ncrr: navigating the translational researcher primate models and resources stuart zola, phd...
TRANSCRIPT
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