Health and Human Development, National Institutes of Health, USA1995-1998 Staff Physician (1995), Assistant Professor (1996), The First Department of Internal Medicine,

Yokohama City University Hospital[Education] 1995 Ph.D., Yokohama City University Graduate School of Medicine,1990 M.D., Yokohama City University School of Medicine


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SS1-4

Chromatin regulation of innate immunity:BRD4 is required for hematopoietic stem cell development andregulates pro and anti-inflammatory responses through super-enhancers

Anup Dey, Wenjing Yang, Ryoji Yagi, Anne Gegonne, Akira Nishiyama, Alex Grinberg, Karl Pfeiffer, Jingfang eff Zhu, William Paul, Dinah Singer, Jun Zhu, Keiko OzatoSection on Molecular Genetics of Immunity, National Institute of Child Health and Human Development, NIH

Ozato laboratory is interested in chromatin and transcriptional regulation of innate immunity. We work on the DNA binding transcriptional factor, IRF8 and bromodomain protein BRD4. IRF8 binds to the promoters and enhancers of genes involved in cytokine signaling. It plays a critical role in the protection against various pathogens. BRD4 binds to acetylated histones and activates transcriptional elongation of many cellular and viral genes. BRD4 occupies the TSS and gene body of most of not all expressed genes. It also binds to numerous enhancers, including super-enhancers. In many cases, cytokine induced transcription is dependent on IRF8 and BRD4, which triggers chromatin exchange in target genes. Our recent data from cytokine-stimulated macrophages show that IRF8 and BRD4 contribute to transcription-coupled chromatin exchange, resulting in histone H3.3 deposition. The newly deposited H3.3 serves as a lasting epigenetic mark, likely influencing global transcription programs in macrophages.

Here we asked whether BRD4 regulates the development and activity of innate immunity by testing conditional deletion of Brd4 in the mouse. This work was promoted by a number of recent studies showing that BRD4 small molecule inhibitors suppress the growth of many blood cancers, and reduce inflammation. These inhibitors block binding of acetyl histones to the bromodomain, for which BRD4 is a primary target. Because of the anti-cancer and anti-inflammation, these inhibitors offer a new therapeutic promise. For effective use of the inhibitors in therapy, however, it is important to have full understanding of the role of BRD4 in normal hematopoietic/immune cells. We show that Brd4 deletion in early hematopoiesis blocks generation and differentiation of hematopoietic stem cells (HSCs). As a result, all immune cells, lymphocytes and myeloid cells and red blood cells were markedly reduced in Brd4 KO embryos leading to death in utero. This and additional data with later Brd4 deletion indicated that BRD4 is critically required for promoting proliferation of normal cells.

On the other hand, conditional Brd4 deletion in macrophages had a less dramatic effect both in vivo and in vitro. In particular, induction of inflammatory cytokines and chemokines by LPS was only partially affected by Brd4 deletion. Interestingly, many genes activated by NFkB were normally expressed in Brd4 KO macrophages, indicating that NFkB bypasses the requirement of BRD4 for transcription. Nevertheless, ChIP-Seq analyses showed that BRD4 clusters on lengthy regulatory DNAs, coinciding with RNA polymerase II binding and H3K27ac histone marks, meeting the definition of super-enhancers. BRD4 super-enhancers were located near the genes controlling macrophage lineage and innate immune responses. Together, BRD4 directs every step of immune cell development and exerts complex regulatory influence on inflammation.


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Keiko Ozato, Ph.D.

Position and Affiliation:Chief, Section on Molecular Genetics of Immunity, Division of Developmental Biology,National Institute of Child Health and Human Development,National Institutes of Health, Building 6, Room 2A01, 6 Center DriveBethesda, MD 20892-2753

Keiko Ozato received Ph.D in Developmental Biology from Kyoto University, Kyoto, Japan in 1973 (Thesis adviser, Prof. T.S Okada). She then moved to the USA and obtained her postdoctoral training in Carnegie Institution of Washington and Johns Hopkins University, Baltimore (Adviser, Prof. J.D. Evert) between 1973 and 1978, and then in National Cancer Institution, National Institutes of Health (NIH, Adviser, Dr. D.H. Sachs). In 1981, Ozato was appointed as a tenure-track investigator in National Institute of Child Health and Human Development (NICHD) and received tenure in 1987. Since then Ozato has worked on gene regulation in innate immunity and directed a laboratory of 6-12 post and pre-doctoral workers. With the publication of more than 370 scientific papers, Ozato is an established investigator with a broad recognition in the fields. She has been invited to speak in various meetings and symposia. For example, in 2016, she was a plenary speaker for the NIH Research Festival on Super Enhancers, Keystone Symposium on Chromatin/Transcription and New York Academy of Science Symposium on Bromodomain proteins among others. In the same year Ozato served as an Invited Editor for the JICR Special Edition on “IFN Regulatory Factors in Innate Immune Responses: The Role in Epigenetic Regulation”.

Recognizing the importance of nurturing scientists of the next generation, Ozato makes concerted efforts in mentoring, encouraging independent thinking, initiative taking, and cooperation. Finally, as an Asian female scientist, Ozato is sensitive to issues they face in a professional setting in the USA and Japan. Thus, she has been active in promoting Japanese scientists in the NIH and elsewhere in the USA. For these efforts and her contribution to research, Ozato received the Order of Sacred Treasure, a honorary medal from Japanese Emperor for my long standing contribution to research and efforts to promote Japanese scientists in NIH.


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SS2-1

Dectin-Stimulated Dendritic Cells Induce Unique IL-10-Producing T Cells with Regulatory Properties

Warren Strober, Atsushi Kitani, Ivan Fuss and Masaki TajimaMucosal Immunity Section, LHD, NIAID, NIH

Stimulation of dendritic cells via the C-type lectin Dectin-1 is often thought to occur mainly via stimulation of cells by fungal organisms but in reality the stimulating ligand of this receptor, β-glucan, is a polysaccharide distributed in both plants and a wide variety of microbes. On this basis, induction of various effector and regulatory T cells following stimulation with Dectin-stimulated dendritic cells is potentially involved in the development of a variety of diseases having nothing to do with fungal infection. In the present study we report that Dectin-1 (or Dectin-2)-stimulated dendritic cells can induce TCR-activated T cells to become a new class of IL-10-producing regulatory T cell, termed Tr2 cells. These cells are distinguishable from previously identified IL-10-producing regulatory cells such as Tr1 cells or from IL-10-producing Th2 cells by global gene expression analysis and other criteria. IL-10 gene transcription is induced in these cells by two complementary mechanisms. The first involves IL-4 production by the T cell and induction of GATA3, a factor that exerts both canonical and epigenetic function at separate IL-10 transcriptional sites. The second involves mTOR (TORC1) signaling and rapamycin-sensitive translation of the LIP isoform of C/EBPβ. The LIP generated in this manner forms a complex with CREB1 and thereby facilitates binding of a transcriptional CREB1-LIP complex to adjacent sites on the IL-10 promoter. Of interest, concomitant stimulation of dendritic cells by TLR ligand inhibits Tr2 cell induction, most likely by preventing T cell IL-4/GATA3 production. The regulatory role of Tr2 cells is readily manifest during C. albicans infection wherein induction of these cells in renal tissue by Candida hyphae leads to IL-10-mediated inhibition of effector T cell responses in the kidney. In view of recent studies showing that in vivo Dectin stimulation can attenuate experimental type I diabetes or gut inflammation, it is reasonable to assume that Dectin-induced Tr2 regulatory cells also regulate effector T cell responses causing various autoimmune diseases


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Warren Strober, M.D.

Position and Affiliation:Senior Investigator, Mucosal Immunity Section,NIAID/DIR, NIH

[Research Interest]Pathogenesis of Inflammatory Bowel Diseases; Immunologic Regulation of Mucosal Homeostasis; Immunologic and Clinical Abnormalities in Immunodeficiency Diseases.

[Biographical Sketch]　Dr. Strober is Senior Investigator in the Laboratory of Host Defenses of the National Institutes of Allergy and Infectious Diseases. During his tenure at NIH he has held several research and administrative positions including that of Deputy Director of NIAID Intramural Research Program and Interim Director of the NIAMS Intromural Research Program. His research has been recognized by many awards including: PHS Distinguished Service Medal, 1997; Nelson Prize, University of California at Davis, 2000; Doctor of Medicine, Honoris Causa, Charite Hospital – Humboldt University, Berlin, Germany, 2007; Outstanding Mentor Award, 2007; NIH Merit Award (Laboratory Group Award), 2007; Ismar Boas Medal, German Society of Digestive Diseases and Metabolic Diseases, 2008; Scientific Achievement Award for Basic Science, Crohn’s and Colitis Foundation, 2008; William Beaumont Award, American Gastroenterological Association, 2009; Lifetime Achievement Award, Society of Mucosal Immunology, 2009.

　His research group has produced a number of important achievements including fundamental discoveries relating to the cytokine abnormalities in inflammatory bowel disease and the influence of genetic abnormalities in these diseases. In addition, he has made key discoveries into the immunologic basis of mucosal homeostasis.


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SS2-2

CD11b-CD103- dermal dendritic cells express RALDH1 and regulate skin fibrosis via retinoic acid-dependent development of induced regulatory T cells

Shunsuke Miura1, Yoshihide Asano1, Ryosuke Saigusa1, Takashi Yamashita1, Takashi Taniguchi1, Takehiro Takahashi1, Yohei Ichimura1, Tetsuo Toyama1, Ayumi Yoshizaki1, Shinichi Sato1, Takafumi Kadono1,2.1Department of Dermatology, University of Tokyo Graduate School of Medicine, Tokyo, Japan.2Department of Dermatology, St Marianna University School of Medicine, Kawasaki, Japan.

Skin fibrosis is a common pathological skin condition among various skin-restricted and systemic diseases. Corticosteroids and/or immunosuppressants are mostly effective for this clinical entity, but the underlying immune response still remains enigmatic. In particular, the role of dermal dendritic cells (DCs) is totally unknown. Therefore, we investigated the role of dermal DCs in bleomycin (BLM)-induced skin fibrosis, especially focusing on the role of CD103, a critical molecule associated with the phenotype of those cells. Dermal thickness and collage contents were decreased in BLM-treated Cd103-/- mice compared with BLM-treated wild-type mice, along with the decreased expression of TGF-b1 and CTGF. The proportion of regulatory T cells (Tregs) was significantly increased, while the proportions of Th1, Th2, and Th17 cells were significantly decreased in the skin of BLM-treated Cd103-/- mice. With respect to dermal DC subsets in the lesional skin, BLM injection enhanced the proportion of CD11b-CD103- DCs in wild-type mice, which was further augmented in Cd103-/- mice. Importantly, RALDH1/ALDH1A1, a cytosolic enzyme oxidizing retinaldehyde to retinoic acid, was preferentially expressed by CD11b-CD103- DCs and its expression levels were remarkably elevated in BLM-injected skin lesions, to a greater extent in Cd103-/- mice than in wild-type mice. In humans, RALDH1-positive DCs were decreased in the lesional skin of patients with systemic sclerosis, morphea, chronic graft-versus-host disease, and dermatosclerosis associated with venous ulcers. This study shed new light on RALDH1-producing dermal DCs as a regulator of inducible Tregs in skin fibrotic disorders.


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Yoshihide Asano

Position and Affiliation: Associate Professor, Department of Dermatology, Graduate School of Medicine, The University of Tokyo.

[Research Interest]Systemic sclerosis, Autoimmunity, Vasculopathy, fibrosis

[Biographical Sketch]Education1998 M.D. Faculty of Medicine, The University of Tokyo, Tokyo, Japan2004 Ph.D. Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

Professional Experience1998-2000 Resident, Department of Dermatology, The Tokyo University Hospital, Tokyo, Japan2004-2005 Dermatologist, Kanto Medical Center, NTT EC, Tokyo, Japan2005-2006 Assistant Professor, Department of Dermatology, Graduate School of Medicine, The

University of Tokyo, Tokyo, Japan2006-2008 Postdoctoral fellow, Division of Rheumatology and Immunology, Medical University of South

Carolina, Charleston, SC, USA2009- Assistant Professor, Department of Dermatology, Graduate School of Medicine, The

University of Tokyo, Tokyo, Japan2015- Associate Professor, Department of Dermatology, Graduate School of Medicine, The

University of Tokyo, Tokyo, Japan


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SS2-3

Neural control of gut homeostasis in Drosophila immunity

Shoichiro KurataDepartment of Molecular Genetics, Graduate School of Pharmaceutical Sciences, Tohoku University

The role of the nervous system in innate immunity has remained unexplored since Metalnikov’s initial report in 1924 (1), in which he demonstrated that Galleria mellonella larvae lost their resistance against a Vibrio cholera challenge after cauterization of the third thoracic ganglion. Shiraishi and Natori also reported that the induction of Sarcophaga lectin in response to body injury in ligation experiments is mediated by tissues, such as the brain, located in the anterior part of Sarcophaga peregrina larvae (2).

We screened for GAL4 enhancer-trap Drosophila strains and labeled specific neuronal subsets. To inhibit neuronal activity, we induced overexpression of Kir2.1, a mammalian inwardly rectifying K+ channel. We identified an NP3253 line that is susceptible to oral infection by Gram-negative bacteria. The neuronal subset driven by the NP3253 line includes some of the enteric neurons innervating the anterior midgut, and these flies have a disorganized proventricular structure with high permeability of the peritrophic matrix and epithelial barrier. The findings revealed that neural control is crucial for maintaining the barrier function of the gut, and provide a route for genetic dissection of the complex brain-gut axis in the model organism Drosophila adults (3).

References1. Metalnikov, S. (1924) Phagocytose et réactions des cellules dans l’immunité. Ann. Inst. Pasteur 38, 787-

826.2. Shiraishi, A. and Natori, S. (1988) Humoral mediator-dependent activation of the Sarcophaga lectin

gene. FEBS Letters 232, 163-166.3. Kenmoku, H. et al. (2016) A subset of neurons controls the permeability of the peritrophic matrix and

midgut structure in Drosophila adults. J. Exp. Biol. 219, 2331-2339, 2016.


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Shoichiro Kurata

Position and Affiliation:Professor, Graduate School of Pharmaceutical Sciences, Tohoku University

[Research Interest]Insect immunityDetermination of organ identity

[Biographical Sketch]Education:March 1990 Faculty of Pharmaceutical Sciences, University of Tokyo, JAPAN, Ph.D.

Research Career:1990-1991 Postdoctoral research fellow, Faculty of Pharmaceutical Sciences,University of Tokyo, JAPAN

(Prof. Shunji Natori)1991-1995 Assistant Professor, Faculty of Pharmaceutical Sciences, University of Tokyo, JAPAN1995-1998 Postdoctoral research fellow, Biozentrum, University of Basel. SWITZERLAND (Prof. Walter

Gehring)1998-2007 Associate Professor, Graduate School of Pharmaceutical Sciences, Tohoku University, JAPAN2007-present Professor, Graduate School of Pharmaceutical Sciences, Tohoku University, JAPAN


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SS3-1

A Bright Future for People with Communication Disorders

James F. Battey, Jr National Institute on Deafness and Other Communication Disorders, NIH

Human communication capabilities are a defining property that separates us from all other inhabitants of the earth. In this presentation, I will explore the challenges confronted by individuals with human communication disorders. Advances in biomedical research are providing ways to overcome these challenges. Given these advances, there is a bright future for people with communication disorders.


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James F. Battey, Jr., MD, PhD

Position and Affiliation: Director, National Institute on Deafness and Other Communication Disorders, NIH

[Research Interest] Research on Human Communication Disorders[Biographical Sketch]Dr. James F. Battey, Jr., received his undergraduate education at the California Institute of Technology, where he earned his B.S. with honors in physics. He earned his M.D. and Ph.D. (biophysics) degrees from Stanford University, where he also received residency training in pediatrics. His postdoctoral fellowship at Harvard Medical School was under the direction of the eminent scientist Dr. Philip Leder. While working with Dr. Leder, Dr. Battey was part of a team that cloned the genes encoding the IgE immunoglobulin constant region domains. In addition, he isolated and characterized the human c-myc gene, a key growth regulatory nuclear proto-oncogene that contributes to cancer formation when inappropriately expressed.Dr. Battey is widely recognized for his work on G-protein coupled receptors (GPCRs), a large family of proteins important in cell-to-cell communication, and integral to an array of physiological processes, including taste and smell, vision, immune response, and the transmission of messages between nerve cells. Much of his research has focused on mammalian bombesin receptors－GPCRs that mediate such processes as hormone release, smooth muscle contraction, and cell division－and he has collaborated on a large-scale project to identify molecules that are important for taste.Dr. Battey began his tenure with NIH in 1983, first on the staff of the National Cancer Institute (NCI), where he rose from senior staff fellow to senior investigator. In his work at the NCI-Navy Medical Oncology Branch, he collaborated in the isolation and characterization of human N-myc and L-myc, two additional members of the human myc gene family, important in human neoplasms. He became interested in neuropeptides and their receptors at this time because of their dual function as growth factors and regulatory peptides. His group isolated cDNA and genomic clones for mammalian bombesin-like peptides, key regulators of secretion, growth, and neuronal firing.In 1988, he moved to the National Institute of Neurological Disorders and Stroke as chief of the molecular neuroscience section in the Laboratory of Neurochemistry. In 1992, he returned to the NCI to head the molecular structure section of the Laboratory of Biological Chemistry, where his laboratory cloned and characterized the genes for 3 three subtypes of mammalian receptors for bombesin-like peptides. His team at NCI's Laboratory of Biological Chemistry was among the first to clone the gene encoding cdk5, a member of the cyclin-dependent kinase family, where important proteins are involved in cell cycle control.The U.S. Public Health Service has honored Dr. Battey with its PHS Commendation Medal in 1990 and the Outstanding Service Medal in 1994. He is author or co-author of more than 130 research articles and is co-author of the popular laboratory manual titled Basic Methods in Molecular Biology.Dr. Battey was appointed director of the Intramural Research Program for NIDCD in 1995. He has served as the director of NIDCD since 1998.Dr. Battey also is a co-chair of the Trans-NIH Mouse Initiative.


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SS3-2

Rhythms of Motor Activity and Related Homeostatic Systems and Bipolar Disorder: Opportunities for Cross-Species Research

Kathleen Ries Merikangas1, Ian B. Hickie2, Lihong Cui1, Haochang Shou3, Nora D. Volkow4, Vadim Zipunnikov5

1Intramural Research Program, National Institute of Mental Health, Bethesda, MD, USA2Brain & Mind Centre, University of Sydney, Sydney, Australia 3Department of Biostatistics, University of Pennsylvania, Philadelphia, PA, USA4National Institute of Drug Abuse, Bethesda, MD, USA5Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA

There has been growing recognition of the role of physical activity in human health. Decreased physical activity is associated with several chronic conditions and disorders including obesity, diabetes, and cardiovascular. There is now emerging evidence that motor activation is a core feature of Bipolar Disorder (BPD), with numerous studies showing that people with BPD exhibit greater variability and less daytime motor activity than controls. The manifestations of activity patterns outside of acute episodes add to the accumulating evidence that dysregulation of patterns of activity may constitute a potential biomarker for BPD. The goals of this presentation are: (1) to examine objective patterns of motor activity in a community based family study of BPD; (2) to quantify the inter-relationships of motor activity with other homeostatic regulatory domains including energy, mood, and sleep using ambulatory monitoring; and (3) to evaluate potential reverse translational studies by comparing patterns of motor activity in human and monkey samples. Greater variability and a circadian shift of activity in Bipolar disorder indicate that instability of homeostatic regulation of activity and related processes may underlie this disorder. The subset with bipolar I disorder exhibited dysregulation of both motor activity and energy, and significantly greater non-specific cross-domain reactivity, that may comprise a biomarker for bipolar disorder. In vivo multi-system tracking and similarity in patterns of activity between monkeys and humans suggest that actigraphy provides new opportunities for translational mechanistic cross-species studies that may inform biologic processes underlying human function and diseases.


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Kathleen Ries Merikangas, Ph.D.

Position and Affiliation: Senior Investigator and Chief, Genetic Epidemiology Research Branch, Intramural Research Program, National Institute of Mental Health, NIH

[Research Interest]:Her current research program at the NIMH Intramural Research Program focuses on: (1) population based studies of mental and physical disorders in adults and youth; (2) multigenerational family studies designed to identify the core features and biomarkers of genetic and environmental factors underlying the familial transmission of mood disorders and comorbid conditions including sleep patterns and disorders, migraine, and cardiovascular disorders; and (3) the application of mobile technologies to examine patterns of motor activity, sleep, and emotions a in mood disorders, sleep disorders and migraine. The branch is currently collaborating on a large population- based cohort study of physical mental comorbidity in Lausanne, Switzerland, and coordinating a collaborative network examining motor activity and health, with a particular focus on mood disorders, the mobile Motor Activity Research Consortium on Health (mMARCH).

[Biographical Sketch]:Dr. Merikangas has been a Senior Investigator at the National Institute of Mental Health since 2002. She received a bachelor’s degree summa cum laude in experimental psychology and music from the University of Notre Dame, a master’s degree in clinical psychology, a Ph.D. in chronic disease epidemiology from the University of Pittsburgh School of Public Health, and postdoctoral training in population genetics/genetic epidemiology at the Yale University School of Medicine. She subsequently joined the faculty and became a Professor of Epidemiology and Public Health, Psychiatry and Psychology and the Director of the Genetic Epidemiology Research Unit in the Department of Epidemiology and Public Health. Dr. Merikangas has authored more than 300 scientific publications and has presented lectures throughout the U.S. and in more than 20 countries.


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SS3-3

Endophenotype in the brain: A key concept for understanding the relationships between genes and behavior

Tsuyoshi MiyakawaDivision of Systems Medical Science, Fujita Health University, Japan

Genetic studies have revealed millions of polymorphisms in human genome, and theoretically, these polymorphisms can have infinite possible combinations. However, it is well-accepted that the human personality can be represented by a small number of traits and that extreme forms of personalities can be categorized into a limited number of psychiatric disorders. An interesting question is: how, despite such huge genomic variability, are there distinct categories of individuals showing similar behavioral patterns?

We have been investigating the relationships between genes and behaviors by using a comprehensive behavioral test battery in genetically engineered mice. This test battery covers a broad range of behavioral domains, such as sensorimotor functions, emotionality, and cognition. So far, we have subjected more than 170 different strains of mutant mice to this test battery. Among them, α calcium/calmodulin-dependent protein kinase II heterozygous-knockout (α-CaMKII HKO) mice show several strong behavioral phenotypes, such as hyper-locomotion, abnormalities in social behavior, and a working memory deficit. Detailed molecular and electrophysiological analyses revealed that almost all neurons in their dentate gyrus are in a pseudo-immature status; we named this phenotype “immature dentate gyrus (iDG).” Surprisingly, this phenotype is observed in several other strains of mutant mice showing behavioral phenotypes similar to that of α-CaMKII HKO mice as well as in wild-type mice subjected to chronic anti-depressant treatment or having epileptic seizures. Moreover, molecular expression analyses of post-mortem brains suggest that the iDG phenotype exists in certain populations of patients with psychiatric disorders, such as schizophrenia and bipolar disorder.

The iDG phenotype might be an intermediate phenotype or an endophenotype onto which many unique genetic and non-genetic features converge and through which a similar pattern of behavioral traits emerges.

By using iDG as an example, I will discuss the impact of “endophenotype of the brain” concept on understanding the pathways linking genes to behavior and on investigations into the pathogenesis and pathophysiology of neuropsychiatric disorders.


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Tsuyoshi Miyakawa

Position and Affiliation: Professor, Division of Systems Medical Science, Institute for Comprehensive Medical Science, Fujita Health University

[Research Interest]　Dr. Tsuyoshi Miyakawa has been investigating the relationships between genes, brain and behavior by utilizing a “comprehensive behavioral test battery” on genetically engineered mice. With the battery, his team has assessed more than 180 different strains of mutant mice. They are also seeking for what is happening in the brains of the mice that exhibit significant behavioral alterations. In some strains of mutant mice showing behavioral phenotypes related to psychotic disorders, they discovered that almost all the neurons in the dentate gyrus (DG) stay at pseudo-immature status in adulthood; a phenomenon termed “immature DG (iDG).” They also found that, in normal wild type mice, chronic antidepressant (fluoxetine) treatment or epileptic seizure reverses the neuronal maturation resulting in the iDG phenotype. They are trying to understand physiological and behavioral consequences of the maturation failure of the brain cells and its underlying mechanisms.

[Biographical Sketch]　Dr. Miyakawa is a Professor and the director of Division of Systems Medical Science at Fujita Health University. He received his B.A., M.A., and Ph.D. degrees in Psychology, in 1993, 1995 and 1997, respectively, at the University of Tokyo (Advisor: Dr. Hiroaki Niki). After being a Research Scientist at Niki’s lab at Riken Brain Science Institute, he moved to the US in 1998 and received postdoctoral training from Dr. Jacqueline Crawley in Section on Behavioral Neuropharmacology at National Institute of Mental Health. In 1999, he became a Research Assistant Professor of Pharmacology at Vanderbilt University. He then moved to Picower Center for Learning and Memory, directed by Dr. Susumu Tonegawa, at MIT in 2001 and was a Research Scientist and the supervisor of behavior core facility there.　After returning to Japan in 2003, he became an Associate Professor and the Group Leader of Genetic Engineering and Functional Genomics Unit, Kyoto University Graduate School of Medicine (2003-2007). He was appointed to current position in Fujita Health University in 2007. He is also an Adjunctive Professor and the director of Section of Rodent Behavior Analysis at National Institute for Physiological Sciences (2007-).


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SS3-4

Multi-faceted Researches into Mental Health Problems after the Great East Japan Earthquake – Towards Development of Precision Medicine for Affected Communities

Hiroaki Tomita1, 2, 3, 4

1Department of Disaster Psychiatry, International Research Institute of Disaster Science, Tohoku University2Department of Disaster Psychiatry, Graduate School of Medicine, Tohoku University3Group of Mental Health Promotion, Tohoku Medical Megabank Organization, Tohoku University4Tohoku University Hospital

The Great East Japan Earthquake has not only taken away countless precious lives, but has forced many people to experience severe stress from life-threatening situations, loss of loved ones, and drastic changes in living condition. These stresses greatly affect mental health as well as physical condition in the affected communities. International Research Institute of Disaster Science (IRIDeS) and Tohoku Medical Megabank Organization (ToMMo) were established in Tohoku University as academic cores to facilitate rebuild of communities affected by the Great East Japan Earthquake, and to provide better solution for disaster prevention and health care. Dealings with mental health issues are one of the key tasks of the new organizations. Along with various continuous psychosocial approaches to grasp and improve mental health condition of the communities, several studies are in progress to understand biological aspects of disaster stress-related mental health consequences, such as depression and posttraumatic stress reaction. In this session, epidemiological and clinical data from surveys conducted as part of outreach activities in the area devastated by the Great East Japan Earthquake will be overviewed. In addition, perspectives in biological studies to elucidate the basic mechanisms of depression and posttraumatic stress response based on comprehensive molecular and epidemiological profilings of ToMMo cohorts in integration with animal model studies will be discussed.


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Hiroaki Tomita

Position and Affiliation: Professor, Department of Disaster Psychiatry, International Research Institute of Disaster Science, Tohoku UniversityCo-affiliations:・Department of Disaster Psychiatry, Graduate School of Medicine, 　Tohoku University・Group of Mental Health Promotion, Tohoku Medical Megabank Organization, Tohoku University・Tohoku University Hospital

[Research Interest]Our laboratory conducts health surveys and supporting activities of people affected by Great East Japan Earthquake, and investigate impact of the disaster on mental health condition of the affected people, as well as on mental health care systems in the affected communities to extract information useful for supporting recovery of affected people and preparing for future disasters. Our research also focus on the investigation of the pathogeneses of mental disorders, such as mood disorders and post-traumatic stress disorder, which needs more cautions in medical settings in communities affected by disasters, by integrating basic and clinical medical researches to develop useful tools for prevention, assessment, diagnosis and treatment of mental disorders.

[Biographical Sketch]1989-1996 Department of Neuropsychiatry, School of Medicine, Okayama University1996-2000 Department of Human Genetics, School of Medicine, Nagasaki University2000-2001 Department of Physiology and Biophysics, Collage of Medicine, University of California,

Irvine2001-2006 Department of Psychiatry and Human Behavior, Collage of Medicine, University of California,

Irvine2006-2012 Associate Professor, Department of Biological Psychiatry, Graduate School of Medicine,

Tohoku University2012-Current Professor, Department of Disaster Psychiatry, Tohoku University


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SS4-1

Salivary Gland Morphogenesis Guides Gland Regeneration

Matthew P Hoffman BDS PhDMatrix and Morphogenesis Section, National Institute for Dental and Craniofacial Research, National Institutes of Health, DHHS, Bethesda MD, USA

We aim to understand how salivary gland development occurs so that we can design therapies to regenerate or repair the permanent loss of gland function that occurs after removal of salivary tumors, irradiation of head and neck tumors, and Sjogrens syndrome. The permanent loss of salivary gland function results in severe oral complications and reduces the patients quality of life. We focus on interactions among the various cell types in the gland, including the epithelial, neuronal, and mesenchymal cells, and their extracellular matrix microenvironment, or niche. We discovered that parasympathetic nerves, which are critical for adult salivary gland function are also essential for gland development. Our recent advances suggest that WNT and FGF signaling within the epithelium control the initiation of neuronal-epithelial interactions. This initiates dynamic bi-directional signaling between the parasympathetic nerves and epithelium that direct the epithelial progenitors to form an exquisitely branched gland during organogenesis. We have used salivary gland explant culture and irradiation to injure the tissue in vitro. The Keratin 5-positive progenitors survive, parasympathetic function is diminished, and epithelial apoptosis reduces expression of the neurotrophic factor neurturin, which consequently increases neuronal apoptosis. Treatment with neurturin before irradiation, reduces neuronal apoptosis, restores parasympathetic function, and increases epithelial regeneration. Furthermore, adult human salivary glands damaged by irradiation also had reduced parasympathetic innervation and neurturin expression. We propose that neurturin may be used to protect the parasympathetic nerves from irradiation damage and improve regeneration. We continue to use viral vectors that express neurotrophic factors to infect salivary glands in vivo and ex vivo to improve the function of surviving nerves in repairing the gland. Therefore, the neurotrophic factors we have identified during gland development are being tested as potential treatments for adult gland regeneration.


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Matt Hoffman

Position and Affiliation: Senior Investigator Matrix and Morphogenesis Section, Deputy Scientific Director, National Institute for Dental and Craniofacial Research, NIH, Bethesda MD, USA

[Research Interest] Salivary gland developmental biology, branching morphogenesis, stem/progenitor cells, tissue regeneration, neurotrophic factors, FGFR signaling and heparan sulfate. We investigate interactions among epithelial, neuronal, and mesenchymal cells, and their extracellular matrix microenvironment during development and regeneration.

[Biographical Sketch]Matthew Hoffman, BDS, PhD, is a Senior Investigator and Chief of the Matrix and Morphogenesis Section and the Deputy Scientific Director (DSD) of the National Institute for Dental and Craniofacial Research. Matt, who was born in New Zealand, earned a BDS from the University of Otago in Dunedin, New Zealand in 1986. He worked for 2 years in a hospital dental clinic in Wellington, and later conducted research at the New Zealand Medical Research Council. He earned a Fulbright Travel Scholarship in 1989 to do aPhD in Microbiology and Immunology at the University of Rochester and received a PhD in 1994. He moved to NIDCR as a Postdoctoral Fellow in 1994 and became Staff Scientist in 2000, Tenure-Track Investigator in 2004, Senior Investigator in 2011, Deputy Branch Chief in 2015, and Deputy Scientific Director in 2016.


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SS4-2

Epiprofin is a multi-functional factor essential to promote dental epithelial stem cell commitment to the ameloblast lineage and its proliferation and differentiation

Yoshihiko Yamada1, Kiyoshi Sakai1, Yuta Chiba1, Bing Hev1, Darius Mahboubi1, Craig Rhodes1, Yasuo Yoshitomi1, Satoshi Fukumoto2, and Takashi Nakamura2

1Molecular Biology Section, NIDCR, NIH, Bethesda, MD, USA2Division of Pediatric Dentistry, Tohoku University Graduate School of Dentistry, Sendai, Japan.3Department of Oral Health and Development Sciences, Tohoku University Graduate School of Dentistry, Sendai, Japan

Tooth development is an attractive system for understanding ectodermal organ development. Dental epithelial stem cells give rise to all dental epithelial cell types, including enamel matrix-secreting ameloblast. Sox2-positive stem cells differentiate into the inner dental epithelium (IDE), which forms a single cell layer and proliferates rapidly before further differentiation into secretory and mature ameloblast. The aim of the project is to identify the molecular mechanisms that regulate stem cell commitment to the ameloblast lineage and its proliferation and differentiation during enamel organ development. Epiprofin (Epfn/Sp6) is a member of the Sp zinc-finger transcription factor family. During tooth development, Epfn is expressed in the dental epithelium at the initiation stage and in the ameloblast lineage with increasing levels of expression and in mature dentin matrix-secreting odontoblast. In Epfn KO teeth, proliferation of ameloblast progenitors is very reduced and ameloblast differentiation is completely inhibited, resulting in no enamel formation and abnormal dentin structure.

To identify Epfn binding genes and its target sequences for better understanding of Epfn functions, we performed ChIP sequencing by chromatin immunoprecipitation with purified Epfn antibody from the nuclei of dental epithelial cells and dental mesenchyme cells of P1 mouse molars. These genes include expected tooth genes and others. Unexpectedly, the consensus sequence motif found in Epfn binding regions is TAATTA, a consensus target sequence of homeodomain proteins. This is unexpected because the Sp family proteins, such as Sp1, are thought to bind to GC-rich sequences. Epfn can activate a reporter construct containing the TAATTA motif.

We found that low levels of Epfn inhibits Sox2-inducing transcriptional activity of Tbox1 (Tbx1), which maintains dental epithelial cells by inducing Sox2 in transfection analyses using clonal primary dental epithelia stem cell line PDE cells. In contrast, high levels of Epfn expression promotes differentiation of PDE cells to ameloblasts. These results suggest that Tbx1 maintains the stem cells, and Epfn regulates stem cell commitment to the ameloblast lineage. Our data also suggest that the expression levels of Epfn regulate its functions during ameloblast development

We also created K5-Epfn-transgenic mice expressing Epfn under the control of the epithelial cell-specific promoter, keratin 5 (K5-Epfn). K5-Epfn mice developed abnormally shaped incisors and molars. Interestingly, ameloblasts differentiated ectopically and enamel was formed on the lingual side of the K5-Epfn incisors, whereas ameloblasts and enamel were found only on the labial side in wild-type mice. Furthermore, dental mesenchymal cell proliferation was promoted by FGF9 from the dental epithelium induced by Epfn. These results suggest that Epfn regulates the balance between cell proliferation and differentiation in dental epithelial and mesenchymal cells during tooth development.


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Yoshihiko Yamada

Position and Affiliation: Senior Investigator and Chief, Molecular Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland

[Research Interest]The overall goal of research is to discover novel molecular mechanisms that underlie the development of hard tissues and ectodermal organs, by identifying novel functions of previously unstudied genes and defining the roles of the extracellular matrix (ECM). We have focused on the novel roles of protein factors and ECM components in proliferation, differentiation, and cell adhesion during development of teeth, cartilage, and other tissues. These studies are aimed towards developing reagents useful for diagnostic and therapeutic applications. Most recently, we identified several novel proteins from a tooth germ cDNA library, including the transcription factor epiprofin (Epfn), the odontoblast adhesion protein fibulin7 (Fbln7), and the gap junction protein Pannexin 3 (Panx3). W These proteins are expressed in teeth as well as in other tissues such as cartilage, bone, and skin. We found that Epfn regulates dental epithelial stem cell fate to the ameloblast lineage and is essential for tooth development and morphology. We showed that Panx3 regulates both chondrocyte and osteoblast differentiation via the activation of intracellular Ca2+ signaling pathways through multiple channel activities: hemichannel, endoplasmic reticulum (ER) Ca2+ channel, and gap junction.Fbln7 is a cell adhesion molecule and interacts with other ECM molecules, grow factors and receptors. We found that Fb,n7 and its fragments has anti-angiogenic activity in vitro and in vivo. We expect that identification of common and distinct molecular mechanisms for the function of these proteins in specific tissue types will uncover key concepts that underlie both normal development and diseases.

[Biographical Sketch]EDUCATION:1962-1966 BS, Biology, Osaka University, Faculty of Science, Osaka, Japan1966-1968 MS, Biology, Osaka University, Graduate School of Science, Osaka, Japan1968-1971 PhD, Biology, Osaka University, Graduate School of Science, Osaka, JapanEMPLOYMENT HISTORY:1972-1975 Research Associate, University of Pittsburgh, School of Medicine, Dept. of Biochemistry,

Pittsburgh, PA1975-1979 Research Assistant Professor, University of Pittsburgh, School of Medicine, Dept. of

Biochemistry, Pittsburgh, PA1979-1983 Visiting Scientist, Laboratory of Molecular Biology, National Cancer Institute, NIH, Bethesda,

MD1983-1984 Principal Investigator, Laboratory of Developmental Biology and Anomalies, National Institute

of Dental Research, NIH, Bethesda, MD1985-present Senior Investigator and Chief, Molecular Biology Section, National Institute of Dental and

Craniofacial Research, NIH, Bethesda, MD


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SS4-3

Regulation of proteostasis and calcium homeostasis in the ER and of autophagy

Kazuhiro Nagata, Yohei Yamamoto and Ryo UshiodaLaboratory of Molecular and Cellular Biology, Faculty of Life Sciences, Kyoto Sangyo University, Kamigamo, Kita-ku, Kyoto 603-8555, Japan

Terminally misfolded secretory and membrane proteins are retrotranslocated from the endoplasmic reticulum (ER) into the cytosol where they are degraded via ubiquitin-proteasome pathway, a process termed as ER-associated degradation (ERAD). We previously reported that ERdj5, an ER-resident disulfide reductase, plays a central role in ERAD by cleaving the disulfide bonds of the misfolded proteins that are recognized by EDEM (ER-degradation enhancing a-mannosidase-like protein). Recently, we found that ERdj5 reduces the luminal disulfide bond of SERCA2b, a Ca2+-ATPase on the ER membrane, thereby activating its pump function. Notably, we found that ERdj5 activates SERCA2b at lower ER luminal [Ca2+] ([Ca2+]ER), while higher [Ca2+]ER induces ERdj5 to form oligomers that are no longer able to interact with the pump, suggesting [Ca2+]ER-dependent regulation. These results identify ERdj5 as a master regulator of ER calcium homeostasis, and thus shed light on the importance of crosstalk among redox, Ca2+ and protein homeostasis in the ER.

We also found another novel J-protein in the ER, ERdj8, which negatively regulates macro-autophagy. Autophagy degrades abnormal organelle and proteins, and hence retains the intracellular homeostasis. ERdj8 localizes at the ER-mitochondria contact site, at which autophagosomal membranes originate. We identified that ERdj8 regulates the size of autophagosomes by retarding the dissociation of isolation membranes from the ER. The mechanism determining the size of autophagosomes has never been reported, and our finding would provide a novel insight on the regulation of cellular homeostasis by autophagy.


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Kazuhiro NagataPosition and Affiliation: Director of the Institute for protein dynamics, Kyoto Sangyo University

[Research Interest]Protein folding and quality control by molecular chaperones

[Biographical Sketch]Professional Appointments:1979-1986 Lecturer, Chest Disease Research Institute, Kyoto University1984-1986 Visiting Associate, Laboratory of Molecular Biology, National Cancer

Institute, NIH (USA)1986-1998 Professor and Chairman, Department of Cell Biology, Chest Disease

Research Institute, Kyoto University1998-2010 Professor and Chairman, Department of Molecular and Cellular Biology,

Institute for Frontier Medical Sciences, Kyoto University2010 Professor Emeritus, Kyoto University2010-2013 Professor & Dean, Faculty of Life Sciences, Kyoto Sangyo University2013-present Professor, Faculty of Life Sciences, Kyoto Sangyo University2016-present Director, Institute for Protein Dynamics, Kyoto Sangyo University

Honors and Committee members:1995-present Editorial Board, Cell Stress and Chaperones1999-2002 Editor-in-chief, Cell Structure and Function2002-2005 President, Japan Society for Cell Biology2003-2010 Vice President, Asian-Pacific Organization for Cell Biology2004-2005 President, Cell Stress Society International2009 Awarded the Medal with Purple Ribbon (Japanese government)2015-present Editorial Board, Scientific Report2015 Lifetime honorary membership of Japanese Society for Cell Biology


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SS4-4

Roles of Rab family small GTPases in polarized trafficking in epithelial cells

Mitsunori FukudaGraduate School of Life Sciences, Tohoku University

Epithelial cells have a clearly defined apical–basolateral asymmetry, which is established through division of their plasma membrane into two functionally and morphologically distinct domains, to perform their physiological functions. MDCK (Mardin-Darby canine kidney) II cells, a widely used model of polarized epithelia, develop into two different epithelial structures depending on culture conditions – two-dimensional (2D) monolayers when grown on synthetic supports such as normal culture dish or three-dimensional (3D) cysts when surrounded by extracellular matrix. The establishment of epithelial polarity is accompanied by transcytosis of an apical marker protein podocalyxin (PCX)/gp135 from the outer plasma membrane to the newly formed apical domain, although its exact route and regulation remain poorly understood. In this study, we analyzed Rab family small GTPases engaged in the transcytotic pathway of PCX by comprehensive colocalization and knockdown screenings and found that different sets of Rabs coordinate its transport during cell polarization into 2D monolayers and 3D cysts. Moreover, we demonstrated that Rab35 differently regulates PCX trafficking in 2D and 3D environments through interaction with distinct effectors. In this symposium, I will discuss the differences between membrane trafficking mechanisms during 2D and 3D epithelial development.


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Mitsunori Fukuda

Position and Affiliation:Professor, Laboratory of Membrane Trafficking Mechanisms, Department of Developmental Biology and Neurosciences, Graduate School of Life Sciences, Tohoku University, Sendai, Miyagi 980-8578, Japan

[Research Interest]Elucidation of the molecular mechanism of “membrane traffic”, e.g., neurite outgrowth, melanosome transport, autophagy, and epithelial polarization, that underlies various life phenomena especially focusing on the Rab family small GTPases.

[Biographical Sketch]1996 Ph. D., The University of Tokyo, Faculty of Medicine1996-1998 Researcher, the Japan Society for the Promotion of Science1998-2002 Research Scientist, Laboratory for Developmental Neurobiology, Brain Science Institute, The

Institute of Physical and Chemical Research (RIKEN)2002-2007 Initiative Research Scientist, Fukuda Initiative Research Unit, RIKEN2006-present Professor, Laboratory of Membrane Trafficking Mechanisms, Department of Developmental

Biology and Neurosciences, Graduate School of Life Sciences, Tohoku University


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SS5-1

TTF-1/NKX2-1: an enigmatic double-edged sword in lung adenocarcinoma

Takashi TakahashiDivision of Molecular Carcinogenesis, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine

Emerging evidence, though currently sparse, suggests that “lineage-specific transcription factors” with developmental roles in normal progenitor cells of particular lineages may also confer dependency for survival to certain types of cancer cells. We previously found that TTF-1, a homeobox-containing transcription factor also called NKX2-1, plays a role as a “lineage-survival” oncogene in lung adenocarcinoma. However, TTF-1-positive lung adenocarcinomas curiously tend to be associated with better prognosis, which we found to be at least in part due to TTF-1-mediated induction of myosin binding protein H and consequential inhibition of ROCK1. This deleterious effect for cancer motility, invasion and metastasis appeared to be negated by promoter DNA methylation in a considerable fraction of TTF-1-positive lung adenocarcinomas.

We have also shown that TTF-1 transcriptionally activates the receptor tyrosine kinase-like orphan receptor 1 (ROR1) gene, which in turn sustains a favorable balance between prosurvival PI3K-AKT and proapoptotic p38 signaling, in both ROR1 kinase-dependent and -independent manners. While EGFR signaling is involved as a “driving force” in lung adenocarcinoma pathogenesis, it is of note that ROR1 appears to play a “sustainer role” for the interaction of EGFR-ERBB3 and ERBB3 phosphorylation, and consequential PI3K activation in a ROR1 kinase-independent manner. Interestingly, ROR1 inhibition effectively overcomes EGFR-TKI resistance conferred by either EGFR T790M double mutation or bypass signaling through various other receptor tyrosine kinases such as MET and IGF-IR. In this connection, an unexpected role of ROR1 as a scaffold protein of caveolin-1 (CAV1) and cavin-1, both which are known to be essential for caveolae formation, was found to be involved. I will also present our recent findings of an additional function of ROR1 in relation to the caveolae biology as well as a non-transcriptional function of TTF-1 conferring tolerance to DNA replication stress in lung adenocarcinoma.

Taken together, our findings shed light on the mechanistic insight into how TTF-1 plays roles as a double-edged sword in the pathogenesis of lung adenocarcinoma, and also identify ROR1 as an “Achilles’ heel” of this devastating cancer, warranting future development of novel therapeutic means targeting ROR1.


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Takashi Takahashi, M.D., Ph.D.

Position and Affiliation: Director, Center for Neurological Diseases and Cancer; and Professor, Division of Molecular Carcinogenesis, Nagoya University of Graduate School of Medicine

Research Interest: Molecular dissection of the pathogenesis of lung cancer and its clinical translation

Bibliographic sketch: 1979 M.D., Nagoya University1979-1988 Clinical training (Surgery) 1984-1988 Research Fellow, Aichi Cancer Center Research Institute (ACCRI)1988 Ph.D., Nagoya University1988-1990 Postdoctoral fellow, NCI-Navy MOB, NCI, NIH, USA1990-1995 Investigator and Section head, Laboratory of Chemotherapy, ACCRI1995-2004 Chief, Laboratory of Molecular Oncology, ACCRI2004-present Professor, Division of Molecular Carcinogenesis, Nagoya University Graduate School of

Medicine2012-present Director, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of

Medicine

Selected publications related to presentation:1 Liu Z, et al. TTF-1/NKX2-1 binds to DDB1 and confers replication stress resistance to lung

adenocarcinomas. Oncogene (in press)2 Yamaguchi T, et al.. ROR1 sustains caveolae and survival signaling as a scaffold of cavin-1 and

caveolin-1. Nat Commun 7: 10060, 2016. 3 Yamaguchi T, et al. NKX2-1/TTF-1: an enigmatic oncogene that functions as a double-edged sword for

cancer cell survival and progression. Cancer Cell 23:718-723, 2013.4 Hosono Y, et al. MYBPH, a transcriptional target of TTF-1, inhibits ROCK1, and reduces cell motility

and metastasis. EMBO J 31:481-493, 2012. 5 Yamaguchi T, et al. NKX2-1/TITF1/TTF-1-induced ROR1 is required to sustain EGFR survival

signaling in lung adenocarcinoma. Cancer Cell 21: 348-361, 2012. 6 Tanaka H, et al. Lineage-specific dependency of lung adenocarcinomas on the lung development

regulator TTF-1. Cancer Res 67:6007-6011, 2007.7 Yatabe, Y., Mitsudomi, T., and Takahashi, T. TTF-1 expression in pulmonary adenocarcinomas. Am J

Surg Pathol 26: 767-773, 2002.


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SS5-2

Interplay of MYC oncogene and ubiquitin-proteasomal degradation of a TFIID component in proliferation switch

Tadashi Nakagawa, Masaki Hosogane, Ryo Funayama, Keiko NakayamaDivision of Cell Proliferation, ART, Graduate School of Medicine, Tohoku University, Sendai, Miyagi 980-8575, Japan.

Transforming growth factor–β (TGF-β) is a pleiotropic cytokine. In the process of tumorigenesis, TGF-β functions as a pro-oncogenic factor through induction of the epithelial-mesenchymal transition (EMT), whereas it also has the ability to inhibit cell proliferation and to induce apoptosis. However, the molecular mechanism by which tumor cells evade the restraining effect of TGF-β on cell proliferation has remained unclear. Based on recent reports that cellular differentiation is regulated by general transcription factor IID (TFIID), a promoter recognition complex that is required for recruitment of RNA polymerase II (Pol II) to target genes to initiate transcription, we hypothesized that TFIID is also involved in TGF-β signaling.

TFIID is composed of TATA box binding protein (TBP) and TBP-associated factors. We found that one of the TFIID components was degraded by proteasome following ubiquitylation in response to TGF-β. We identified a ubiquitin ligase induced by TGF-β for degradation of this TFIID component. The ubiquitin ligase identified was associated with proliferation arrest, but not EMT. ChIP-seq and RNA-seq analyses revealed that this TFIID component bound to and positively regulated the expression of most ribosomal protein genes, which was disrupted by short-term treatment of TGF-β. In contrast, sustained TGF-β exposure led to recovery of cell proliferation and this effect was accompanied by suppression of identified ubiquitin ligase. Amplification of MYC proto-oncogene was found to be responsible for this suppression. Together, our findings have uncovered that TGF-β regulates cell proliferation by altering TFIID, which is inhibited by long-term TGF-β-induced MYC amplification, independently of EMT.


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Tadashi Nakagawa

Position and Affiliation:Assistant Professor, Division of Cell Proliferation, ART, Graduate School of Medicine, Tohoku University, Sendai, Miyagi 980-8575, Japan.

[Research Interest]Chromatin regulation by ubiquitin system　Alteration of chromatin structure is essential for any DNA-templated events such as replication, transcription and repair in eukaryotic cells. We are investigating how ubiquitin system participates in this process.

Molecular mechanism of amyotrophic lateral sclerosis (ALS) pathogenesis　Many genetic mutations in ALS patients are being identified, but molecular characterization of these mutations remains largely unexplored. Abnormal protein aggregation is a hallmark of neurons and glia in ALS patients and it is proposed that protein degradation is involved in this abnormality. We are investigating how ALS-related proteins are associated with ubiquitin-proteasome system, the disruption of which could be the basis of ALS pathogenesis.

[Biographical Sketch]2013-present Assistant Professor, Tohoku University, Graduate School of Medicine2008-2013 Postdoctoral Research Fellow, University of North Carolina at Chapel Hill2008 Ph.D., Kyushu University, Graduate School of Medicine


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SS5-3

Stem cells and cancer of thyroid

Shioko Kimura, Manabu Iwadate, Yoshinori TakizawaLaboratory of Metabolism, Center for Cancer Research, NCI, NIH

A subpopulation of cancer cells has stem-like characteristics that are thought to be responsible for metastasis and relapse. Adult stem cells are undifferentiated cells that are found throughout the body, however, it remains unclear whether they are present in all organs. In recent years, the presence of adult stem cells in the thyroid has been described, while their nature remains largely unknown and no cell surface markers have been identified. Our research focuses on the identification and characterization of adult stem cells in thyroid in order to understand their possible role and/or involvement in thyroid carcinogenesis. We previously demonstrated that the Hoechst dye-resistant side population (SP) cells of mouse thyroid, ranging from 0.3-1.4% of the total population of cells, exhibit stem/progenitor cells-like characteristics. We successfully established a Side Population cells-derived Thyroid cell Line (SPTL) from mouse thyroid SP cells. SPTL cells did not express pluripotent markers such as Oct4, Nanog, and Rex1, while they expressed Gata4 and Gata6, the known endoderm specification genes, suggesting that SPTL cells may have already been committed to form endoderm lineage cells. Only ~1% of SPTL cells expressed Nkx2-1 but not Pax8, the two transcription factors critical for thyroid differentiation and function, while none of the other thyroid differentiation marker genes such as thyroglobulin and thyroid peroxidase were expressed. When GFP-SPTL cells were directly injected into mouse thyroid, a few GFP-SPTL cells with weak expression of NKX2-1 were found in part of thyroid follicle. These results suggest that SPTL cells have the potential to be thyroid stem cells. SPTL cells may provide an excellent tool to study stem cells of the thyroid, which circumvents the problems associated with the study of stem cells of small organs such as the thyroid due to the scarcity of the material.

RNA-seq analysis revealed that SPTL cells highly express genes involved in epithelial-mesenchymal transition and exhibited a gene expression pattern similar to anaplastic thyroid carcinoma. Further, the TGF-beta signaling pathway was found to be critical for SPTL cells, and the balance between the TGF-beta signaling and Nkx2-1 expression may govern whether SPTL cells stay as stem cells or differentiate into thyroid. We are currently studying the relationship between Nkx2-1 expression, TGF-beta signaling of both SMAD and non-SMAD pathways, and the differentiation status of SPTL cells.


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Shioko Kimura

Position and Affiliation:Senior Investigator, Head of Endocrinology Section Laboratory of Metabolism, Center for Cancer Research National Cancer Institute, National Institutes of Health

[Research Interest]The research of Dr. Kimura’s laboratory focuses on the identification and characterization of adult thyroid stem cells and their roles in thyroid cancer, and understanding the role of homeodomain transcription factor, NKX2-1 in relation to adult stem cells, differentiation and carcinogenesis of thyroid. She also studies a novel cytokine Secretoglobin (SCGB) 3A2, the downstream target for NKX2-1 in lung in order to understand its role in the function, homeostasis and carcinogenesis of lung.

[Biographical Sketch]Dr. Kimura obtained her Ph.D. in chemistry from the Hokkaido University, Sapporo, Japan. She did postdoctoral study first at the Department of Biochemistry, Queen’s University, Kingston, Ontario, Canada, and then in the Laboratory of Developmental Pharmacology, National Institute of Child Health and Human Development. She moved to the Laboratory of Molecular Carcinogenesis, National Cancer Institute to carry out an independent research. Since 1998, she has been head of the Endocrinology Section, Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute.


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------------------ Memo ------------------

Concurrent Workshops:

CW1 : Workshop 1-Infectious DiseasesCW2 : Workshop 2-Kidney Diseases


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CW1-1

The Challenges in Treating Chronic Norovirus Infection

Kim Y. GreenCaliciviruses Section, Laboratory of Infectious Diseases, NIH, Bethesda, Maryland U.S.A.

Noroviruses cause acute gastroenteritis in all age groups. The symptomatic phase of the illness generally lasts two to three days, but norovirus can be detected in stool for several days to weeks after symptoms resolve. In contrast, immunocompromised patients may shed norovirus for months to years following an acute infection. Immune reconstitution by gene therapy or stem cell transplantation can often lead to successful clearance of chronic norovirus infection. Our laboratory has studied a cohort of immunocompromised patients with chronic norovirus infection at the NIH Clinical Center. We determined the overall prevalence of norovirus infection in this cohort to be approximately 12%, with a number of patients showing evidence of long-term chronic infection. The predominant norovirus genotype was GII.4, and a number of GII.4 variants were associated with infection. Using Next-generation sequencing (NGS), we investigated the genomic diversity of norovirus strains in these patients over time, with some patients receiving treatment to clear their norovirus infection. Our data show that NGS can provide a powerful tool in determining the mechanistic action of antibodies or antiviral drugs during treatment, and inform strategies to circumvent escape and resistance.


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Kim Y. Green

Position and Affiliation: Senior Investigator, Caliciviruses Section, Laboratory of Infectious Diseases, National Institutes of Health

[Research Interest]Noroviruses in the Caliciviridae are a major cause of acute gastroenteritis in all age groups. One of the major specific areas of research in our laboratory is to develop experimental systems in which to study norovirus replication and immunity. We have conducted comparative studies among diverse members of the Caliciviridae in an effort to learn common themes in calicivirus replication that will inform our understanding of the human noroviruses. Recent breakthroughs include the first visualization of calicivirus replication in real time by the introduction of a fluorescent protein marker in the feline calicivirus genome, a proof of concept study for human norovirus vaccines in an animal model, and the mapping of functional epitopes in a predominant norovirus genotype. The predominant norovirus strain associated with gastroenteritis outbreaks is named GII.4. We have studied how the surface of the GII.4 virion has changed over the decades to gain insight into how norovirus vaccines should be designed. In this computer-generated image of the GII.4 norovirus capsid protein, a model of the GII.4 virus in 1974 (orange) is superimposed over a more recent GII.4 strain (pink). The blue sticks represent a histo-blood group carbohydrate molecule that many noroviruses recognize on intestinal cells. This binding site has changed little in GII.4 noroviruses for over three decades. However, other regions show minor differences that might influence antibody recognition.

[Biographical Sketch]Dr. Green earned her Ph.D. from the University of Tennessee Center for Health Sciences in Memphis in the department of microbiology and immunology. She joined the NIAID Laboratory of Infectious Diseases in 1986 and has focused on the study of viruses associated with gastroenteritis. In recent years, her research program has addressed the role of noroviruses in human disease, with an emphasis on the development of prevention and control strategies.


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CW1-2

Identification of the functional receptor for murine norovirus

Kei Haga and Kazuhiko KatayamaLaboratory of Viral Infection I, Kitasato Institute for Life Sciences, Graduate School of Infection Control Sciences, Kitasato University

Norovirus infection is the leading cause of acute gastroenteritis worldwide. An efficient culture system for human norovirus has not yet been established. In contrast, murine norovirus (MNV) can be easily amplified in the macrophage cell line RAW264.7 and is frequently used as a model virus to understand the basic virology of noroviruses. Yet, the mechanism of MNV infection is still not fully understood. Since directly supplying noroviral genome into cells produces infectious virions, identifying a specific cell-surface receptor for norovirus may reveal the infection mechanism.

To identify candidate host genes that are important for MNV infection, we transduced a genome-wide CRISPR/Cas9 guide RNA (gRNA) library into RAW264.7 cells with a levntiviral vector. Then, we isolated the cells that escaped from MNV-induced cytopathic effect and analyzed the integrated gRNAs in these cells by next-generation sequencing.

We identified murine CD300lf as a functional receptor. Treating RAW264.7 cells with a polyclonal antibody against CD300lf significantly reduced production of viral progeny. Additionally, ectopic CD300lf expression in unsusceptible cell lines that were derived from different animal species enabled MNV infection. We also found that the N-terminal region of extracellular domain is important for MNV binding and that the cytoplasmic domain is dispensable for MNV infection. Furthermore, CD300ld, which is considered to have a biologically opposite function of CD300lf and is highly homologous in N-terminal region of extracellular domain, also functions as an MNV receptor.

Our finding suggests that the host cell tropism of norovirus is determined by the cell-surface receptor protein. Identification of MNV receptor contributes to the understanding of MNV life cycle and suggests that specific receptors exist for other norovirus genogroups.


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Kazuhiko Katayama

Position and Affiliation:ProfessorLaboratory of Viral Infection I, Kitasato Institute for Life Sciences, Graduate School of Infection Control Sciences, Kitasato UniversityE-mail: [email protected]

[Research Interest]My main research focus is a basic research of norovirus, sapovirus and rotaviruses to develop antiviral reagents, disinfectants and vaccine to prevent and control viral gastroenteritis. Particularly, human norovirus (HuNoV) is the leading cause of gastroenteritis worldwide. My research group mainly focus on HuNoV study. We developed RT-PCR, real-time PCR and genotyping systems for HuNoV that has become a golden standard protocol. From 2005-2007, I studied a norovirus reverse genetics system in prof. Mary K. Estes's lab at Baylor College of Medicine. My research group successfully developed a reverse genetics system for murine norovirus (MNV) and HuNoV and published in PNAS in 2014. We also found MNV receptor CD300lf and CD300ld and published in PNAS last year. However, Since the discovery of HuNoV, many aspects of HuNoV life cycle are not well understood because of lack of efficient in vitro viral culture system. Now we are trying to establish an efficient HuNoV cultivation system using novel ex vivo human duodenal organoids (HDOs) and also investigating HuNoV receptor molecule.

[Biographical Sketch]Kazuhiko Katayama is professor at Laboratory of Viral Infection I, Kitasato Institute for Life Sciences, Graduate School of Infection Control Sciences, Kitasato University in Japan. He graduated from the Tokyo University of Agriculture and Technology in 1985. He obtained his Ph.D. at the University of Tokyo in 2000. After graduation, he worked as a research scientist in infectious disease and diagnostics at Bio Medical Laboratories, Inc., for 16 years and then moved to Virology II, National Institute of Infectious Diseases as a section chief of gastroenteritis virus lab in 2001. He recently moved to Kitasato University in 2016.


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CW1-3

Genetic diversity of norovirus and sapovirus in multiple infection among birth cohort children

Mayuko Saito1, Gerardo Sanchez2, Holger Mayta2, Gilman RH3, Xiaofang Liu1, Lilia Cabrera4, Sarah Blythe Ballard3, Kentaro Tohma1, Monica Pajuelo2, Jean E Crabtree5, Dermot Kelleher6, Vitaliano Cama7, Caryn Bern8, Hitoshi Oshitani1 and Sapovirus Working Group1Tohoku University Graduate School of Medicine, 2Universidad Peruana Cayetano Heredia, 3Johns Hopkins Bloomberg School of Public Health, 4Asociacion Benefica PRISMA, 5University of Leeds, 6Trinity College, 7Center for Disease Control and Prevention, 8University of California San Francisco

Norovirus and sapovirus are single-stranded positive-sense RNA belonging to the family Caliciviridae. After introduction of rotavirus vaccine, the importance of these two viruses for child diarrhea is increasing as the first and second leading cause of hospitalization among children with acute viral gastroenteritis. Due to limited availability of culture methods and animal model for human norovirus and sapovirus infection, immunological studies have been still limited. We have previously reported frequent norovirus infection and high diversity of norovirus detected in birth cohorts during their first two years of life in peri-urban community in Peru. Sapovirus infection was further tested in 100 children, who were randomly selected from the 189 children who had completed two-year follow-up (i.e. up to 24-month-old) in the same cohort. The genotyping results of partial VP1 gene showed that repeated infection of the same genotype in a same child is very rare in sapovirus infection as well as norovirus infection. Heterologous immunity to prevent the subsequent infection of the different genotypes seemed limited. The duration and level of the immunity against the same genotype is ambiguous since level of the circulation of each genotype changes over time within a community. Similar to norovirus infection, prolonged shedding, frequent asymptomatic infection and high diversity were also observed in sapovirus infection. These characteristics possibly support the chance of having mixed infection with different genotypes of the same virus in a single host, which increase the chance of recombination of the genes.


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Mayuko Saito

Position and Affiliation:Associate Professor, Department of Virology, Tohoku University Graduate School of Medicine

[Research Interest](1) Infectious disease epidemiology, mainly viral diarrhea (2) Validation and development of diagnostic test for infectious disease

screening in resource-limited settings(3) Risk factors of infection and severe infectious disease

[Biographical Sketch]Mayuko Saito is a physician epidemiologist, Associate Professor of the Department of Virology, Tohoku University Graduate School of Medicine. She obtained medical degree at Saga Medical School and was trained in general internal medicine and clinical epidemiology in Japan. After completion of Master of Public Health degree at Johns Hopkins Bloomberg School of Public Health, she studied infectious disease epidemiology, including tuberculosis, brucellosis, norovirus and other tropical diseases with working group in Peru, mainly supported by Asociacion Benefica PRISMA, Universidad Peruana Cayetano Heredia and University of California San Diego. Her recent work is focusing on community studies regarding viral pathogens associated with child diarrhea, such as norovirus and sapovirus infection in communities in Peru and Philippines. She has been also a member of research group for development of monitoring system of norovirus in sewage (CREST project) in Japan with New Industry Creation Hatchery Center at Tohoku University. She supported field epidemiology in the Ebola outbreak in Sierra Leone in 2014.


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CW1-4

Norovirus monitoring in sewage as a tool for detecting infectious gastroenteritis and genotypes circulating in human populations

Shinobu Kazama1, Takayuki Miura1, Yoshifumi Masago2, Yoshimitsu Konta1, Kentaro Tohma3, Takafumi Manaka3, Xiaofang Liu3, Daisuke Nakayama4, Takashi Tanno5, Mayuko Saito3, Hitoshi Oshitani3, Tatsuo Omura1New Industry Creation Hatchery Center, Tohoku University,2Institute for the Advanced Study of Sustainability, United Nations University, 3Department of Virology, Graduate School of Medicine, Tohoku University, 4Nakayama Clinic, 5Medical Corporation Matsushima Hospital

Occurrence and genotypes of norovirus in sewage have been investigated to study prevalence of norovirus infections in human populations since sewage theoretically receives noroviruses excreted in feces or vomitus from all infected individuals in the catchment area. However, the statistical relationship between norovirus concentration in sewage and gastroenteritis cases, and the clinical importance of genotypes detected in sewage are not well documented. In this study, we carried out both environmental and clinical surveillance of noroviruses for four norovirus seasons in 2012−2016. We applied cross-correlation analysis between the concentrations of norovirus GI or GII in sewage samples collected weekly and the number of gastroenteritis cases reported in the study area. Norovirus genotypes in sewage were also analyzed using pyrosequencing and compared with those identified in patients’ stools. The highest correlation coefficient was observed between the GII concentration and the gastroenteritis cases without time lag, indicating that the concentration changed synchronously with the number of cases. A total of 18 norovirus genotypes and up to 8 genotypes per sample were detected in sewage, which included 11 out of 13 genotypes identified in the stool samples. The GII.4 Sydney 2012 variant was most frequently detected in both sewage and stool samples in the 2012−2014 norovirus seasons, while GII.17 in the 2014−2016 norovirus seasons. Appearance of the Sydney 2012 variant was simultaneously observed in both the samples. Phylogenetic analysis revealed that a strain belonging to the GII.17 Kawasaki 2014 lineage had been introduced to the study area in 2012−2013 norovirus season. These results demonstrated that monitoring of noroviruses in sewage is useful for sensitive detection of norovirus epidemic and temporal change of genotypes in human populations.


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Shinobu Kazama, Ph.D.

Position and Affiliation: Assistant professor, New Industry Creation Hatchery Center, Tohoku University

[Research Interest]Fate of enteric viruses in environment, Development of methods for the detection of enteric viruses in environment, Survival and inactivation mechanisms of pathogens by disinfection (e.g. water or wastewater treatment processes),

[Biographical Sketch]EducationMar.2011 Doctor of science degree, Human Environmental Sciences, Ochanomizu University,

Japan

Professional experienceNov.2016-present Assistant professor, New Industry Creation Hatchery Center, Tohoku University, Japan. Apr.2013-Oct.2016 Postdoctoral research fellow, New Industry Creation Hatchery Center, Tohoku

University, Japan. Mar.2012-Feb.2013 Scientific collaborator at Swiss Federal Institute of Technology in Lausanne,

Switzerland, supported by the JSPS Institutional Program for Young Researcher Overseas Visits

Apr.2011-Mar.2013 Postdoctoral research fellow, Graduate School of Humanities and Sciences, Ochanomizu University, Japan


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CW2-1

APOL1 genetic variants explain much of the increased kidney disease risk among African Americans

Koji Okamoto, Jurgen Heymann and Jeffrey B. Kopp Kidney Disease Section, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892

African Americans have an increased risk for kidney disease; in the USA approximately 2% of Whites and approximately 8% of Blacks will develop end-stage kidney disease. We undertook a search for a genetic locus that might account for this predilection, looking for genomic regions that were more likely to be of African origin in cases, defined as focal segmental glomerulosclerosis (FSGS) and HIV-associated nephropathy (HIVAN), compared to controls (HIV-positive African Americans with HIV and lacking kidney disease, whom we hypothesized would lack the risk variants). We identified a peak of excess African ancestry on chromosome 22, which we first attributed to MYH9. Subsequently, this locus was shown to be accounted for by variants in APOL1, encoding apolipoprotein L1. APOL1 is an innate immune protein that circulates on HDL and kills Trypanosoma brucei, the cause of African sleeping sickness. The East African form, T. brucei rhodesiense, evolved a counter-measure, serum resistance antigen (SRA), which binds and inactivates APOL1. Two APOL1 codon-changing variants arose ~10,000 y ago, termed G1 and G2, that do not bind SRA and restore trypanosomal killing. The combined allele frequency of APOL1-G1 and –G2 variants is 50% in West Africa and 35% among African Americans. The effect of these genetic variants is largely recessive. There are ~39 million African Americans and ~13% (5 million) have two APOL1 risk alleles; among these, we estimate that 20-25% will develop kidney disease in their lifetime. Current therapies often fail to halt kidney disease progression.

The odds ratios (OR) for kidney disease among those with two APOL1 risk alleles, compared to other African Americans are as follows: FSGS, 17 and HIVAN, 29 in the USA and 89 in South Africa; hypertensive-attributed kidney disease that progresses to end-stage kidney disease, 7. 72% of FSGS and HIVAN cases have 2 APOL1 risk alleles. In South Africa, the OR for APOL1 in HIVAN is 89. Other APOL1 renal phenotypes include collapsing glomerulopathy in lupus nephritis and reduced renal allograft survival.

APOL1 expression in the kidney is most prominent in podocytes and microvascular endothelial cells. Work in various laboratories has suggested several possible mechanisms of injury, including cell death due to lysosomal dysfunction, impaired mitochondrial function activation of inflammasome leading to enhanced production of IL-1b, and activation of protein kinase R by extended stem loop structures in the risk variant RNAs. On-going work will clarify which injury pathways are most relevant to human disease and could lead to targeted and more effective therapy.


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Jeffrey B. Kopp

Position and Affiliation: Branch Chief, Kidney Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of [email protected]

[Research Interest]Our research group studies focal segmental glomerulosclerosis (FSGS), a set of syndromes characterized clinically by proteinuria and tendency to progress to end-stage kidney disease and histologically by segmental scarring of the kidney glomeruli. FSGS syndromes include primary, adaptive and APOL1 forms, as well as the less common high-penetrance genetic, virus-associated, and medication-associated forms. In particular, we are interested in understanding the mechanisms by which APOL1 genetic variants, which arose in Africa to protect against Trypanosomal infection, confer substantial risk for FSGS, HIV-associated nephropathy, and arterionephrosclerosis (hypertension-attributed chronic kidney disease). We are also interested in testing novel therapies for FSGS, and are currently engaged in a phase I study of ManNAc (N-acetyl glucosamine), a precursor of sialic acid; the goal is to restore reduced sialic acid on proteins expressed by glomerular podocytes.

[Biographical Sketch]Dr. Kopp graduated from Harvard College and the University of Pennsylvania School of Medicine, and trained in internal medicine and nephrology at the University of Washington. He came to NIH in 1987 as a post-doctoral fellow and has been with the NIDDK since 1995. He serves on the nephrology consultation service at the NIH Clinical Center and coordinates a research program that seeks to understand FSGS patho-mechanisms and develop targeted therapies.


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CW2-2

Mechanism of the progression from podocyte injury to glomerulosclerosis in chronic kidney disease

Katsuhiko Asanuma1, Naritoshi Shirata1, Katsuhiko Nishimori2

1Medical Innovation Center, TMK project, Graduate School of Medicine, Kyoto University, 2Department of Molecular and Cell Biology, The Laboratory of Animal Breeding and Genetics, Graduate School of Agricultural Science, Tohoku University

It has recently become clear that initial glomerular injury affects glomerular visceral epithelial cells (also called as podocytes), making them important target cells for progression of chronic kidney disease (CKD) and end-stage kidney disease. Podocytes are injured in many human kidney diseases including minimal change disease, focal segmental glomerulosclerosis, diabetic nephropathy, membranous nephropathy, and lupus nephritis. Podocytes serve as the final barrier to urinary protein loss through the formation and maintenance of foot-processes and an interposed slit-diaphragm (SD). Chronic podocyte injury may cause podocyte detachment from the GBM, which leads to glomerulosclerosis.

Previously we have reported that dendrin, which is a component of the SD, translocates to the nucleus in injured podocytes, promoting podocyte apoptosis. Moreover, nuclear translocation of dendrin was also found in human kidney biopsy specimens from patients with glomerular diseases characterized by podocyte loss and glomerulosclerosis. Under physiological conditions, an SD protein called MAGI-2 is necessary for inhibiting dendrin nuclear translocation.

In this talk, we will try to make a brief overview about the role of SD associated proteins in progression of CKD.


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Katsuhiko Asanuma

Position and Affiliation:Associate ProfessorKyoto University Graduate School of MedicineMedical Innovation Center, TMK project

[Research Interest]In the center of our research activity is the elucidation of the mechanism of podocyte injury in chronic kidney disease (CKD). The final goal of this study is to find a novel therapeutic target against CKD.Another major focus in our laboratory is podocyte cell biology (autophagy, ubiquitin-proteasome pathway and endocytosis). A combination of genetic, structural, molecular and cell biological approaches are employed to unravel our interests in our laboratory.

[Biographical Sketch]Dr. Asanuma is a physician who received his MD from Juntendo University in 1995, and then received his Ph.D from Juntendo University in 2002. He joined Professor Peter Mundel’s laboratory as a postdoctoral researcher at the Division of Nephrology, Albert Einstein College of Medicine and Mount Sinai School of Medicine, NY. In 2006, he became an Assistant Professor at Juntendo University Faculty of Medicine, Division of Nephrology.In 2013, he moved to Kyoto University School of Medicine, Medical Innovation Center, TMK project as an Associate Professor.He was awarded the Japanese Society of Nephrology young investigator award and best citation award in 2011.


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CW2-3

Development of a novel mitochondrial drug, MA-5

Takaaki ABE, M.D., Ph.D.Division of Medical Science, Tohoku University Graduate School of Biomedical Engineering, Department of Clinical Biology and Hormonal Regulation, Tohoku University Graduate School of Medicine, Sendai 980-8574 Japan

Mitochondrial dysfunction causes various mitochondrial diseases, kidney injuries and cardiomyopathy. Intracellular ATP depletion and the increasing mitochondria-derived reactive oxygen species (mitROS) are considered as major pathophysiologic mechanisms of disease progression in mitochondrial abnormalities. Anti-oxidant quinones have been used clinically to prevent the progression of mitochondrial diseases but the effectiveness is yet to be established.

We recently found that several indole-derivatives increased ATP levels in Hep3B cells by screening of 41 newly synthesized indole derivatives. Among those compounds, we focused on the most potent indole derivative #5 (Mitochonic acid-5, MA-5) (Tohoku J. Exp. Med. 2015, JASN 2016). MA-5exhibited therapeutic effects in fibroblasts from mitochondrial diseases patients with various types of genetic abnormalities. The mechanism of MA-5 was to accelerate the supercomplex formation of F1-Fo ATPase, leading to the ATP synthesis without changing proton gradient. This system hibernates under normal conditions, but when the oxidative phosphorylation pathway is damaged, MA-5 binds with mitofilin/Mic60, accelerating dimer formation, increasing ATP as well as mitochondrial morphology and dynamics.

Therefore, MA-5 might be a novel therapeutic strategy to treat mitochondrial diseases. Clinical trial is now planning with the support of the Japan Agency for Medical Research and Development (AMED).


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Takaaki ABE, M.D., Ph.D.

Position and Affiliation:ProfessorDivision of Medical Science, Tohoku University Graduate School of Biomedical Engineering, Department of Clinical Biology and Hormonal Regulation, Tohoku University Graduate School of Medicine

[Research Interest]・Acute and chronic kidney disease・Mitochondrial medicine・Gut microbiota・podocyte biology

[Biographical Sketch]Takaaki ABE received training in Nephrology and Internal Medicine in Tohoku University at Sendai,

Japan. He developed an interest in neuroscience as a graduate student under Dr. Shigetada Nakanishi, Kyoto University and identified the metabotropic glutamate receptor mGluR5. Then, he moved to the laboratory of Dr. Seteven Hebert, Renal Division of Brigham and Women's Hospital and Harvard Medical School as a post-doctoral fellow supported by JSPS and the Human Frontier Research Program.

He studied and isolated various uremic solute transporters (e.g. SLCO4C1) and their pathophysiological roles in chronic kidney disease (CKD) and now he is an editorial board member of the American Journal of Physiology (Renal Physiology).

Recently, he reported that indole acetic acid found in CKD patients increased erythropoietin production and synthesized its analog mitochonic acid MA-5, which increased cellular ATP and rescued fibroblasts from various mitochondrial disease patients such as Leigh, MELAS, LHON, Kearns-Sayre syndrome. He also found that MA-5 is also effective in the mitochondrial DNA defect disease model “Mitomice” rescuing cardiomyocytes and renal tubular respiration. MA-5 has been nominated as a rare disease drug “seed” by AMED and granted support for a first use in humans within the coming year in Japan.


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------------------ Memo ------------------

Workshop:

Career Development for 　　　 Biomedical Science Researchers


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Reiko Toyama

Position and Affiliation: Program Director Developmental Biology and Structural Variation BranchEunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), NIH

[Research Interest]Vertebrate development and embryologyPineal gland developmentCareer development in biomedical research Science education

[Biographical Sketch]Dr. Toyama obtained her doctoral degree from the University of Tokyo, Japan, in biochemistry. Subsequently, she received her post-doctoral training in molecular biology and developmental biology at NIMH and NICHD. In the following years, she worked as a Staff Scientist at the NICHD. Dr. Toyama studied early vertebrate development and embryology using zebrafish as a model system to understand the molecular mechanisms underlying morphogenesis and organogenesis. Currently, she is responsible for administrating research in the area of embryonic developmental biology, especially in vertebrate organogenesis. In addition to her scientific and administrative duties, she has strong interest in other areas including science education and promoting the careers of women in science.

Poster Sessions


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P-1 Cochlear gene therapy with ancestral AAV in adult mice: complete transduction of inner hair cells without cochlear dysfunctionJun Suzuki1,2,3, Ken Hashimoto1,2,3, Ru Xiao4,5, Luk H. Vandenberghe4,5,6 and M. Charles Liberman1,2

1Department of Otology and Laryngology, Harvard Medical School, 2Eaton-Peabody Laboratories, Massachusetts Eye & Ear Infirmary, 3Department of Otorhinolaryngology-Head and Neck Surgery, Tohoku University Graduate School of Medicine, 4 Grousbeck Gene Therapy Center, Schepens Eye Research Institute and Massachusetts Eye & Ear Infirmary, 5Ocular Genomics Institute, Department of Ophthalmology, Harvard Medical School, 6Harvard Stem Cell Institute, Harvard University

P-2 NRF2 is a key target for prevention of noise-induced hearing loss by reducing oxidative damage of CochleaYohei Honkura1,2, Shohei Murakami2 , Masayuki Yamamoto3, Tetsuaki Kawase1, Yukio Katori1, Hozumi Motohashi2 1Department of Otolaryngology-Head & Neck Surgery, Tohoku University Graduate School of Medicine, 2Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, 3Department of Medical Biochemistry, Tohoku University Graduate School of Medicine

P-3 β-TRCP directs Lipin1 ubiquitination and degradation to promote hepatic lipogenesisSeira Hoshikawa1,2, Asami Watahiki2,3, Hidefumi Fukushima2, Satoshi Fukumoto1,2, Hiroyuki Inuzuka2

1Division of Pediatric Dentistry, 2Division of Center for Advanced Stem Cell and Regenerative Research, and 3Molecular and Regenerative Prosthodontics, Tohoku University Graduate School of Dentistry

P-4 Directional migration of cancer cells in response to a stiffness gradient is potentiated by rapid protrusion and retraction dynamicsBrian J. DuChezNational Institute of Dental and Craniofacial Research, NIH

P-5 Bicarbonate efflux via glutamate transporter triggers astrocyte-to-neuron signalingNaoko Kubo1, Kaoru Beppu1, Niklas Gerkau2, Behrouz Moshrefi2, Christine R. Rose2, and Ko Matsui1

1Division of Interdisciplinary Medical Science, Center for Neuroscience, Tohoku University Graduate school of Medicine, 2Institute for Neurobiology, Faculty of Mathematics and Natural Sciences, Heinrich-Heine-University Duesseldorf

Poster Session 1 (17:20-18:16) Poster Hall 1 Moderators: James F. Battey, NIDCD, NIH Kazuhiko Igarashi, Tohoku University Graduate School of Medicin


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P-6 Fibronectin derived peptides conjugated chitosan matrix promotes neurite outgrowth and cell adhesion via integrin and syndecanKentaro Hozumi, Kyotaro Nakamura, Mari Miyagi, Rika Nagao, Keiko Takasaki, Fumihiko Katagiri, Yamato Kikkawa, Motoyoshi NomizuDepartment of Clinical Biochemistry, Tokyo University of Pharmacy and Life Sciences

P-7 Novel biomarkers dist inguishing pancreat ic head cancer from distal cholangiocarcinoma by proteomicsTsutomu Takenami, Shimpei Maeda, Hideaki Karasawa, Tatsuyuki Takadate, Michiaki UnnoDepartment of Surgery, Tohoku University Graduate School of Medicine

P-8 Synthetic analogs of curcumin as modulators of multidrug resistance-linked ABC transportersMegumi Obara1, Shinobu Ohnuma1, Eduardo E. Chufan2, Masaharu Ishida, Katsuyoshi Kudoh, Norihiko Sugisawa, Takeshi Naitoh, Hiroyuki Shibata3, Yoshiharu Iwabuchi4, Shinobu Ohnuma1 and Suresh V. Ambudkar2, Michiaki Unno1Department of Surgery, Tohoku University Graduate School of Medicine, 2Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, 3Depertment of Clinical Oncology, Akita University Graduate School of Medicine, 4Department of Organic Chemistry, Tohoku University Graduate School of Pharmaceutical Sciences


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P-9 Low-intensity pulsed ultrasound (LIPUS) inhibits proinflammatory cytokine secretion from murine macrophages triggered by E. coli LipopolysaccharideMizuki Suto1, Kentaro Maruyama1, Sousuke Kanaya1,2, Eiji Nemoto1

1Division of Periodontoligy and Endodontology, 2Liaison Center for Innovative Dentistry, Tohoku University Graduate School of Dentistry

P-10 Periodontal bacteria induce the production of MIF-associated neutrophil extracellular traps by human neutrophilsHiroyuki Tada1, Takashi Nishioka2

1Division of Oral Microbiology, 2Division of Oral Diagnosis, Tohoku University Graduate School of Dentistry

P-11 Host kinases in human Influenza virus replicationClyde Dapat and Hitoshi OshitaniDepartment of Virology, Tohoku University Graduate School of Medicine

P-12 Dengue virus type 1 genotype II detected in a Dengue surveillance study in Tarlac, PhilippinesHannah Karen Mina Labayo1, Mariko Saito-Obata1,2, Clyde Dapat1, Michiko Okamoto1, Cecile Lopes-Zuasula3, Edewisa Mercado2, Inez Medado2, Ava Kristy Sy2, Socorro Lupisan2, Rosario Capeding2 , Hitoshi Oshitani1

1Tohoku University, Sendai, Japan, 2Research Institute of Tropical Medicine, Manila, Philippines, 3Tarlac Provincial Hospital, Tarlac city, Philippines

P-13 The new norovirus GII typing assay amplifying polymerase-and capsid-regionsHang Xu, Xiaofang Liu Kentaro Tohma Yoshifumi Masago, Daisuke Nakayama, Yasuko Kayama, Kazuhisa Kawamura, Takafumi Manaka, Robert H. Gilman, Holger Mayta, Amado O. Tandoc III, Edelwisa S. Mercado, Mayuko Saito, Tatsuo Omura, Hitoshi Oshitani for Norovirus Working GroupDepartment of Virology, Tohoku University Graduate School of Medicine, New Industry Creation Hatchery Center, Tohoku University, Nakayama Clinic, Kayama Pediatric Clinic, Kawamura Pediatric Clinic, Department of International Health, Johns Hopkins School of Public Health, Department of Cellular and Molecular Sciences, Universidad Peruana Cayetano Heredia, Research Institute for Tropical Medicine

Poster Session 2 (17:20-18:02) Poster Hall 1 Moderators: Kim Y. Green, NIAID, NIH Hitoshi Oshitani, Tohoku University Graduate School of Medicine


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P-14 Autophagic maintenance of intestinal homeostatic responses to enteric bacteria in DrosophilaHiroki Nagai, Tamaki Yano and Shoichiro KurataMolecular genetics, Graduate school of Pharmaceutical Science, Tohoku University, Japan


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P-15 A novel regulatory role for TRAF2 and TRAF5 in the IL-6-driven Th17 developmentHiroyuki Nagashima1, Yuko Okuyama1, Takaya Hayashi1, Naoto Ishii1, Takanori So1

1Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine

P-16 BCR-ABL inactivates the enhancer of the Irf8 gene and represses its expression.Haruka Sasaki1, Akira Nishiyama1, Shin-ichi Koizumi2, Jun Nakabayashi1, 3, Naofumi Kaneko1, Tomohiko Tamura1, 3

1Department of Immunology, Yokohama City University Graduate School of Medicine, 2Immune Signal Unit, Okinawa Institute of Science and Technology Graduate University, 3Advanced Medical Research Center, Yokohama City University

P-17 CD103+CD11b− salivary gland dendritic cells have antigen cross-presenting capacityLu Lu1,2, Yukinori Tanaka1,3, Naoto Ishii4, Takashi Sasano2 and Shunji Sugawara1

1Division of Oral Immunology, Department of Oral Biology, 2Division of Oral Diagnosis, Department of Oral Medicine and Surgery, 3Division of Pediatric Dentistry, Department of Oral Health and Development Sciences, Tohoku University Graduate School of Dentistry, 4Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine

P-18 Fasting regulates NLRP3 inflammasome activation in humans by modulating mitochondrial integrityJavier TrabaCardiovascular and Pulmonary Branch, National Heart Lung and Blood Institute, NIH

P-19 A Bach2-Cebp gene regulatory network for the commitment of multipotent hematopoietic progenitorsAri Itoh-Nakadai, Kazuhiko IgarashiDepartment of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University

PPoster Session 3 (17:20-18:44) Poster Hall 1 Moderators: Warren Strober, NIAID, NIHWarren J. Leonard, NHLBI, NIHTakanori So, Tohoku University Graduate School of Medicine


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P-20 Bach2 keeps homeostasis in lung by maintaining the function of alveolar macrophages in inflammatory environmentRisa Ebina-Shibuya1,2, Mitsuyo Matsumoto1, Makoto Kuwahara3, Kyoung-Jin Jang4,5, Manabu Sugai4,5, Yoshiaki Ito6, Ryo Funayama7, Keiko Nakayama7, Yuki Sato1, Naoto Ishii8, Yasunobu Okamura9, Kengo Kinoshita9, Kohei Kometani10,14, Tomohiro Kurosaki10,11, Akihiko Muto1, Masakazu Ichinose2, Masakatsu Yamashita3, Kazuhiko Igarashi1,12,13

1Department of Biochemistry, Tohoku University Graduate School of Medicine, 2Department of Respiratory Medicine, Tohoku University Graduate School of Medicine, 3Department of Immunology, Graduate School of Medicine, Ehime University, 4Department of Experimental Therapeutics, Institute for Advancement of Clinical and Translational Science, Kyoto University Hospital, 5Division of Molecular Genetics, Department of Biochemistry and Bioinformative Sciences, School of Medicine, University of Fukui, 6Cancer Stem Cells and Biology Programme, Cancer Science Institute of Singapore, National University of Singapore, 7Department of Cell Proliferation, United Center for Advanced Research and Translational Medicine, Tohoku University Graduate School of Medicine, 8Department of Immunology, Tohoku University Graduate School of Medicine, 9Graduate School of Information Sciences, Tohoku University, 10RIKEN Center for Integrative Medical Sciences, 11WPI Immunology Frontier Research Center, Osaka University, 12Center for Regulatory Epigenome and Diseases, Tohoku University Graduate School of Medicine, 13AMED-CREST, Japan Agency for Medical Research and Development, 14Present addresses: Department of Cellular and Molecular Immunology, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany

P-21 Insufficiency of NOD1 leads to Helicobacter pylori-induced gastric intestinal metaplasia through induction of Cdx2Naoki Asano1,2, Akira Imatani1, Tomohiro Watanabe2,3, Jun Fushiya, Yutaka Kondo1, Xiaoyi Jin1, Tetsuhiko Mikami1, Takeshi Kanno1, Waku Hatta1, Nobuyuki Ara1, Kiyotaka Asanuma1, Tomoyuki Koike1, Warren Strober2, Tooru Shimosegawa1

1Division of Gastroenterology, Tohoku University Graduate School of Medicine, 2Mucosal Immunity Section, NIAID, NIH, 3Department of Gastroenterology and Hepatology, Kindai University Faculty of Medicine

P-22 The role of IRF8 in innate immune defense against nontuberculous mycobacteria infectionSumihito Togi, Bachu Mahesh, Bo Yan, Vishal Nehru, Misa Togi, Masashi Matsuyama, Shamira Shallom, Adrian Zelazny, Katrin Mayer-Barber, Steven Holland, Keiko OzatoNIH/NICHD

P-23 Investigation of the role of iron in gene expression regulations during erythropoiesisHiroki Kato1,2, Masahiro Kobayashi2, Tohru Fujiwara2, Akihiko Muto1, Yukihiro Inoguchi3, Kenji Ichiyanagi3, Hiroyuki Sasaki3, Hideo Harigae2 and Kazuhiko Igarashi1

1Department of Biochemistry, Tohoku University Graduate School of Medicine, 2Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, 3Division of Epigenomics and Development, Medical Institute of Bioregulation, Kyushu University


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P-24 Immunoregulatory receptor LILRB4 on plasmablasts is related to autoantibody production in SLEMasanori Inui1, Akiko Sugahara-Tobinai1, Ari Itoh-Nakadai1, Hiroshi Fujii2, Tomonori Ishii2, Toshiyuki Takai1

1Depertment of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University, 2Depatment of Hematology and Rheumatology, Tohoku University Graduate School of Medicine

P-25 Expression of gp49B on plasma cells from autoimmune-prone mice and its relevance to progression of autoimmune diseaseYi Li Wong, Masanori Inui, Toshiyuki TakaiDepartment of Experimental Immunology, Institute of Development, Aging and Cancer, Tohoku University

P-26 OX40 binding and regulation of T cell activation by the scaffolding IQGAP1 proteinYuko Okuyama1, Hiroyuki Nagashima1, Masuko Ushio-Fukai2, Michael Croft3, Naoto Ishii1, and Takanori So1

1 Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, 2 Department of Pharmacology, University of Illinois at Chicago, 3 Division of Immune Regulation, La Jolla Institute for Allergy and Immunology


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P-27 Evaluation of Biobank Sample Correctness in Tohoku Medical Megabank OrganizationHisaaki Kudo1, Kaname Kojima1, Riu Yamashita1, Yosuke Kawai1, Takahiro Nobukuni1, Ichiko Nishijima1, Noriko Ishida1, Takahiro Terakawa1, Atsushi Hozawa1, Kozo Tanno2, Soichi Ogishima1, Mamoru Sato2, Atsushi Shimizu2, Makoto Sasaki2, Masao Nagasaki1, Masayuki Yamamoto1, Naoko Minegishi1, and the Tohoku Medical Megabank Project Study Group1,2 1Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan, 2Iwate Tohoku Medical Megabank Organization, Iwate Medical University, Yahaba-cho, Japan

P-28 Genome-wide genotype imputation of Japanese population-specific SNP arrayYosuke Kawai, Takahiro Mimori, Kaname Kojima, Naoki Nariai, Inaho Danjoh, Rumiko Saito, Jun Yasuda, Masayuki Yamamoto, Masao Nagasaki and the Tohoku Medical Megabank Project Study Group Tohoku Medical Megabank Organization, Tohoku University

P-29 Association study of rare variants on serum urate level by using whole genome cohort study samplesKazuharu Misawa1, Takanori Hasegawa2, Kaname Kojima1, Atsushi Hozawa1, Takako Takai-Igarashi1, Naoko Minegishi1, Jun Yasuda1, Soichi Ogishima1, Shigeo Kure1, Kengo Kinoshita1, Masayuki Yamamoto1, and Masao Nagasaki1

1Tohoku Medical Megabank Organization, Tohoku University, Japan, 2Human Genome Center, Institute of Medical Science, University of Tokyo, Japan

P-30 The association between the history of hypertensive disorders of pregnancy, obesity and hypertension in later life by age group: A cross-sectional analysisMaiko Wagata1,2, Naoki Nakaya1, Naho Tsuchiya1, Tomohiro Nakamura1, Hirohito Metoki1, Nobuo Yaegashi1,2, Shigeo Kure1, Masayuki Yamamoto1, Shinichi Kuriyama1, Atsushi Hozawa1, Junichi Sugawara1, 2

1 Tohoku Medical Megabank Organization, Tohoku university, 2 Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine

Poster Session 4 (17:20-18:37) Poster Hall 1 Moderators: Teri A. Manolio, NHGRI, NIH Steven Kleeberger, Immunity, NIEHS, NIH


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P-31 Clinical and Demographic Evaluation of a Holoprosencephaly Cohort from the Kyoto Collection of Human EmbryosYu Abe1, Paul Kruszka1, Ariel F. Martinez1, Erich Roessler1, Kohei Shiota2, Shigehito Yamada2, Maximilian Muenke1 1National Human Genome Research Institute, National Institutes of Health, Bethesda, US, 2Congenital Anomaly Research Center, Kyoto University Graduate School of Medicine, Kyoto, Japan

P-32 Potentially translated ‘non-coding’ RNAs in human and their biological functionsRiu Yamashita3, Akinobu Matsumoto1, Alessandra Pasut1, Masaki Matsumoto2, Jacqueline Fung1, Emanuele Monteleone1,4, Alan Saghatelian5, Keiichi I. Nakayama2, John G. Clohessy1, Pier Paolo Pandolfi1 1Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA., 2Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan., 3Department of Integrative Genomics, Tohoku Medical Megabank Organization (ToMMo), Tohoku University School of Medicine, Tohoku University, Sendai, JAPAN, 4Molecular Biotechnology Center and Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy., 5Department of Chemistry and Chemical Biology, Harvard University, USA.

P-33 Paneth Cell Phenotype is Associated with Novel Genetic Determinants and Clinical Outcome in Japanese Crohn's Disease PatientsTakeo Naito1, Ta-Chiang Liu2, Yoichi Kakuta1, Richard Head2, Zhenqiu Liu3, Talin Haritunians3, Dalin Li3, Katsuya Endo4, Yoshitaka Kinouchi4, Dermot P.B. McGovern3, Thaddeus S. Stappenbeck2, Tooru Shimosegawa1

1Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan, 2Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA, 3F. Widjaja Family Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA, 4Tohoku University, Health Administration Center, Center for the Advancement of Higher Education, Sendai, Japan

P-34 Identification of somatic genetic alterations in ovarian clear cell carcinomas with next generation sequencingYusuke Shibuya1, Sakae Saito2, Kaname Kojima2, Bin Li1, Hideki Tokunaga1, Masao Nagasaki2, Jun Yasuda2, Nobuo Yaegashi1 1Department of Obstetrics and Gynecology, Tohoku University Hospital, 2Department of Integrative Genomics, Tohoku Medical Megabank Organization


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P-35 The μ-opioid receptor gene polymorphism c.118A>G may influence negative emotions among Japanese populationYumiko Kubo1,2, Hikaru Takeuchi3, Yoshie Kikuchi2, Chiaki Ono2, Yoshiyuki Kasahara1,2, Zhiqian Yu1, 2, Shuken Boku4, Akitoyo Hishimoto4, Ichiro Sora4, Yasuyuki Taki5, 6, Ryuta Kawashima3, 7, Hiroaki Tomita1, 2, 6 1Department of Disaster Psychiatry, Tohoku University Graduate School of Medicine; 2Department of Disaster Psychiatry, International Research Institute of Disaster Science, Tohoku University; 3Division of Developmental Cognitive Neuroscience, Institute of Development, Aging and Cancer, Tohoku University; 4Department of Psychiatry, Kobe University Graduate School of Medicine; 5Department of Nuclear Medicine and Radiology, Institute of Development, Aging and Cancer, Tohoku University; 6Tohoku Medical Megabank Organization, Tohoku University; 7Smart Ageing International Research Center, Institute of Development, Aging and Cancer, Tohoku University

P-36 Aberrant DNA methylation of apoptosis-inducing Gene X plays a key role in human prostate cancerToshiya Miyauchi1, Akira Horii1, Teppei Okubo2, Koji Mitsuzuka2, Yoichi Arai2, and Shinichi Fukushige1,3 Departments of 1Molecular Pathology, 2Urology, and 3Center for Regulatory Epigenome and Diseases, Tohoku University School of Medicine, Sendai, Japan

P-37 Genetic Analyses in Four Pedigrees with Hereditary Pheochromocytoma/Paraganglioma Syndrome (HPPS)Mie Yamanaka1, Sho Fujiwara1, Kiyoto Shiga3, Takenori Ogawa2, Noriko Kimura4, Akira Horii1 Departments of 1Molecular Pathology and 2Otolaryngology-Head and Neck Surgery, Tohoku University School of Medicine, 3Department of Otolaryngology and Head and Neck Surgery, Iwate Medical University School of Medicine, 4Department of Clinical Research, Pathology division, National Hospital Organization, Hakodate Hospital


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P-38 Muse cells can differentiate into atrial and ventricular cardiomyocyte-like cells by Cardiotrophin-1-dependent cytokine InductionMohamed Amin1,3, Yoshihiro Kushida1, Shohei Wakao1, Kazuki Tatsumi1,2, Mari Dezawa1

1Dept. Stem Cell Biology and Histology, Tohoku Univ. Graduate School of Medicine, Sendai, Japan., 2Tohoku Laboratory Non-clinical Research Division, Clio, Inc., Sendai, Japan., 3Dept. Clinical Biochemistry, Faculty of Pharmacy, Mansoura Univ.,Mansoura, Egypt.

P-39 Actin dynamics and endosome formation are essential for transduction of primary cilium-derived signalingMasaki Saito, Takeya Sato, Teruyuki YanagisawaDepartment of molecular Pharmacology, Tohoku University Graduate School of Medicine

P-40 Evaluation of corrosion damage on stainless steel surgical instruments caused by cleaning solutions: An electrochemical studyMary Kanyi1, Masatoshi Takahashi1, Hanako Sakatsume1, Yoshiaki Saiki1, Mitsuo Kaku1, Shiro Endo1, Teiji Tominaga1, Atsuhiro Nakagawa1, Atsushi Kikuchi2, Yukyo Takada1

1Tohoku University, Sendai, Japan, 2KEDC Co. Ltd. Sendai, Japan

P-41 Characterization of the DsRed reporter transgene expression for Doublecortin in the inner earXiaoyi Li, Rafal Olszewski, Soumya Korrapati, Michael HoaAuditory Development and Restoration Program, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MD 20892, USA.

P-42 Fin morphology is regenerated by a combination of the different growth period and the different growth rate between fin regions in zebrafish caudal finToshiaki Uemoto, Gembu Abe, Koji Tamura

Graduate school of life sciences, Tohoku University

P-43 Effect of IL-18 on mechanical loading-induced osteoclastogenesis and bone resorptionOchi Y, Kitaura H, Kimura K, Ishida M, Sugisawa H, Saeed J, Kishikawa A, Qi J, Takano-Yamamoto T.Tohoku University Graduate School of Dentistry Division of Orthodontics and Dentofacial Orthopedics

Poster Session 5 (17:20-18:23) Poster Hall 1 Moderators: Matthew P. Hoffman, NIDCR, NIH Kazuhiro Nagata, Kyoto Sangyo University


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P-44 A signaling independent of Wnt/GSK3β signaling is required for Wnt3a-mediated dental follicle differentiationYukihiko Sakisaka1, Sousuke Kanaya1,2, Takashi Nakamura3, Masato Tamura4, Hidetoshi Shimauchi1, and Eiji Nemoto1

1Department of Periodontology and Endodontology, 2Liason Center for Innovative Dentistry, and 3Department of Dental Pharmacology, Tohoku University Graduate School of Dentistry, Sendai, Japan, 4Department of Biochemistry and Molecular Biology, Hokkaido University Graduate School of Dentistry, Sapporo, Japan

P-45 Teneurin-4 is a transmembrane protein regulating myelination by oligodendrocytes in the central nervous systemNobuharu Suzuki1,2, Chikako Hayashi1, Naomi Kikura1, Mai Hyodo1, Yo Mabuchi1, Susana de Vega2,3, Eri Arikawa-Hirasawa4, Yoshihiko Yamada2, and Chihiro Akazawa1

1Department of Biochemistry and Biophysics, Graduate School of Health Care Sciences, Tokyo Medical and Dental University, 2The Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland, USA, 3Department of Pathophysiology for Locomotive and Neoplastic Disease and Department of Pathology and Oncology, School of Medicine, Juntendo University, and 4Research Institute for Diseases of Old Age and Department of Neurology, Faculty of Medicine, Juntendo University

P-46 Sex differences of CRF-expressing neurons in the bed nucleus of the stria terminalis of the mouseHiroko Otsuka1, Katsuya Uchida1, Masahiro Morisita2, Shinji Tsukahara2, Toshimitsu Fuse1, Yuto Kagotani1, Satoshi Yamagata1, Tatsuya Sato1, Manabu Abe3, Kenji Sakimura3, Keiichi itoi1,4

1Laboratory of Information Biology, Graduate School of Information Sciences, Tohoku University, 2 Area of Regulatory Biology, Division of Life Science, Graduate School of Science and Engineering, Saitama University, 3Department of Cellular Neurobiology, Brain Research Institute, Niigata University, 4Department of Neuroendocrinology, Graduate School of Medicine, Tohoku University


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P-47 Stepwise and mutual activation between distal enhancer and proximal promoter in the induction of cell differentiation-related genesAkira Nishiyama1, Jun Nakabayahi2, Kentaro Fushimi1, Tomohiko Tamura1,2

1Department of Immunology, Yokohama City University Graduate School of Medicine, Yokohama, Japan, 2Advanced Medical Research Center Yokohama City University, Yokohama, Japan

P-48 Isolation and characterization of the earliest dendritic cell-primed progenitorsDaisuke Kurotaki1, Wataru Kawase1, Jun Nakabayashi2, Herbert C. Morse III3, Keiko Ozato4, Yutaka Suzuki5, and Tomohiko Tamura1,2

1Department of Immunology, Yokohama City University Graduate School of Medicine, Japan; 2Advanced Medical Research Center, Yokohama City University, Japan, 3Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, NIH, USA, 4Program in Genomics of Differentiation, Eunice Kennedy Shriver National Institute of Child Health and Human development, NIH, USA, 5Department of Computational Biology and Medical Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Japan

P-49 Regulatory mechanism of spindle assembly checkpoint by mitotic kinase Plk1 and its role in mitotic progressionMasanori Ikeda and Kozo TanakaDepartment of Molecular Oncology, Institute of Development, Aging and Cancer, Tohoku University

P-50 Centrosomal kinase Aurora A is required for the robust system of equal chromosome segregationKenji Iemura, Kozo TanakaDepartment of Molecular Oncology, Institute of Development, Aging and Cancer, Tohoku University

P-51 Defects in efficient chromosome alignment cause chromosomal instabilityKinue Kuniyasu, Kenji Iemura, Kozo TanakaDepartment of Molecular Oncology, Institute of Development, Aging and Cancer, Tohoku University

P-52 The significance of spatio-temporal control of SAM synthesis by methionine adenosyltransferase 2A in epigenetic gene expressionNguyen Chi Long, Kazuhiko IgarashiDepartment of Biochemistry, Tohoku University

Poster Session 6 (17:20-18:09) Poster Hall 1 Moderators: Keiko Ozato, NICHD, NIH Keiko Nakayama, Tohoku University Graduate School of Medicine


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P-53 winged eye induces cell fate conversion of Drosophila imaginal disc in concert with a histone methylaseKeita Masuko, Naoyuki Fuse, Shoichiro KurataMolecular Genetics., Graduate school of Pharmaceutical Science., Tohoku University, Japan


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P-54 Metabotropic glutamate receptor 1 promotes cementoblast proliferation via MAP kinase signaling pathwaysHidehiro Komatsu1, Sousuke Kanaya1,2, Hidetoshi Shimauchi1 and Eiji Nemoto1

1Department of Periodontology and Endodontology, and 2Liaison Center for Innovative Dentistry, Tohoku University Graduate School of Dentistry, Sendai, Japan

P-55 TBC1D12 is a novel Rab11-binding protein that modulates neurite outgrowth in PC12 cellsMai E. Oguchi, Kenta Noguchi, Mitsunori FukudaLaboratory of Membrane Trafficking Mechanisms, Department of Developmental Biology and Neurosciences, Graduate School of Life Sciences, Tohoku University

P-56 Is the pre-post ratio of motor projection dependent on the number of competitors? ‒ a quantitative connectomics studyTakahiro Takahashi, Hiromu YawoDepartment of Developmental Biology and Neurosciences, Tohoku University Graduate School of Life Sciences

P-57 Quantitative analysis of chondrogenic patterning in cell culture of developing limb mesenchymeKeiichi Kitajima1, Naofumi Kawahira2, Gembu Abe1, Yoshihiro Morishita2, Koji Tamura1

1Graduate school of life science, University of Tohoku, 2RIKEN Quantitative Biology Center

P-58 Extracellular calcium increases gene expression of fibroblast growth factor-2 via a PKA and ERK1/2 pathway in mouse dental papilla cellsBinlu Xiao1, Sousuke Kanaya1,2, Yukihiko Sakisaka1, Mizuki Suto1, Kentaro Maruyamaa, Masahiro Saito3, and Eiji Nemoto1,2

1Department of Periodontology and Endodontology, Tohoku University Graduate School of Dentistry, 2Liaison Center for Innovative Dentistry, Graduate School of Dentistry, Tohoku University, 3Division of Operative Dentistry, Department of Restorative Dentistry, Tohoku University Graduate School of Dentistry

Poster Session 7 (17:20-18:30) Poster Hall 1 Moderators: Yoshihiko Yamada, NIDCR, NIH Mitsunori Fukuda, Tohoku University Graduate School of Life Sciences


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P-59 Hydroxyapatite plus phosphatidylserine-containing liposomes induce bone repair in rat calvarial defectsJunko Hatakeyama1, Hisashi Anan1, Noriyoshi Matsumoto1, Fumiko Takayama2, Zhou Wu2, Etsuko Matsuzaki1, Tadahiko Minakami1, Yuji Hatakeyama3, Toshio Izumi1, Hiroshi Nakanishi2

1Departments of Operative Dentistry and Endodontology, Fukuoka Dental College, Fukuoka, Japan, 2Departments of Aging Science and Pharmacology, Faculty of Dental Science, Kyushu University, Fukuoka, Japan, 3Departments of Molecular Cell Biology and Oral Anatomy, Fukuoka Dental College, Fukuoka, Japan

P-60 The effect of oxygen supply and incorporation of calcium phosphate microparticles into 3-D cellular aggregates for bone tissue engineeringTomoya Sato, Takahisa Anada, Takuo Kamoya, Yukari Shiwaku, Kaori Tsuchiya, Teruko Takano-Yamamoto, Keiichi Sasaki, Osamu SuzukiTohoku University Graduate school of Dentistry, Sendai, Japan

P-61 The mechanisms of osteoblast differentiation and proliferation stimulated by zinc in MC3T3-E1 cells.Takashi Yoshida1, Mengkai Guang1,2, Takashi Nakamura1 and Minoru Wakamori1

1Division of Molecular Pharmacology and Cell Biophysics, Department of Oral Biology, Graduate School of Dentistry, Tohoku University, 2Department of Oral Implantology, State Key Laboratory of Oral Diseases, West China College of Stomatology, Sichuan University,

P-62 Preparation of a novel biomaterial using polyion complex matrixJun Kumai, Kyotaro Nakamura, Chikara Fujimori, Fumihiko Katagiri, Kentaro Hozumi, Yamato Kikkawa and Motoyoshi Nomizu.Department of Clinical Biochemistry, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences Hachiouji-si, Tokyo, Japan

P-63 The novel bisphosphonate, [4- (methylthio) phenylthio] methanebisphosphonate facillitates bone formation by local administration to the alveolar bone in ratsAiko Takizawa, Mirei Chiba, Yuka Narusawa, Makoto Nishimura, Takeru Ota, Mayumi Yasuda, Keiko Suzuki, Takuya Kanemitsu, Takashi Itoh, Haruhide Hayashi, Kaoru Igarashi, Hisashi ShinodaDivision of Oral Physiology, Department of Oral Function and Morphology, Graduate School of Dentistry, Tohoku University, Sendai, Japan.


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P-64 Anti-tumor activities of ceramide nanoliposomes in ovarian cancerXuewei Zhang1, Kazuyuki Kitatani1,2, Masafumi Toyoshima1, Masumi Ishibashi1, Toshinori Usui2, Junko Minato1, Shogo Shigeta1, Nobuo Yaegashi1,2

1Department of Obstetrics and Gynecology, Tohoku University Graduate School of Medicine, Tohoku University, 2Tohoku Medical Megabank Organization, Tohoku University

P-65 Acceptance of systemic chemotherapy at lung metastasisAriunbuyan Sukhbaatar, Sachiki Horie, Shiro Mori, Kodama Tetsuya, Tetsu TakahashiGraduate School of Dentistry, Tohoku University, 4-1 Seiryo, Aoba, Sendai, Japan

P-66 Construction of tetracycline-inducible progesterone receptor A and B expression in lung neuroendocrine tumor cell modelTeeranut Asavasupreechar 1,2, Hironobu Sasano2, Viroj Boonyaratanakornkit 1

1Clinical Biochemistry and Molecular Medicine Program, Clinical Chemistry Department, Faculty of Allied Health Sciences, Chulalongkorn University, Bangkok Thailand, 2Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan.

P-67 Functional analysis of BAP1 in intrahepatic cholangiocarcinomaKentaro Ishii, Masaharu Ishida, Shinobu Ohnuma, Katsuyoshi Kudoh, Fuyuhiko Motoi, Takeshi Naitoh, Michiaki UnnoDepartment of Surgery, Tohoku University Graduate School of Medicine

P-68 Aging aggravates alcoholic liver injury and fibrosis in mice by downregulating sirtuin1 expression in the liverTeresa Ramirez1*, Yong-Mei Li1*, Shi Yin1,3*, Ming-Jiang Xu1, Dechun Feng1, Zhou Zhou1, Mengwei Zang4, Partha Mukhopadhyay5, Zoltan V. Varga5, Pal Pacher5, Bin Gao1,Hua Wang1,2

1Laboratory of Liver Diseases, National Institutes of Health, National Institute on Alcohol Abuse and Alcoholism, Bethesda, MD, 20892, USA; 2Department of Oncology, The First Affiliated Hospital, Institute for Liver Diseases of Anhui Medical University, Hefei, 230032, China; 3Departmentof Geriatrics, Affiliated Provincial Hospital of Anhui Medical University, China; 4Barshop Institute for Longevity and Aging Studies, Department of Molecular Medicine, University of Texas Health Science Center at San Antonio, TX, 78229, USA; 5Laboratory of Cardiovascular Physiology and Tissue Injury, NIAAA, NIH, Bethesda, MD 20892, USA

Poster Session 8 (17:20-18:23) Poster Hall 1 Moderators: Shioko Kimura, Laboratory of Metabolism, CCR, NCI, NIH Keiichi Itoi, Tohoku University Graduate School of Information Sciences


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P-69 Role of GPCR and β-arrestin signaling in skeletal muscle metabolism.Jaroslawna MeisterMolecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD 20892, USA

P-70 β-TrCPs in Sertoli cell are required for spermatogenesisAkane Morohoshi, Tadashi Nakagawa, Seiji Nakano, Keiko NakayamaDivision of Cell proliferation, Graduate School of Medicine, Tohoku University

P-71 The post-translational modification of microtubules mediates angiogenic signalingMiho Kobayashi, Yasuhiro Suzuki, Yasufumi SatoDepartment of Vascular Biology, IDAC, Tohoku University

P-72 Roles of OLA1 in DNA damage-induced centrosome amplificationHuicheng Qi, Zhenzhou Fang, Yuki Yoshino, Natsuko ChibaDepartment of Cancer Biology, Institute of Development, Aging and Cancer, Tohoku University


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P-73 Identification of biomarkers for a more individualized therapy for triple negative breast cancer patientsGuestini Fouzia1*; Keely May McNamara1; Katsuhiko Ono1; Minoru Miyashita1; Takanori Ishida1; Noriaki Ohuchi1; Saki Nakagawa1; Hisashi Hirakawa1; Kentaro Tamaki3; Yasuyo Oi4; Yoshiaki Rai4; Yoshiaki Sagara4; Hironobu Sasano1

1Tohoku University, 2Tohoku Kosai Hospital, 3Nahanishi Clinic, 4Sagara Hospital

P-74 MK2461, a Multitargeted Kinase Inhibitor, Suppresses the Progression of Pancreatic Cancer by Disrupting the Interaction Between Pancreatic Cancer Cells and Stellate CellsKoetsu Inoue1, Hideo Ohtsuka1, Masanori Tachikawa2, Fuyuhiko Motoi1, Masahiro Shijo1, Daisuke Douchi1, Shuhei Kawasaki1, Kei Kawaguchi1, Kunihiro Masuda1, Koji Fukase1, Takeshi Naitoh1, Michiaki Unno1, Tetsuya Terasaki2

1Tohoku University Graduate School of Medicine, Department of Surgery, 2Tohoku University Graduate School of Pharmaceutical Sciences

P-75 Significance of the androgen receptor in triple negative breast cancer patients treated with neoadjuvant chemotherapyFreeha Khalid, Fouzia Guestini; Keely May McNamara, Hironobu SasanoDepartment of Anatomic Pathology, Tohoku University Graduate School of Medicine

P-76 OLFM4 immunolocalization in breast carcinoma as a potent prognostic predictorAkifumi Mayama1,2, Hiroyoshi Suzuki2, Kiyoshi Takagi1, Yoshiaki Onodera3, Yasuhiro Miki3, Takanori Watanabe4,

Kazuhiro Sakamoto5, Ryuichi Yoshida6, Takanori Ishida7, Hironobu Sasano3,8 Takashi Suzuki1

Departments of 1Pathology and Histotechnology, 3Anatomic Pathology, and 7Surgical Oncology, Tohoku University Graduate School of Medicine, Sendai, Japan., Departments of 2Pathology and Laboratory Medicine and 4Breast Surgery, National Hospital Organization Sendai Medical Center, Sendai, Japan, Departments of 5Pathology Medicine and 6Breast Surgery, Osaki Citizen Hospital, Osaki, Japan, 8Department of Pathology, Tohoku University Hospital, Sendai, Japan

P-77 Involvement of orphan nuclear receptor COUP-TFII in development of therapeutic resistance to erlotinib in non-small cell lung carcinomaSamaneh Yazdani1, Yasuhiro Miki1, Shuko Hata1, Hironobu Sasano1,2

1Department of Pathology, Tohoku University Graduate School of Medicine, 2Department of Pathology, Tohoku University Hospital, Sendai, Japan

Poster Session 9 (17:20-18:30) Poster Hall 1 Moderators: Reiko Toyama, NICHD, NIHTakashi Takahashi, Graduate School of Medicine, Nagoya University


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P-78 Influence of cancer associated fibroblasts (CAFs) on tumor immunity in lung adenocarcinomaChihiro Inoue1, Yasuhiro Miki2, Ryoko Saito1, Shuko Hata3, Hironobu Sasano1

1Department of Anatomic Pathology, Tohoku University Graduate school of Medicine. , Department of Disaster Obstetrics and Gynecology, International Research Institute of Disaster Science (IRIDeS), Tohoku University., 3Department of Pathology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University

P-79 IL-6 and HGF derived from Cancer-associated fibroblasts induced androgen synthetic enzymes expression in estrogen receptor negative breast cancerKoyko Kikuchi1, Keely May McNamara1, Yasuhiro Miki2, Ju-Yeon Moon3, Man-Ho Choi3, Fumiya Omata1, Minako Sakurai1, Yoshiaki Onodera1, Yoshiaki Rai4, Yasuyo Ohi4, Yasuaki Sagara4, Minoru Miyashita5, Takanori Ishida5, Noriaki Ohuchi5 and Hironobu Sasano1

1Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan, 2Department of Disaster Obstetrics and Gynecology, International Research Institute of Disaster Science (IRIDeS), Tohoku University, Sendai, Japan, 3Molecular Recognition Research Center, Korea Institute of Science and Technology, Seoul, Korea, 4Sagara Hospital, Social Medical Corporation Hakuaikai, Kagoshima, Japan, 5Department of Surgery, Tohoku University School Graduate of Medicine, Sendai, Japan

P-80 Generation and application of CRF neuron-selective channelrhodopsin-2 expressing mouseSatoshi Yamagata1, Isumi Akiba1, Tatsuya Sato1, Katsuya Uchida1, Li Zhou3, Rie Natsume3, Manabu Abe3, Kenji Sakimura3, Keiichi Itoi1, 2

1Laboratory of Information Biology, Graduate School of Information Sciences, Tohoku University, 2Department of Neuroendocrinology, Graduate School of Medicine, Tohoku University, 3Department of Cellular Neurobiology, Brain Research Institute, Niigata University

P-81 S100A10 is playing an important role in progression of human lung cancerKimiaki Sato1,2, Masaki Makita2, Kazumori Arai3, Yuriko Saiki2, Akira Sakurada1, Yoshinori Okada1, Akira Horii2

Departments of 1Thoracic Surgery and 2Molecular Pathology,Tohoku University School of Medicine, Sendai, Japan., 3Department of Pathology, Shizuoka General Hospital, Shizuoka, Japan

P-82 Examination of steroid signatures in breast cancer and their association with traditional classificationsKeely May McNamara1, Ju-Yeon Moon2, Hironobu Sasano1, Man-Ho Choi2

1Department of Anatomical Pathology, Tohoku University School of Graduate Medicine, Sendai, Japan, 2Molecular Recognition Research Center, Korea Institute of Science and Technology, Seoul, Korea


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P-83 The role of fragile X mental retardation protein (FMRP) and its mRNA targets in brain developmentCristine R. Casingal, Takako Kikkawa, Hitoshi Inada, Noriko OsumiDepartment of Developmental Neuroscience, United Center for Advanced Research and Translational Medicine (ART), Tohoku University Graduate School of Medicine

P-84 Exploring the role of Fabp7 and essential polyunsaturated fatty acids on astrocyte proliferation as a contributor to mental disordersInês dos Reis, Hitoshi Inada and Noriko OsumiDepartment of Developmental Neuroscience, Tohoku University Graduate School of Medicine

P-85 Inspection using fMRI of the suppressant effect to envy and schadenfreude by the self-esteem improvement through the recollection of ‘the rest experience with others’Shohei Yamazaki, Motoaki Sugiura, Kelssy H. dos S. Kawata, Yukako Sasaki, Rui Nouchi, Kohei Sakaki, Shigeyuki Ikeda, Ryuta KawashimaInstitute of Development, Aging and Cancer, Dept. Human Brain Science, Tohoku University

P-86 The relevant nuclei of Parkinson’s disease were elucidated by the quantitative activation-induced manganese-enhanced MRISatomi Kikuta1,2, Yukiyo Nakamura3, Yukio Yamamura3, Yuchio Yanagawa4, Noriyasu Homma1,5, Hajime Tamura1, Jiro Kasahara3, Makoto Osanai1, 5

1 Tohoku University Graduate School of Medicine, 2 JSPS Research Fellow, 3 Graduate School and Faculty of Pharmaceutical Science, Tokushima University, 4 Gunma University Graduate School of Medicine, 5 Graduate School of Biomedical Engineering, Tohoku University

P-87 Nutrient-driven O-GlcNAc cycling impacts Neurodevelopmental Timing and MetabolismStephanie Olivier-van stichelen , Peng Wang , Joshua W Ohde, Marcella E comly, Dona C Love , John A. HanoverNIDDK, National Institutes of Health

Poster Session 10 (17:20-18:37) Poster Hall 2 Moderators: Kathleen R. Merikangas, NIMH, NIHNoriko Osumi, Tohoku University Graduate School of Medicine


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P-88 A Varp-binding protein, RACK1, regulates dendrite outgrowth through stabilization of Varp protein in melanocytesSoujiro Marubashi1, Norihiko Ohbayashi1,2, Mitsunori Fukuda1

1Laboratory of Membrane Trafficking Mechanisms, Department of Developmental Biology and Neurosciences, Graduate School of Life Sciences, Tohoku University, 2Department of Physiological Chemistry, Faculty of Medicine and Graduate School of Comprehensive Human Sciences, University of Tsukuba

P-89 Effect of ALS-related VCP mutants on cytosolic TDP-43 aggregationYujiao Yu, Tadashi Nakagawa and Keiko NakayamaDivision of Cell Proliferation, Tohoku University Graduate School of Medicine

P-90 Effect of CX3CR1 polymorphisms on the structure and blood volume of the human brainMai Sakai, Hikaru Takeuchi, Zhiqian Yu, Yoshie Kikuchi, Chiaki Ono, Yuta Takahashi, Fumiaki Ito, Hiroo Matsuoka, Osamu Tanabe, Jun Yasuda, Yasuyuki Taki, Ryuta Kawashima, Hiroaki TomitaaDepartment of Disaster Psychiatry, International Research Institute of Disaster Science (IRIDeS), Tohoku University, bDepartment of Disaster Psychiatry, Graduate school of medicine, Tohoku University, cTohoku Medical Megabank Organization, Tohoku University, dDepartment of Developmental Cognitive Neuroscience, Institute of Development, Aging and Cancer, Tohoku University, eDepartment of Psychiatry, Graduate school of medicine, Tohoku University, fDepartment of Nuclear Medicine and Radiology, Institute of Development, Aging and Cancer, Tohoku University, gSmart Ageing International Research Center, Institute of Development, Aging and Cancer, Tohoku University, hDepartment of Functional Brain Imaging, Institute of Development, Aging and Cancer, Tohoku University

P-91 Microglial TNF alpha production is a key component in sustaining fear-memoryZhiqian Yu1,2,3, Hotaka Fukushim1,5, Chiaki Ono1, Mai Sakai1,2, Yoshiyuki Kasahara1,2, Yoshie Kikuchi1, Nicole Gunawansa1, Yuta Takahashi4, Hiroo Matsuoka4, Satoshi Kida5, Hiroaki Tomita1,2,3

1Department of Disaster Psychiatry, International Research Institute of Disaster Psychiatry, Tohoku University, 2Department of Disaster Psychiatry, Graduate School of Medicine, Tohoku University, 3Tohoku Medical Megabank Organization, Tohoku University, 4Department of Psychiatry, Graduate School of Medicine, Tohoku University, 5Departments of Bioscience, Faculty of Applied Bioscience, Tokyo University of Agriculture.

P-92 Oxytocin exposure in pregnant mice influences future emotional and social behaviors of the offspringYoshiyuki Kasahara, Sachie Suzuki, Yuji Onouchi, Ayaka Yoshida, Chiaki Ono, Yoshie Kikuchi, Zhiqian Yu, Hiroaki TomitaDepartment of Disaster Psychiatry, International Research Institute of Disaster Science, Tohoku University


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P-93 Tissue pH evaluation of human postmortem brain tissue and identification of pH- and RNA integrity-sensitive gene expression profiling~for effective quality control in postmortem brain gene expression profiling~Chiaki Ono, ZhiqianYu, Yoshie Kikuchi, Yoshiyuki Kasahara, YasutoKunii, Akiyoshi Kakita, NiwaShinichi, TomitaHiroakiDepartment of Disaster Psychiatry International Research Institute of Disaster Science, Tohoku University


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P-94 Evaluation of the impact of gut microbiota on uremic solute accumulation by CE-TOFMS-based metabolomics approachEikan Mishima, Sadayoshi Ito, Takaaki Abe Division of Nephrology, Endocrinology and Vascular Medicine Tohoku University Graduate School of Medicine

P-95 A novel indole compound MA-35 attenuates renal fibrosis by inhibiting both TNF-α and TGF-β1 pathwaysHisato Shima, Kensuke Sasaki, Takehiro Suzuki, Takao Masaki, Sadayoshi Ito, Takaaki Abe Division of Nephrology, Endocrinology, and Vascular Medicine, Tohoku University Graduate School of Medicine

P-96 The cell-protective effect and its mechanism of novel therapeutic medicine Mitochonic acid (MA)-5 for mitochondrial diseasesTetsuro Matsuhashi, Takehiro Suzuki, Takeya Sato, Shinichiro Kanno, and Takaaki AbeDepartment of Pediatrics, Tohoku University Graduate school of Medicine

P-97 Podocyte-specific MAGI-2 deficiency results in nephrosis and renal failureNaritoshi Shirata1,2, Kan-ichiro Ihara3, Motoko Yanagita1,4, Katsuhiko Nishimori3, Katsuhiko Asanuma1,4 1TMK project, Kyoto Univ., 2Mitsubishi Tanabe Pharmaceutical Corporation, 3Faculty of agriculture, Tohoku Univ., 4Nephrology, Kyoto Univ., Japan

P-98 Anti-angiogenic activity of extracellular matrix protein, fibulin-7 and its C-terminal fragment Fbln7-C in vivoTomoko Ikeuchi1, Susana de Vega2, Patricia Forcinito1, Juan Amaral3, Ignacio Rodrigez3, Eri Arikawa-Hirasawa2, and Yoshihiko Yamada1 1Laboratory of Cell and Developmental Biology, NIDCR, NIH, Bethesda, MD, USA; 2Research Institute for Diseases of Old Age, Juntendo University Graduate School of Medicine, Tokyo, Japan; 3Laboratory of Retinal Cell and Molecular Biology, NEI, NIH, Bethesda, MD, USA

Poster Session11 (17:20-18:44) Poster Hall 3Moderators: Jeffrey B. Kopp, NIDDK, NIHTakaaki Abe, Tohoku University Graduate School of Biomedical Engineering


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P-99 Pannexin 3 and Connexin43 Modulate Skeletal Development via Distinct Functions and Expression PatternsMasaki Ishikawa1,2, Geneva L. Williams1,2, Tomoko Ikeuchi1, Kiyoshi Sakai1,4, Satoshi Fukumoto5, and Yoshihiko Yamada1 1Laboratory of Cell and Developmental Biology, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD USA; 2Division of Biology & Biomedical Sciences, Washington University in St. Louis, St. Louis, MO, USA; 3Operative Dentistry, Tohoku University Graduate School of Dentistry, Sendai, Japan; 4Department of Oral and Maxillofacial Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan; 5Department of Pediatric Dentistry, Tohoku University Graduate School of Dentistry,Sendai, Japan

P-100 New therapeutics for mitochondrial diseases by mitochondria-homing drug MA-5Takehiro Suzuki, Tetsuro Matsuhashi, Takaaki AbeDivision of Medical Science, Tohoku University Graduate School of Biomedical Engineering

P-101 ABCB1 Upregulation Is Responsible for Acquisition of Taxane Resistance in Esophageal Cancer: Both Genetic and Epigenetic Mechanisms Plays a Crucial RoleSumarpo A, Saiki Y, Wang RB, Chen N, Sunamura M, Ishizawa K, Horii A Department of Molecular Pathology, Tohoku University School of Medicine

P-102 Discovering novel inhibitors for P-gp through screening of 5760 compounds in Tohoku University Chemical LibraryNorihiko Sugisawa, Shinobu Ohnuma, Megumi Obara, Masaharu Ishida, Katsuyoshi Kudoh, Michiaki Unno Department of Surgery, Tohoku University School of Medicine

P-103 Long non-coding RNA HOTAIR promotes cell migration via up-regulation of IGFBP2 in clear cell renal carcinomaHiromichi Katayama1,3, Keiichi Tamai1, Sadafumi Kawamura2, Tatsuo Tochigi2, Yoichi Arai3, Kennichi Satoh1 1Division of Cancer Stem Cell, Miyagi Cancer Center Research Institute, 2Department of Urology, Miyagi Cancer Center, 3Department of Urology, Tohoku University School of Medicine


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P-104 Identification of homeobox genes regulating expression of catecholamine-synthesizing enzymes in the locus ceruleusTatsuya Sato1, Katsuya Uchida1, Yasumasa Iwasaki6, Satoshi Yamagata1, Chiaki Tanaka3, 4, Hiroaki Tomita3, 4, 5, Keiichi Itoi1,2

1Laboratory of Information Biology, Graduate School of Information Sciences, 2Department of Neuroendocrinology, Graduate School of Medicine, 3Department of Disaster Psychiatry, International Research Institute of Disaster Science, 4Department of Disaster Psychiatry, Graduate School of Medicine, 5Tohoku Medical Megabank Organization, Tohoku University, Sendai, Japan, 6Medical Sciences Cluster, Clinical Medicine Unit, Kochi University, Kochi, Japan

P-105 Novel piezo actuator-driven pulsed water jet system is safe and effective surgical device in off-clamp laparoscopic partial nephrectomyYoshihiro Kamiyama1, Shinichi Yamashita1, Atsuhiro Nakagawa2, Shinji Fjii1, Koji Mitsuzuka1, Yasuhiro Kaiho1, Akihiro Ito1, Takaaki Abe3, Teiji Tominaga2, Yoichi Arai1

1Department of Urology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan, 2Department of Neurosurgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan, 3Division of Medical Science, Tohoku University Graduate School of Biomedical Engineering, Department of Clinical Biology and Hormonal Regulation, Tohoku University Graduate School of Medicine Sendai, Miyagi, Japan


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Committees

◆Organizing Committee Members of the 2017 Japan-NIH Joint Symposium Tooru Shimosegawa, Dean, Tohoku University Graduate School of Medicine

Kazuhiko Igarashi, Tohoku University Graduate School of Medicine

Hitoshi Oshitani, Tohoku University Graduate School of Medicine

Keiko Nakayama, Tohoku University Graduate School of Medicine

Akira Imatani, Tohoku University Graduate School of Medicine

Keiichi Itoi, Tohoku University Graduate School of Information Sciences

Kouetsu Ogasawara, Institute of Development, Aging and Cancer, Tohoku University

◆Executive Committee Members of the 2017 Japan-NIH Joint Symposium Akira Imatani, Tohoku University Graduate School of Medicine

Takashi Nakamura, Tohoku University Graduate School of Dentistry

Shinobu Ohnuma, Tohoku University Graduate School of Medicine

Naoki Asano, Tohoku University Graduate School of Medicine

Administrative Office:

The 2017 Japan-NIH Joint Symposium Office c/o International Exchange Office, Graduate School of Medicine, Tohoku University

c/o Research Cooperation Section, Graduate School of Medicine Administration Office, Tohoku University

2-1 Seiryo-machi, Aoba-ku Sendai 980-8575, JAPAN

TEL: +81-22-718-5091, e-mail: [email protected]

Documents

The 2017 Japan-NIH Joint Symposium · The 2017 Japan-NIH Joint Symposium Office c/o International Exchange Office, Graduate School of Medicine, Tohoku University c/o Research Cooperation