Tortorella Resume - GIBHenglish.gibh.cas.cn/.../201107/P020140212585735603919.docx · Web view(1) To lead and provide direction to a discovery team and apply basic biology to the

Tortorella, Curriculum Vitae 2014

MICKY D TORTORELLA

Guangzhou Institutes of Biomedicine and HealthChinese Academy of SciencesRoom A419190 Kai Yuan Avenue, Science ParkGuangzhou, China 510530(Cell China) 186-8888-8347(Email China) [email protected](Cell USA) 636-293-9612(Email USA) [email protected]

Background:

The extracellular matrix (ECM) comprises a complex network of many macromolecules such as proteoglycans, collagens, glycoproteins and polysaccharides. These matrix proteins play an essential role in the assembly of cells to form tissues and provide the correct environment for cell migration, differentiation and growth. ECM remodeling is important in numerous biological processes including tissue resorption and repair. My previous work has focused on understanding the biochemical mechanisms involved in the turnover and degradation of the cartilage ECM, which led to the discovery, characterization and crystallization of ADAMTS-4 and -5, two enzymes responsible for aggrecan catabolism in arthritic diseases. Some of my current research continues to focus on elucidating the mechanisms that mediate cartilage and bone degradation during the progression of osteoarthritis (OA) and developing therapies for blocking these processes using innovative biochemical, biophysical, molecular and cell imaging technologies.

The illustration depicts an overlay of the crystal structure of the catalytic domain of ADAMTS-5, a protease responsible for the breakdown of the matrix molecule aggrecan, bound to an inhibitor and eroding human, osteoarthritic articular cartilage stained with hematoxylin and eosin.

Interests:

(1) To lead and provide direction to a discovery team and apply basic biology to the drug discovery process, including identification of novel targets, innovation in

assay development and in vivo models of disease. (2) The role of proteinases in mediating the breakdown of the extracellular matrix in disease.

Experience:

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mailto:[email protected]

mailto:[email protected]


2009 – Present Guangzhou Institutes of Biomedicine and Health (GIBH), Guangzhou ChinaChief Technology Officer & Vice President of Drug Discovery Research

Establish the overall strategic direction for the Drug Discovery Pipeline (DDP) at GIBH.

Provide leadership to enable the discovery of new targets and the development of innovative small molecule therapeutics in response to unmet medical needs within multiple therapeutic areas.

Insure that a sufficient number of new chemical entities are successfully promoted to the Development Track each year, enhancing the pipeline of drugs necessary for GIBH’s sustainable growth.

Oversee the DDP, which includes: Medicinal Chemistry, Structural Biology, Screening, PK/PD and Biomarkers.

Coordinated the successful creation of several companies in China using assets developed at GIBH including GZstem (stem cell based company) in 2010.

2003 — 2009 Pfizer, St Louis MissouriSenior Principal Scientist (Inflammatory Diseases)

Project leader (OA target). Project champion (2 OA targets). Coordinated the efforts of multiple team members to establish

objectives, strategies and timelines. Studied the role of proprotein convertases in the activation of

latent metalloproteinases in articular cartilage. Developed peptide therapeutics for intra-articular injection for

the treatment of OA. Studied the dynamic relationship between aggrecan and

collagen breakdown, chondrocyte cloning, chondrocyte apoptosis, osteophyte formation, subchondral bone sclerosis and pain using KO mice.

Established external strategic alliances to advance project goals.

2001 — 2003 Pharmacia*, Skokie, Illinois. *Acquired by Pfizer in 2003Senior Principal Scientist (Joint Biology)

Project leader (OA target). Coordinated the efforts of multiple team members to establish

objectives, strategies and timelines. Studied the role of ADAMTS proteins in arthritic diseases. Identified several novel mediators of cartilage degradation in

osteoarthritis using pathway mapping and proteonomics.

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Validated multiple biomarkers of cartilage degradation.

1999 — 2001 Imperial College of London, Kennedy Institute of Rheumatology, Hammersmith, London.

Research Scientist (Matrix Biology)

Studied the role of cartilage aggrecanase-1 (ADAMTS-4) and aggrecanase-2 (ADAMTS-5) in in vitro and in vivo models of cartilage degradation.

Explored the role of fibronectin peptides in mediating cartilage erosion and the mRNA and protein expression of aggrecanases.

Researched the role of a novel activity “fibronectinases” in the cleavage of cartilage fibronectin and its importance in cartilage metabolism

Examined the role of an enzyme involved in the C-terminal truncation of aggrecan in older adults and the potential link to OA.

Designed multiple-site-binding inhibitors (substrate plus enzyme).

DuPont Pharmaceuticals, Wilmington, Delaware.

1997 — 1999 Research Scientist1994 — 1997 Staff Scientist1992 — 1994 Associate Scientist

Studied the role of MMPs in the breakdown of articular cartilage.

Identified and purified two novel metalloproteinases, aggrecanase-1 (ADAMTS-4) and aggrecanase-2 (ADAMTS-5) in bovine nasal cartilage implicated in the breakdown of aggrecan in OA.

Characterized the enzyme activity and substrate specificity of ADAMTS-4 and ADAMTS-5.

Developed and validated several aggrecan neoepitope antibodies as biomarkers of cartilage breakdown.

Education:

1999 — 2001 Imperial College of London, Kennedy Institute of Rheumatology, Hammersmith, London. Graduate student in the biochemistry department.

1985 — 1990 University of Delaware, Newark, Delaware. Bachelors in Biological Sciences (Biochemistry track), Cum Laude, GPA 3.5/4.0 Class rank 232/2918; Dean’s list 7/9 semesters.

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Laboratory Proficiencies:

- PCR - Enzyme assays - Protein expression- Cloning - Tissue culture - Mass spectrometry- Peptide chemistry - Cell labelling - Molecular modelling- Affinity sensor - Protein purification - ELISA- Western/Northern - HTS screening - Protein binding assays- N-terminal sequencing - HPLC - Enzymology

Patents:

o USP 20050090466: Inhibitors of PACE4 for the treatment of arthritis.

o USP 6753176: Aggrecan degrading metallo proteases.

o USP 6521436: Nucleic acids encoding aggrecan degrading metallo

proteases.

o USP 6451575: Aggrecan degrading metallo proteases.

o USP 6326162: Assays and peptide substrate for determining aggrecan

degrading metallo protease activity.

o USP Application 60/145527: Thrombospondin Peptides that Inhibit Aggrecanase Activity.

o WO 03/005956: A Hydroxamic Acid Thrombospondin Peptide Analog that Inhibits Aggrecanase Activity.

o USP 6635430: Filtrate plate device and reversible-well plate device.

o USP 2005037432A: Novel biomarkers of aggrecanase activity.

External Collaborations & Strategic Alliances

Professor Anne-Marie Malfait, PhD, MD at Rush Medical Center (www.rush.edu). Understanding the biochemistry of OA pain using transgenic mice.

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http://www.rush.edu/


The Center for World Health & Medicine at Saint Louis University (www.cwhm.org). Development of inhibitors of plasmepsin V as novel anti-malarial agents.

John J. Talley, PhD and Mark Obukowicz, PhD. Development of 3rd generation Cox-2 selective inhibitors for the treatment of inflammation-mediated cancers.

Professor Jufang He, PhD at Hong Kong Polytechnic University (http://www.polyu.edu.hk). Advancement of CCKBR agonists for the improvement of memory.

Dr. Jinsong Zhu, CEO of Plexera Inc. (www.plexera.com). Development of compound micro-array chips for rapid repositioning of clinical candidate compounds.

Publications:

1. Yanmei Zhang, Wei-Xing Dan, Jianqi Liu, Micky D. Tortorella, Zhengchao Tu and John J TalleyPalladium-catalyzed synthesis of trimethylsilyl substituted benzopyran derivatives (2013) The Open Organic Chemistry Journal 7, pp.15-20.

2. Miller RE, Lu Y, Tortorella MD, Malfait AM. Genetically engineered mouse models reveal the importance of proteases as osteoarthritis drug targets (2013) Curr Rheumatol Rep.15(8):350.

3. Morgen, M., Tung, D., Boras, B., Miller, W., Malfait, A.-M., Tortorella, M.Nanoparticles for improved local retention after intra-articular injection into the knee joint (2013) Pharmaceutical Research, 30 (1), pp. 257-268. Cited 1 time.

4. Malfait, A.-M., Seymour, A.B., Gao, F., Tortorella, M.D., Le Graverand-Gastineau, M.-P.H., Wood, L.S., Doherty, M., Doherty, S., Zhang, W., Arden, N.K., Vaughn, F.L., Leaverton, P.E., Spector, T.D., Hart, D.J., Maciewicz, R.A., Muir, K.R., Das, R., Sorge, R.E., Sotocinal, S.G., Schorscher-Petcu, A., Valdes, A.M., Mogil, J.S.A role for PACE4 in osteoarthritis pain: Evidence from human genetic association and null mutant phenotype (2012) Annals of the Rheumatic Diseases, 71 (6), pp. 1042-1048. Cited 4 times.

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http://www.scopus.com/record/display.url?eid=2-s2.0-84873729849&origin=resultslist



http://www.plexera.com/

http://www.polyu.edu.hk/

http://www.cwhm.org/


5. Li, J., Anemaet, W., Diaz, M.A., Buchanan, S., Tortorella, M., Malfait, A.M., Mikecz, K., Sandy, J.D., Plaas, A.Knockout of ADAMTS5 does not eliminate cartilage aggrecanase activity but abrogates joint fibrosis and promotes cartilage aggrecan deposition in murine osteoarthritis models (2011) Journal of Orthopaedic Research, 29 (4), pp. 516-522. Cited 14 times.

6. Zhang, S., Chen, S., Li, W., Guo, X., Zhao, P., Xu, J., Chen, Y., Pan, Q., Liu, X., Zychlinski, D., Lu, H., Tortorella, M.D., Schambach, A., Wang, Y., Pei, D., Esteban, M.A.Rescue of ATP7B function in hepatocyte-like cells from Wilson's disease induced pluripotent stem cells using gene therapy or the chaperone drug curcumin(2011) Human Molecular Genetics, 20 (16), art. no. ddr223, pp. 3176-3187. Cited 19 times.

7. Shieh, H.-S., Tomasselli, A.G., Mathis, K.J., Schnute, M.E., Woodard, S.S., Caspers, N., Williams, J.M., Kiefer, J.R., Munie, G., Wittwer, A., Malfait, A.-M., Tortorella, M.D.Structure analysis reveals the flexibility of the ADAMTS-5 active site(2011) Protein Science, 20 (4), pp. 735-744. Cited 4 times.

6. Dufield, D.R., Nemirovskiy, O.V., Jennings, M.G., Tortorella, M.D., Malfait, A.M., Mathews, W.R.An immunoaffinity liquid chromatography-tandem mass spectrometry assay for detection of endogenous aggrecan fragments in biological fluids: Use as a biomarker for aggrecanase activity and cartilage degradation(2010) Analytical Biochemistry, 406 (2), pp. 113-123. Cited 12 times.

7. Byun, S., Tortorella, M.D., Malfait, A.-M., Fok, K., Frank, E.H., Grodzinsky, A.J.Transport and equilibrium uptake of a peptide inhibitor of PACE4 into articular cartilage is dominated by electrostatic interactions(2010) Archives of Biochemistry and Biophysics, 499 (1-2), pp. 32-39. Cited 5 times.

8. Malfait, A.M., Ritchie, J., Gil, A.S., Austin, J.-S., Hartke, J., Qin, W., Tortorella, M.D., Mogil, J.S.ADAMTS-5 deficient mice do not develop mechanical allodynia associated with osteoarthritis following medial meniscal destabilization(2010) Osteoarthritis and Cartilage, 18 (4), pp. 572-580. Cited 19 times.

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9. Zack, M.D., Melton, M.A., Stock, J.L., Storer, C.E., Barve, R.A., Minnerly, J.C., Weiss, D.J., Stejskal, J.A., Tortorella, M.D., Turk, J.R., Shevlin, K.M., Malfait, A.-M.Reduced incidence and severity of experimental autoimmune arthritis in mice expressing catalytically inactive A disintegrin and metalloproteinase 8 (ADAM8)(2009) Clinical and Experimental Immunology, 158 (2), pp. 246-256. Cited 7 times.

10. Tortorella, M.D., Tomasselli, A.G., Mathis, K.J., Schnute, M.E., Woodard, S.S., Munie, G., Williams, J.M., Caspers, N., Wittwer, A.J., Malfait, A.-M., Shieh, H.-S.Structural and inhibition analysis reveals the mechanism of selectivity of a series of aggrecanase inhibitors(2009) Journal of Biological Chemistry, 284 (36), pp. 24185-24191. Cited 20 times.

11. Zack, M.D., Malfait, A.-M., Skepner, A.P., Yates, M.P., Griggs, D.W., Hall, T., Hills, R.L., Alston, J.T., Nemirovskiy, O.V., Radabaugh, M.R., Leone, J.W., Arner, E.C., Tortorella, M.D.ADAM-8 isolated from human osteoarthritic chondrocytes cleaves fibronectin at Ala271(2009) Arthritis and Rheumatism, 60 (9), pp. 2704-2713. Cited 8 times.

12. Tortorella, M.D., Malfait, F., Barve, R.A., Shieh, H.-S., Malfait, A.-M.A review of the ADAMTS family, pharmaceutical targets of the future(2009) Current Pharmaceutical Design, 15 (20), pp. 2359-2374. Cited 18 times.

13. Malfait, A.M., Tortorella, M., Thompson, J., Hills, R., Meyer, D.M., Jaffee, B.D., Chinn, K., Ghoreishi-Haack, N., Markosyan, S., Arner, E.C.Intra-articular injection of tumor necrosis factor-α in the rat: an acute and reversible in vivo model of cartilage proteoglycan degradation(2009) Osteoarthritis and Cartilage, 17 (5), pp. 627-635. Cited 5 times.

14. Malfait, A.-M., Arner, E.C., Song, R.-H., Alston, J.T., Markosyan, S., Staten, N., Yang, Z., Griggs, D.W., Tortorella, M.D.Proprotein convertase activation of aggrecanases in cartilage in situ(2008) Archives of Biochemistry and Biophysics, 478 (1), pp. 43-51. Cited 30 times.

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15. Tortorella, M.D., Malfait, A.M.Will the real aggrecanase(s) step up: Evaluating the criteria that define aggrecanase activity in osteoarthritis(2008) Current Pharmaceutical Biotechnology, 9 (1), pp. 16-23. Cited 18 times.

16. Shieh, H.-S., Mathis, K.J., Williams, J.M., Hills, R.L., Wiese, J.F., Benson, T.E., Kiefer, J.R., Marino, M.H., Carroll, J.N., Leone, J.W., Malfait, A.-M., Arner, E.C., Tortorella, M.D., Tomasselli, A.High resolution crystal structure of the catalytic domain of ADAMTS-5 (aggrecanase-2)(2008) Journal of Biological Chemistry, 283 (3), pp. 1501-1507. Cited 33 times.

17. Blair, W.S., Cao, J., Jackson, L., Jimenez, J., Peng, Q., Wu, H., Isaacson, J., Butler, S.L., Chu, A., Graham, J., Malfait, A.-M., Tortorella, M., Patick, A.K.Identification and characterization of UK-201844, a novel inhibitor that interferes with human immunodeficiency virus type 1 gp160 processing(2007) Antimicrobial Agents and Chemotherapy, 51 (10), pp. 3554-3561. Cited 9 times.

18. Wittwer, A.J., Hills, R.L., Keith, R.H., Munie, G.E., Arner, E.C., Anglin, C.P., Malfait, A.-M., Tortorella, M.D.Substrate-dependent inhibition kinetics of an active site-directed inhibitor of ADAMTS-4 (aggrecanase 1)(2007) Biochemistry, 46 (21), pp. 6393-6401. Cited 16 times.

19. Hall, T., Fok, K.F., Liu, M.M., Zobel, J.F., Marino, M.H., Malfait, A.-M., Tortorella, M.D., Tomasselli, A.G.A high performance liquid chromatography assay for monitoring proprotein convertase activity(2007) Journal of Chromatography A, 1148 (1), pp. 46-54. Cited 3 times.

20. Hills, R., Mazzarella, R., Fok, K., Liu, M., Nemirovskiy, O., Leone, J., Zack, M.D., Arner, E.C., Viswanathan, M., Abujoub, A., Muruganandam, A., Sexton, D.J., Bassill, G.J., Sato, A.K., Malfait, A.-M., Tortorella, M.D.Identification of an ADAMTS-4 cleavage motif using phage display leads to the development of fluorogenic peptide substrates and reveals matrilin-3 as a novel substrate(2007) Journal of Biological Chemistry, 282 (15), pp. 11101-11109. Cited 19 times.

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21. Song, R.-H., Tortorella, M.D., Malfait, A.-M., Alston, J.T., Yang, Z., Arner, E.C., Griggs, D.W.Aggrecan degradation in human articular cartilage explants is mediated by both ADAMTS-4 and ADAMTS-5(2007) Arthritis and Rheumatism, 56 (2), pp. 575-585. Cited 114 times.

22. Zack, M.D., Arner, E.C., Anglin, C.P., Alston, J.T., Malfait, A.-M., Tortorella, M.D.Identification of fibronectin neoepitopes present in human osteoarthritic cartilage(2006) Arthritis and Rheumatism, 54 (9), pp. 2912-2922. Cited 14 times.

23. Tortorella, M.D., Arner, E.C., Hills, R., Gormley, J., Fok, K., Pegg, L., Munie, G., Malfait, A.-M.ADAMTS-4 (aggrecanase-1): N-Terminal activation mechanisms(2005) Archives of Biochemistry and Biophysics, 444 (1), pp. 34-44. Cited 43 times.

24. Tortorella, M.D., Arner, E.C., Hills, R., Easton, A., Korte-Sarfaty, J., Fok, K., Wittwer, A.J., Liu, R.-Q., Malfait, A.-M.α2-Macroglobulin Is a Novel Substrate for ADAMTS-4 and ADAMTS-5 and Represents an Endogenous Inhibitor of These Enzymes(2004) Journal of Biological Chemistry, 279 (17), pp. 17554-17561. Cited 52 times.

25. Wang, P., Tortorella, M., England, K., Malfait, A.-M., Thomas, G., Arner, E.C., Pei, D.Proprotein Convertase Furin Interacts with and Cleaves Pro-ADAMTS4 (Aggrecanase-1) in the trans-Golgi Network(2004) Journal of Biological Chemistry, 279 (15), pp. 15434-15440. Cited 67 times.

26. Tortorella, M.D., Malfait, A.-M.The Usual Suspects: Verdict Not Guilty?(2003) Arthritis and Rheumatism, 48 (12), pp. 3304-3307. Cited 10 times.

27. Pratta, M.A., Yao, W., Decicco, C., Tortorella, M.D., Liu, R.-Q., Copeland, R.A., Magolda, R., Newton, R.C., Trzaskos, J.M., Arner, E.C.Aggrecan Protects Cartilage Collagen from Proteolytic Cleavage(2003) Journal of Biological Chemistry, 278 (46), pp. 45539-45545. Cited 105 times.

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28. Cherney, R.J., Mo, R., Meyer, D.T., Wang, L., Yao, W., Wasserman, Z.R., Liu, R.-Q., Covington, M.B., Tortorella, M.D., Arner, E.C., Qian, M., Christ, D.D., Trzaskos, J.M., Newton, R.C., Magolda, R.L., Decicco, C.P.Potent and selective aggrecanase inhibitors containing cyclic P1 substituents(2003) Bioorganic and Medicinal Chemistry Letters, 13 (7), pp. 1297-1300. Cited 30 times.

29. Tortorella, M.D., Liu, R.-Q., Burn, T., Newton, R.C., Arner, E.Characterization of human aggrecanase 2 (ADAM-TS5): Substrate specificity studies and comparison with aggrecanase 1 (ADAM-TS4)(2002) Matrix Biology, 21 (6), pp. 499-511. Cited 91 times.

30. Malfait, A.-M., Liu, R.-Q., Ijiri, K., Komiya, S., Tortorella, M.D.Inhibition of ADAM-TS4 and ADAM-TS5 prevents aggrecan degradation in osteoarthritic cartilage(2002) Journal of Biological Chemistry, 277 (25), pp. 22201-22208. Cited 160 times.

31. Osman, M., Tortorella, M., Londei, M., Quaratino, S.Expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases define the migratory characteristics of human monocyte-derived dendritic cells(2002) Immunology, 105 (1), pp. 73-82. Cited 44 times.

32. Yamanishi, Y., Boyle, D.L., Clark, M., Maki, R.A., Tortorella, M.D., Arner, E.C., Firestein, G.S.Expression and regulation of aggrecanase in arthritis: The role of TGF-β(2002) Journal of Immunology, 168 (3), pp. 1405-1412. Cited 93 times.

33. Yao, W., Wasserman, Z.R., Chao, M., Reddy, G., Shi, E., Liu, R.-Q., Covington, M.B., Arner, E.C., Pratta, M.A., Tortorella, M., Magolda, R.L., Newton, R., Qian, M., Ribadeneira, M.D., Christ, D., Wexler, R.R., Decicco, C.P.Design and synthesis of a series of (2R)-N4-hydroxy-2-(3-hydroxybenzyl)-N1- [(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]butanediamide derivatives as potent, selective, and orally bioavailable aggrecanase inhibitors(2001) Journal of Medicinal Chemistry, 44 (21), pp. 3347-3350. Cited 47 times.

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34. Tortorella, M.D., Malfait, A.-M., Deccico, C., Arner, E.The role of ADAM-TS4 (aggrecanase-1) and ADAM-TS5 (aggrecanase-2) in a model of cartilage degradation(2001) Osteoarthritis and Cartilage, 9 (6), pp. 539-552. Cited 163 times.

35. Kashiwagi, M., Tortorella, M., Nagase, H., Brew, K.TIMP-3 Is a Potent Inhibitor of Aggrecanase 1 (ADAM-TS4) and Aggrecanase 2 (ADAM-TS5)(2001) Journal of Biological Chemistry, 276 (16), pp. 12501-12504. Cited 282 times.

36. Pratta, M.A., Tortorella, M.D., Arner, E.C.Age-related changes in aggrecan glycosylation affect cleavage by aggrecanase(2000) Journal of Biological Chemistry, 275 (50), pp. 39096-39102. Cited 55 times.

37. Tortorella, M., Pratta, M., Liu, R.-Q., Abbaszade, I., Ross, H., Burn, T., Arner, E.The thrombospondin motif of Aggrecanase-1 (ADAMTS-4) is critical for aggrecan substrate recognition and cleavage(2000) Journal of Biological Chemistry, 275 (33), pp. 25791-25797. Cited 127 times.

38. Tortorella, M.D., Pratta, M., Liu, R.-Q., Austin, J., Ross, O.H., Abbaszade, I., Burn, T., Arner, E.Sites of aggrecan cleavage by recombinant human aggrecanase-1 (ADAMTS-4)(2000) Journal of Biological Chemistry, 275 (24), pp. 18566-18573. Cited 154 times.

39. Abbaszade, I., Liu, R.-Q., Yang, F., Rosenfeld, S.A., Ross, O.H., Link, J.R., Ellis, D.M., Tortorella, M.D., Pratta, M.A., Hollist, J.M., Wynn, R., Duke, J.L., George, H.J., Hillman Jr., M.C., Murphy, K., Wiswall, B.H., Copeland, R.A., Decicco, C.P., Bruckner, R., Nagase, H., Itoh, Y., Newton, R.C., Magolda, R.L., Trzaskos, J.M., Hollis, G.F., Arner, E.C., Burn, T.C.Cloning and characterization of ADAMTS11, an aggrecanase from the ADAMTS family(1999) Journal of Biological Chemistry, 274 (33), pp. 23443-23450. Cited 340 times.

40. Arner, E.C., Pratta, M.A., Decicco, C.P., Xue, C.-B., Newton, R.C., Trzaskos, J.M., Magolda, R.L., Tortorella, M.D.Aggrecanase. A target for the design of inhibitors of cartilage degradation

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(1999) Annals of the New York Academy of Sciences, 878, pp. 92-107. Cited 41 times.

41. Tortorella, M.D., Burn, T.C., Pratta, M.A., Abbaszade, I., Hollis, J.M., Liu, R., Rosenfeld, S.A., Copeland, R.A., Decicco, C.P., Wynn, R., Rockwell, A., Yang, F., Duke, J.L., Solomon, K., George, H., Bruckner, R., Nagase, H., Itoh, Y., Ellis, D.M., Ross, H., Wiswall, B.H., Murphy, K., Hillman Jr., M.C., Hollis, G.F., Newton, R.C., Magolda, R.L., Trzaskos, J.M., Arner, E.C.Purification and cloning of aggrecanase-1: A member of the ADAMTS family of proteins(1999) Science, 284 (5420), pp. 1664-1666. Cited 472 times.

42. Arner, E.C., Pratta, M.A., Trzaskos, J.M., Decicco, C.P., Tortorella, M.D.Generation and characterization of aggrecanase. A soluble, cartilage- derived aggrecan-degrading activity(1999) Journal of Biological Chemistry, 274 (10), pp. 6594-6601. Cited 106 times.

43. Arner, E.C., Hughes, C.E., Decicco, C.P., Caterson, B., Tortorella, M.D.Cytokine-induced cartilage proteoglycan degradation is mediated by aggrecanase(1998) Osteoarthritis and Cartilage, 6 (3), pp. 214-228. Cited 106 times.

44. Tortorella, M.D., Pratta, M.A., Fox, J.W., Arner, E.C.The interglobular domain of cartilage aggrecan is cleaved by hemorrhagic metalloproteinase HT-d (Atrolysin C) at the matrix metalloproteinase and aggrecanase sites(1998) Journal of Biological Chemistry, 273 (10), pp. 5846-5850. Cited 27 times.

45. Trzaskos, J.M., Scherele, P.A., Manos, E.J., Feezer, W.S., Tortorella, M.D., Arner, E.C., Favata, M.F.Inhibition of mapkk (MEK) prevents upregulation of metalloproteinases in fibroblasts(1997) FASEB Journal, 11 (9).

46. Tortorella, M.D., Arner, E.C.A fluorescent enzyme-linked immunosorbent assay (FELISA) for stromelysin using a polyclonal antisera to human stromelysin with broad species cross-reactivity(1997) Inflammation Research, 46 (SUPPL. 2), pp. S120-S121. Cited 4 times.

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47. Tortorella, M.D., Arner, E.C.A high-throughput assay for stromelysin using a casein-resorufin substrate(1997) Inflammation Research, 46 (SUPPL. 2), pp. S122-S123. Cited 7 times.

48. Arner, E.C., Decicco, C.P., Cherney, R., Tortorella, M.D.Cleavage of native cartilage aggrecan by neutrophil collagenase (MMP-8) is distinct from endogenous cleavage by aggrecanase(1997) Journal of Biological Chemistry, 272 (14), pp. 9294-9299. Cited 37 times.

49. Arner, E.C., DiMeo, T.M., Pratta, M.A., Tortorella, M.D.Interleukin-1 induces aggrecanase-mediated cleavage in human articular cartilage without up-regulating stromelysin or glycosaminoglycan release(1995) Acta Orthopaedica Scandinavica, Supplement, 66 (266), pp. 153-154. Cited 1 time.

50. Arner, E.C., Tortorella, M.D.Signal transduction through chondrocyte integrin receptors induces matrix metalloproteinase synthesis and synergizes with interleukin-1(1995) Arthritis and Rheumatism, 38 (9), pp. 1304-1314. Cited 83 times.

Reviews and Book Chapters:

1. Tortorella M.D., Malfait F., Barve R.A., Shieh H.S., and Malfait A.M.

(2009) A Review of the ADAMTS Family, Pharmaceutical Targets of the

Future. Curr Pharm Des. 15(20):2359-74 Review.

2. Tortorella M.D. and Malfait A.M. (2008) Will the real aggrecanase(s) step up: evaluating the criteria that define aggrecanase activity in osteoarthritis. Curr Pharm Biotechnol. 9(1):16-23 Review.

3. Malfait A.M., Tortorella M.D., and Arner E.C. (2005) The ADAM Family of Proteases: ADAMTS-4 and ADAMTS-5. Series: Proteases in Biology and Disease, Vol. 4. Springer. Book Chapter 14.

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4. Tortorella M.D. and Malfait A.M. (2003) The usual suspects: verdict not guilty? Arthritis & Rheum. 48:3304-7 Editorial.

Abstracts/External Presentations:

1. Arner E.C. and M.Tortorella. Signal transduction through chondrocyte integrin receptors up-regulates matrix metalloproteinase synthesis and synergizes with interleukin-1. Orthopaedic Research Society Meeting, February 1994. (podium)

2. Arner E.C., T.M. DiMeo and M.D. Tortorella. Intra-articular injection of RGD peptides and fibronectin fragments induce cartilage degradation in the rabbit. Gordon Research Conference on Bioengineering and Orthopedic Science, August, 1994.

3. Arner E.C. and M.Tortorella. Integrin signalling induces articular chondrocyte matrix metalloproteinase synthesis. Philadelphia Immunology Conference. November, 1994.

4. Arner E.C., T.M. DiMeo and M.Tortorella. RGD peptides and fibronectin fragments induce cartilage proteoglycan degradation and stromelysin synthesis in vivo. Second International Congress of the Osteoarthritis Research Society. December, 1994. (podium)

5. Tortorella, M.D., J.M. Trzaskos, R.L. Magolda, and E.C. Arner Elution of active stromelysin from cartilage stimulated with interleukin-1. Orthopaedic Research Society Meeting. February, 1995.

6. C.E. Hughes H. Wang, B. Caterson, M.D. Tortorella, and E.C. Arner. Timecourse of IL1-induced "aggrecanase" cartilage catabolism indicates the presence of both different rates of release and different pools of aggrecan metabolites. Orthopaedic Research Society Meeting. February, 1995.

7. E.C. Arner, T.M. DiMeo, M.A. Pratta, and M.D. Tortorella. Interleukin-1 induces aggrecanase-mediated cleavage in human articular cartilage without up-regulating stromelysin or glycosaminoglycan release. Eric K. Fernstrom Symposium on Molecular Markers for Joint and Skeletal Diseases. May, 1995.

8. E.C. Arner, P. Gunyuzulu, G. Davis, M. Hillman, Jr., H. Ross, M.D. Tortorella Cleavage of native cartilage aggrecan by neutrophil collagenase (MMP-8). Matrix Metalloproteinase Gordon Research Conference, July, 1995.

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9. C.E. Hughes, B. Caterson, M.D. Tortorella, and E.C. Arner Catabolic neoepitopes as markers of proteoglycan degradation in arthritis. Matrix Metalloproteinase Gordon Research Conference. July, 1995

10. M.A. Pratta, M.D. Tortorella, P. Gunyuzulu, G.L Davis, H. George and E.C. Arner Co-induction of MMP-3 and MMP-8 synthesis in human chondrocytes in response to interleukin-1. Trans 42nd Ann Meeting Orthop Res Soc 21(1): 170, 1996. (podium)

11. M.A. Pratta, T.M. DiMeo, M.D. Tortorella and E.C. Arner. Effect of dexamethasone on interleukin-1 induction of stromelysin-1 synthesis in cartilage and isolated chondrocytes. Trans 42nd Ann Meeting Orthop Res Soc 21(2): 319, 1996.

12. E.C. Arner, T.M. DiMeo, M.A. Pratta, and M.D. Tortorella. Interleukin-1 induces aggrecanase-mediated cleavage in human articular cartilage. Trans 42nd Ann Meeting Orthop Res Soc 21(2): 364, 1996.

13. M.D. Tortorella, C.E. Hughes, H. Wang, B. Caterson, C.P. Decicco and E.C. Arner Matrix metalloproteinase inhibitors block aggrecanase-mediated cleavage of cartilage proteoglycan. Trans 42nd Ann Meeting Orthop Res Soc 21(1): 148, 1996. (podium)

14. E.C. Arner, P. Gunyuzulu, G. Davis, M. Hillman, Jr., H. Ross, M.D. Tortorella Neutrophil collagenase cleaves purified aggrecan and native cartilage aggrecan in situ at the aggrecanase site. Trans 42nd Ann Meeting Orthop Res Soc 21(1): 146, 1996. (podium)

15. E.C. Arner, T.M. DiMeo and M.D. Tortorella. RGD peptides and fibronectin fragments induce cartilage degradation in the rabbit. Eighth International Conference of the Inflammation Research Association, October 27-31, 1996. (podium)

16. E.C. Arner, C.P. Decicco, R.A. Copeland, J.V. Giannaras, C.S. Carlson, R.L. Magolda, M.D. Tortorella. "Aggrecanase" activity in cartilage from different species. Eighth International Conference of the Inflammation Research Association, October 27-31, 1996.

17. E.C. Arner, C.P. Decicco, R.A. Copeland, J.V. Giannaras, M.D. Tortorella. "Aggrecanase" mediates interleukin-1-induced cartilage degradation. Eighth International Conference of the Inflammation Research Association, October 27-31, 1996.

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18. T.M. DiMeo, T. Taylor, M.D. Tortorella, B.D. Jaffee and E.C. Arner. Knee joint involvement in rat adjuvant arthritis: a source of connective tissue for evaluation of disease pathology. Eighth International Conference of the Inflammation Research Association, October 27-31, 1996.

19. M.D. Tortorella, E.C. Arner. A fluorescent enzyme-linked immunosorbent assay (FELISA) for MMP-3 using a polyclonal antisera to human MMP-3 with broad species cross reactivity. Eighth International Conference of the Inflammation Research Association, October 27-31, 1996.

20. M.D. Tortorella, J.M. Trzaskos, E.C. Arner. A high-throughput assay for stromelysin using a casein-resorufin substrate. Eighth International Conference of the Inflammation Research Association, October 27-31, 1996.

21. M.D. Tortorella, M.A. Prata, L.M. Bauerle, C.P. Decicco, E.C. Arner. Matrix metalloproteinase inhibitors, but not NASAIDs, steroids or tetracyclines, inhibit "aggrecanase"-mediated cartilage degradation. Eighth International Conference of the Inflammation Research Association, October 27-31, 1996.

22. E.C. Arner, C.P. Decicco, M.A. Pratta, R.C. Newton, J.M. Trzaskos, R.L Magolda, M.D. Tortorella. “Aggrecanase”, and not MMP-1, -2, -3, -8 or –9, is critical for IL-1-induced cartilage aggrecan degradation. Trans. Orthop. Res. Soc. 22:454, 1997.

23. M.D. Tortorella, J.M. Trzaskos, E.C. Arner. Identification and characterization of an assay which defines the cartilage degrading enzyme, “aggrecanase”. Trans. Orthop. Res. Soc. 22:452, 1997.

24. E.C. Arner, C.P. Decicco, M.A. Copeland, J.M. Trzaskos, R.L. Magolda, M.D. Tortorella. Characterization of soluble bovine cartilage “aggrecanase”. Trans. Orthop. Res. Soc. 22:103, 1997. (podium)

25. M.D. Tortorella, E.C. Arner. Fibronectin fragments induce matrix metalloproteinases production and aggrecanase-mediated cartilage degradation. Trans. Orthop. Res. Soc. 22:106, 1997. (podium)

26. J.M. Trzaskos, P.A. Scherle, E.J. Manos, W.S. Feeser, M.D. Tortorella, E.C. Arner, M.F. Favata. Inhibition of MEK prevents upregulation of metalloproteinases in fibroblasts. ASBMB, August, 1997.

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27. E.C. Arner, M.A. Pratta, R.C. Newton, J.M. Trzaskos, R.L. Magolda, M.D. Tortorella. Comparison of cleavage efficiency of aggrecanase and stromelysin for the aggrecan core protein. Trans 43nd Ann Meeting Orthop Res Soc 1998

28. M.A. Pratta, M.D. Tortorella, R.C. Newton, J.M. Trzaskos, R. Magolda, C. P. DeCicco, B. Schumaker, K.E. Kuettner, A.A. Cole and E.C. Arner. Interleukin-1 stimulation of bovine nasal cartilage results exclusively in upregulation of aggrecanase-mediated cleavage. Trans 43nd Ann Meeting Orthop Res Soc 1998 (podium)

29. Tortorella M.D., M.A. Pratta, J.W. Fox, E.C. Arner. The interglobular domain of cartilage aggrecan is cleaved by hemorrhagic metalloproteinase HT-d (atrolysin C) at the matrix metalloproteinase and aggrecanase sites Trans 43nd Ann Meeting Orthop Res Soc 1998 (podium)

30. Arner E.C., M.D. Tortorella, M.A. Pratta, B.D. Jaffee, R.A. Copeland, C-B. Xue, R.C. Newton, J.M. Trzaskos, R.L. Magolda, C.P. Decicco. Aggrecanase: a target for the design of inhibitors of cartilage degradation. New York Academy of Sciences Conference on Inhibition of Matrix Metalloproteinases: Therapeutic Applications. October 21-24, 1998. (podium)

31. E.C. Arner, T. Burn, M.A. Pratta, R. Liu, J.M. Trzaskos, R.C. Newton, C.P. Decicco, A.Rockwell, R. Copeland, F. Yang, R. Bruchner, H. George, R.L. Magolda, M.D. Tortorella. Isolation and identification of “aggrecanase”: a novel cartilage aggrecan-degrading metalloproteinase (ADMP) 45th Ann Meeting Orthop Res Soc 1999 (podium).

32. M.A. Pratta, M.D. Tortorella, E.C. Arner. Aggrecan glycosylation affects cleavage by aggrecanase. 45th Ann Meeting Orthop Res Soc 1999.

33. M.D. Tortorella, T. Burn, H. George, R. Liu, L. Abbaszade, J.M. Hollis, S.A. Rosenfeld, D.M. Ellis, H. Ross, B.H. Wiswall, K. Murphy, R. Wynn, J.L. Duke, M.C. Hillman, Jr., G.F. Hollis, R.L. Magolda, A. Cole, K. Kuettner, M.A. Pratta, E.C. Arner. Sites of cleavage of aggrecan by the recombinant human aggrecan-degrading-metallo-protease (ADMP), “aggrecanase”. 45th Ann Meeting Orthop Res Soc 1999 (podium).

34. E.C. Arner, T. Burn, M.A. Pratta, R. Liu, J.M. Trzaskos, R.C. Newton, C.P. Decicco, A. Rockwell, R. Copeland, F. Yang, R. Bruchner, H. George, R.L. Magolda, M.D. Tortorella. Isolation,

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purification, cloning and expression of aggrecanase. Keystone Symposium on Metalloproteases: Chemistry, Biology and Medicine. February 25-March 3, 1999 (podium).

35. M.D. Tortorella, E.C. Arner, T. Burn and H.Nagase. Purification, cloning and characterization of aggrecanase-1 and aggrecanase-2: two novel members of the ADAMTS family. Proteases and their Inhibitors, Tiers, Italy. Feb 29-30, 2000 (podium).

36. Micky Tortorella, Anne-Marie Malfait and Hideaki Nagase. The role of ADAM-TS4 (aggrecanase-1) and ADAM-TS5 (aggrecanase-2) in cartilage degradation. Cold Spring Harbor Meeting: Proteolysis and Biological Control. May 2-6, 2001 (podium).

37. Micky Tortorella, Elizabeth Arner and Anne-Marie Malfait. Inhibition of ADAM-TS4 (Aggrecanase-1) and ADAM-TS5 (Aggrecanase-2) prevents aggrecan degradation in osteoarthritic cartilage. Japanese Cartilage Metabolism Society (JCMS). Maebashi, Japan. March 8-9, 2002 (keynote speaker).

38. Anne-Marie Malfait, Elizabeth Arner and Micky Tortorella. 2-Macroglobulin is Cleaved at a Novel site by ADAMTS-4 and ADAMTS-5 and Represents an Endogenous Inhibitorof These Enzymes. Trans 49th Ann Meeting Orthop Res Soc 2003 (podium)

39. Micky Tortorella, Elizabeth Arner and Anne-Marie Malfait. Fibronectin fragments, but not IL-1 and TNFa, induce aggrecanase- mediated catabolism of aggrecan in human articular cartilage. Trans 49th Ann Meeting Orthop Res Soc 2003 (poster).

40. Malfait, A M; Arner, E C; Hills, R; Korte-Sarfaty, J; Fok, K; Pegg, L; Munie, G; Tortorella, M D. N-Terminal activation of ADAMTS-4 (Aggrecanase-1). Trans 51st Ann Meeting Orthop Res Soc 2005 (poster).

41. Micky Tortorella and Anne-Marie Malfait. PACE4 Drives Osteoarthritis Through Activation of ADAMTS-4 And ADAMTS-5 In The Extracellular Matrix of Articular Cartilage. The 2005 MMP Gordon Research Conference (Oral).

42. Micky Tortorella, Elizabeth Arner and Anne-Marie Malfait. Isolation from the Extracellaulr Matrix of OA, A Proprotein Convertase That Activates Both Latent ADAMTS-4 and ADAMTS-5. Trans 52st Ann Meeting Orthop Res Soc 2006, Chicago, IL (Oral).

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43. Micky Tortorella. ADAMTS4 and 5 in arthritis and cancer. Key note speaker. IUPHAR 2006 - 15th World Congress of Pharmacology (Part II), Metalloproteinases as Therapeutical Targets for Cancer Therapy, Beijing, China, 2-7 July 2006

44. Micky Tortorella. PACE4 Drives Osteoarthritis through Activation of ADAMTS-4 and ADAMTS-5 in the Extracellular Matrix of Cartilage. Key note speaker. Gordon Research Conference: Proprotein Processing, Trafficking & Secretion. July 9-14, 2006 Colby-Sawyer College New London, N H.

45. Micky Tortorella. High Resolution Crystal Structure of the Catalytic Domain of ADAMTS-5 (Aggrecanase-2). Poster Presentation. Segal North American Osteoarthritis Workshop. September 7-9, 2007, Chicago, Illinois.

46. Micky Tortorella. Crystal Structure of the Catalytic Domain of ADAMTS-5 (Aggrecanase-2). Podium Presentation. Midwest Connective Tissue Workshop. December 14-15, 2007, Chicago, Illinois.

47. Micky Tortorella. Key note speaker. Crystal Structure of the Catalytic Domain of ADAMTS-5 (Aggrecanase-2). 1st Annual Protein and Peptide Conference (PepCon). April 22-24, 2008, Shenzhen, China.

48. Micky Tortorella, Ingar Lau, Anne-Marie Malfait, Joe Leone, Cindy

Deppeler, Marc Zack, Bill Hood, Elizabeth Arner, Robert L. Hills. Expression and Characterization of the Disintegrin and Thrombospondin Domain of ADAMTS-4: A Protein Therapeutic for Treating Osteoarthritis? Poster Presentation. Segal North American Osteoarthritis Workshop. May 2-4, 2008, Chicago, Illinois.

49. Marc Zack, Anne-Marie Malfait and Micky Tortorella. A Disintegrin and Metalloproteinase-8 (ADAM8): The identification and characterization of a novel target for the treatment of arthritic disorders. Podium Presentation. Midwest Connective Tissue Workshop. May 7-8, 2010, Chicago, Illinois.

50. Micky D. Tortorella, Christopher B. Little, Ashutosh Barai, Susan

Smith, Lily Song, Charles Anglin, Ruth TenBrink, John Freskos, Alfredo G.

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Tomasselli and Anne-Marie Malfait. Healthy minds, healthy joints: Defining a new role for BACE-1 in cartilage erosion. Poster Presentation. Osteoarthritis Research Society International Meeting. September 23-26, 2010, Brussels, Belgium.

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Documents

Tortorella Resume - GIBHenglish.gibh.cas.cn/.../201107/P020140212585735603919.docx · Web view(1) To lead and provide direction to a discovery team and apply basic biology to the