NCRR: Navigating the Translational Researcher Primate Models and Resources Stuart Zola, PhD...

NCRR: Navigating the Translational Researcher

Primate Models and Resources

NCRR: Navigating the Translational Researcher

Primate Models and Resources

Stuart Zola, PhDProfessor, Department of Psychiatry and Behavioral Sciences,

Director, Yerkes National Primate Research Center,

Co-Director, Alzheimer’s Disease Research Center,

Co-Director, Center for Behavioral Neuroscience

Emory University,

Senior Research Career Scientist, VA Medical Center, Atlanta

Member, International Brotherhood of Magicians

Resources

Eight National Primate Research Centers National Institutes of Health, and

National Center for Research Resources (NCRR)

~ 26,000 Nonhuman primates

Emory University Georgia StateGeorgia Tech

Yerkes National Primate Research Center

A Unique Research Environment of Collaborative Research Groups

26 States NIH

- Imaging Center (fMRI, PET)- Microarray Facility - Affymetrix Rhesus gene chip- Chimpanzee colony- Rhesus colony and six other species- Aging populations in all species- Enrichment and psychological well-being programs - Behavioral assessments that reach across all species- Center for Aids Research- Vaccine Research Center- Center for Behavioral Neuroscience- Living Links Center

Emory Univ.Yerkes NPRC

NIH/NCRR Biomedical Informatics Research Network (BIRN)

Mediator architectureKnowledge-based mediationIntegrated view definitions

What is data mediation?

The Biomedical Informatics Research Network (BIRN) will use a “mediator architecture” to link multiple databases with different schemas, maintained at different research institutionsinto a data federation. This type of architecture is flexible, scalable, and powerful. It allows individual researchers to manage their own data in databases tailored to meet their specific needs. Those searching the system, however, will see the BIRN Data Federation as if it werea single database. Queries will be issued against the “mediator”, a virtual database that combines the individual data sources in meaningful ways. This combination is achieved using “Integrated View Definitions” which describe how the mediator represents the source databases. A user will submit a query to the mediator (or more precisely, to one of the integrated views the mediator can expose). The mediator will then parse the query and submit one or more queries to the relevant data sources.

Biomedical Informatics Research Network (BIRN)

Nonhuman Primate Resources National Primate Research Centers

Criteria and Procedures for Accessing National Primate Research CentersCalifornia National Primate Research CenterNew England National Primate Research CenterOregon National Primate Research CenterSouthwest National Primate Research CenterTulane National Primate Research CenterWashington National Primate Research CenterWisconsin National Primate Research CenterYerkes National Primate Research Center

Baboon and Monkey Research ResourcesBaboon Research ResourcesCaribbean Primate Research Center ProgramSquirrel Monkey Breeding and Research Resource

Chimpanzee Biomedical Research ResourcesAlamogordo Primate FacilityApplied Research for Improving Behavioral Management of Captive ChimpanzeesPrimate Foundation of ArizonaUniversity of Louisiana at LafayetteUniversity of TexasYerkes National Primate Research Center

Specific-Pathogen-Free Macaque ResourcesHerpes B-Virus Diagnosis: National Resource LaboratoryNew England National Primate Research CenterSpecific-Pathogen-Free Rhesus MacaquesSpecific-Pathogen-Free Rhesus

Monkey Genetic Analysis Resources Genetic Analysis of Complex Traits

Genetics Typing LaboratoryReferral Center for Animal Models of Human Genetic Disease

NCRR

Integrated Primate Biomaterials and Information ResourceCoriell Institute for Medical Research (www.ipbir.org)

Purpose: to assemble, characterize, and distribute high-quality DNA samples of known provenance with accompanying demographic, geographic, andbehavioral information in order to stimulate and facilitateresearch in primate genetic diversity and evolution, comparative genomics, and population genetics.

NIA Primate Aging Database (http://pad.primate.wisc.edu)

Purpose: to collect data on normal aging in a wide rangeof NHP species. Blood chemistry, body weight acrossthe lifespan. Currently 400,000 data points from 16different species.

NCRR Rhesus monkey genetic tools workshop, April 19-20

Primate Models

Nonhuman primates provide research models for conditions that affect us throughout our life-span.

•Autism•Visual System Development•Cognitive Development•Social//Emotional Development•Genetics, Proteomics•Immune System Function•Cancer•AIDS•Malaria •Cocaine Addiction•Cardiovascular Disease •Transplantation Medicine•Alzheimer’s Disease•Parkinson’s Disease•Neurological Basis of Behavior•Cognitive and Social Changes in Aging

MCIDementia,including AD

Normal

Neuropathology

Cognitive Ability

Changes in CognitionAnd Neuropathology Across Time

and the Diagnosis of Mild Cognitive Impairment (MCI)

PrimarilyMemory

PrimarilyHippocampus

Other CognitiveAbilities

Additional Brain Regions

Recognition Memory:

Assessed in identical waysin humans and monkeys

50

60

70

80

90

100

10 sec 15 sec 1 min 10 min

Normal

Amnesic Pts.

50

60

70

80

90

100

10 sec 15 sec 1 min 10 min

ControlHippocampus

Humans Monkeys

Recognition Memory

Noninvasive Infrared Eye-Tracking: Familiarization

The Preferential Looking Task

Noninvasive Infrared Eye-Tracking: Test

Control Subjects

Noninvasive Infrared Eye-Tracking: Test

MCI patients andmonkeys with hippocampal damage

2 sec 2 min30

40

50

60

70

80Control (16)

MCI (6)PD (4)

Delay

Mea

n %

Tim

e V

iew

ing

No

vel S

tim

ulu

s

No significantdifferences

MCI vs PD, CON P<.01, .001

No evidence of deficits in attention,motivation, or perception in MCI

MCI fall to chance within a 2-min delay

2 sec 2 min0.20

0.25

0.30

0.35

0.40Control (16)

MCI (16)PD (4)

DelayMea

n F

ixat

ion

Du

rati

on

on

No

vel S

tim

ulu

s

PD vs MCI P<.01, .05

PD vs CONP<.05 2 sec

MCI patients fixate for shorter time than the PD patientsPD patients fixate longer than CON and MCI

PET Imaging in Rhesus Monkeys

• DAT Occupancy• anesthetized monkeys• [18F] FECNT

• Brain Activation• awake monkeys• [15O] water

Rhesus30 directionsEPI1.3x1.3x1.3 microns

Dec 14, 05 (Wed) Chimp Jeanie Acute Stroke

ADC mapT2-WI Flash T2* & DWI trace

Pathway of Motor tract

Sylvian Fissure Temporal Lobe

Motor-Swallow

Motor-Face

Motor-Hand

Motor-Foot

Flow void of ICA

Flow void of MCA

Yerkes NPRC Chimpanzee Projects Include:Cognition and Aging

Hepatitis CMalariaAIDS

Yerkes NPRC Social Cognition: Joystick StudiesYerkes NPRC Social Cognition: Joystick Studies

Face recognitionInversion effectKin recognitionCategorize facial expressions ->Affect recognition using multimodal cues

Transgenic Monkeys• Born with mutant gene, e.g.,

over-expression of protein• Short time to expression• Treatment interventions• Behavioral assessments

Biomarkers and Brain Imaging

Amyloid plaques PET scan

Vaccines for Noninfectious Diseases

• Elan vaccine, AN-1792• Designed to attack and clear

out plaques.• Mice immunized at a young

age were protected from plaque deposits; in animals that already had deposits, they were halted and in some cases reversed.

• Clinical trials stopped; inflammation of brain.

• Deposits of amyloid in blood vessel walls in old monkeys.

Sequencing of Human and Nonhuman Primate Genomes (Chimpanzee, Rhesus monkey…)

• Yerkes Chimpanzee, Clint

• Differences in genome important;Similarities in genome important.

• Where and when are genes important for memory function expressed?

• How are cells expressing these genes influenced by the environment? Newfinding of structural variation in normalsubjects. Individual differences?

• Where do we spot points of vulnerability that can make the difference between healthy memory and diseases that impair memory?

GenomicsGenomics BehaviorBehavior ImagingImaging

Nonhuman Primate Models

Microarray

Optical

Infrared Eye-tracking

PET

MRI

Gene Expression

Transgenics

Basic and Translational Research

3-Dimensional Video Tracking

DiagnosisDiagnosisInterventionsInterventionsTherapiesTherapies

Experiential Impact Analysis

BioinformaticsTranslates Data into Knowledge

BioinformaticsTranslates Data into Knowledge

DeclarativeMemorySystem

Yerkes NPRC Chimpanzee Cognitive Testing Facility

Familiarization

Delay

Test

Familiar Novel

Delay