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NAVIGATING THE TRANSLATIONAL RESEARCHER THROUGH A COMPLEX OF ANIMAL AND BIOLOGICAL RESOURCES

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Title: NAVIGATING THE TRANSLATIONAL RESEARCHER THROUGH A COMPLEX OF ANIMAL AND BIOLOGICAL RESOURCES


1
NAVIGATING THE TRANSLATIONAL RESEARCHER THROUGH A
COMPLEX OF ANIMAL AND BIOLOGICAL RESOURCES
NCRR/NIH MARCH 2006
  • Michael G. Katze
  • University of Washington
  • Washington National Primate Center

2
SEATTLE AND THE UNIVERSITY OF WASHINGTON
WWW.WASHINGTON.EDU
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WaNRC Resources
  • Core Scientific Staff
  • Intellectual Resources
  • Primate Resources
  • Primate Psychological Well-Being
  • Specialized Facilities Equipment
  • Research Support Staff
  • Animal Models Development
  • Infant Primate Research Laboratory
  • Primate Medicine / Surgery
  • Primate Pathology
  • Primate Genomics
  • Microarray satellite facility
  • Imaging (PET, MRI, CT, fluoroscopy)
  • Occupational Health and Safety
  • AIDS Virology Services Core
  • Immunology Core
  • Antigen Delivery Core
  • Colony Health Diagnostics Laboratory
  • Immunogenetics Typing
  • Biological Structure Technology Laboratory (BSTL)
  • Information Technologies
  • Bioengineering
  • Tissue Distribution Program
  • Primate Information Center
  • Primate Supply Information Clearinghouse

6
Outline
  • Mission of Meeting and Reality Check
  • My .02 as a Virologist
  • RESOURCES Non-Human Primate Genomics, Animal
    Models, Bioinformatics
  • Pandemic Influenza
  • Future of Virology
  • Questions to be Answered

7
Background
  • NCRR is investigating a potential new resource
    that will make it easier for researchers to find
    and to use NIH-supported animal and other
    biological resources. The initial developmental
    focus of the envisioned resource will be a
    web-based portal to provide translational
    researchers with direct links to the full
    spectrum of clinically relevant model systems.
  • The central component of the portal will be an
    animal information service center designed to
    enhance processing and retrieval of information
    from existing animal model databases into the
    forms most appropriate for the target users.
    Researchers will be able to tap into various
    perspectives on the most recent scientific
    knowledge about a problem and combine data of
    different types and from multiple sources in ways
    that are not currently available.
  • A second phase proposes to develop technology
    that will provide automated ways to optimize,
    sustain viability, and enable scalability of this
    resource over the longer term.

8
Objectives
  • The workshop aims to identify potential
    architectures and components to serve as the
    basis for developing a comprehensive new
    resource to describe the user communities and
    their needs determine the necessary
    characteristics of the new resource and how to
    leverage currently available resources and shared
    cyberinfrastructure in its creation and ensure
    that this translational resource will evolve in
    concert with the expanding knowledge in
    biomedical science and information technology
    that it will embody.

9
Reality Check
  • Translational Research is
  • Poorly Defined Lost in Translation on the Road
    Map
  • Too Visionary (Which is a Bad Thing?)
  • Interdisciplinary by Nature
  • Therefore Aggravating Culture Clashes
  • Study Section Unfriendly
  • Technologically Intensive
  • Computationally Intensive
  • Extremely Expenive Need Innovative Funding
    Strategies

10
Infectious Disease Prototype?
  • My .02 Functional Genomics and Non-Human
    Primate Models for Pandemic Influenza

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Biological Sciences Division Pacific Northwest
National Laboratory
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Never Met A Virus We Didnt Like
  • SARS
  • Measles
  • West Nile Virus
  • HIV-1
  • HIV-2
  • SIV
  • SHIV
  • Influenza
  • Ebola
  • Marburg
  • Vaccinia
  • Herpes Simplex Virus
  • Hepatitis C Virus

14
Functional Genomics Approaches To Study Viral
Host Interactions
  • The human (mouse, rat, etc.) genome is completely
    sequenced.
  • Rhesus Macaque Genome Is Done!
  • Global transcriptional profiling is possible.
  • Proteomics becoming high-throughput.
  • Computational biology sufficiently mature to
    interpret massive data sets.

15
Primate Genomics Interactions
NIH/DOE FUNDING NCRR P51 R24 NIDA
P30 NIAID-NIDDK-NHLBI DOE
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WWW.MACAQUE.ORG
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22,500 Probe 2nd Generation Rhesus Array
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KATZE LAB COMPUTING BIOINFORMATICS
INFRASTRUCTURE (Wallace/Proll)
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Katze Lab Software Overview
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EAM
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EAM
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Katze Lab Informatics SystemsRaw Data Through
Functional Predictions
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An Integrated Approach to Infectious Disease
Use of cell culture, mouse, and macaque animal
models to study viral infection Combine
traditional histopathological, virological, and
biochemical approaches with functional genomics
and proteomics Signatures of virulence and
insights into mechanisms of host defense
response, viral evasion, and pathogenesis
26
Avian Flu Spreads to Euro Disney (Near Paris,
France)
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Influenza and Pneumonia Deaths by Age
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Life Expectancy in the U.S. 1900-2001
Palese, P. (2004). Nature Med. Supp. 10 S82-S87.
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Transcriptional Macaque Model of Influenza
Pathogenesis
Year 1
Year 2
Year 3
Pilot study (Texas Strain) Can We Do This? 4
animals, 2 end points
Phase 1.5 (Texas Strain) New Live Vaccine NS1
(1-126) Texas Safety Efficacy
Phase 1 (Texas Strain) New Prognostic
Diagnostic Tool Validation Refinement of Pilot
Work
You are here
Yes, We Can
9 animals, 3 end points
12 animals, 2/3 end points
qRT-PCR on lung tissue qRT-PCR on bronchial brush
Bpxs IHC
Immune Studies (PBMC, BAL, dendritic cells,
serum) Arrays on CD4 CD8 cell
population Arrays on isolated dendritic cells
Baskin et al JVI, 2004
30
Global Gene Expression Profiling Of The Cellular
Response in Texas Infected Macaques.
On Macaque Arrays
  • 18,000 unique (Rhesus) macaque genes
  • 1,014 human oligonucleotides relevant to
    infectious disease research
  • 51 viral genes (from 20 viruses)
  • High degree of genetic similarity between rhesus
    and pigtailed macaques

31
Gross Pathology Demonstrates Texas Baseline
Histopathology Shows Texas Baseline Progression
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Bronchial brush into secondary or tertiary bronchi
View of secondary bifurcation from the carina
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PATHWAY ANALYSIS IN MACAQUE LUNGS FLU INFECTED
(L) VS UNINFECTED (R)
34
Pandemic Influenza Virus Reconstruction JEFF
TAUBENBERGER
  • Genomic RNA sequences were recovered from
  • Fixed, parafin-embedded lung samples from WWI
    soldiers (AFIP National Tissue Repository)
  • Lungs from exhumed frozen corpses (Alaska)
  • HA segment Reid, et al. (1999) PNAS. 961651.
  • NA segment Reid, et al. (2000) PNAS. 976785.
  • NS segment Basler, et al. (2001) PNAS. 982746.
  • MA segment Reid, et al. (2002) J. Virol.
    7610717.
  • NP segment Completed 2002. J Virol Nov-2004.
  • 3 Polymerase Gene segments Nature-2005.

35
1918 Reconstructed Flu Virus and Macaques
  • Yoshi Kawaoke Wisconsin
  • Heinz Feldmann Winnipeg
  • Experiment just completed in BSL4 in Winnipeg

36
Reconstructed 1918 Flu VirusMouse Lung Genomics
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Experimental Design
13 mice/virus infected with 106 PFU
4 mice/group sacrificed on day 4 p.i. for
determination of viral titers in eggs
9 mice/group observed for morbidity (weight
loss) and mortality for 14 days p.i.
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Increased Mortality in 1918 Infected Mice
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Global Host Response to 1918 Infection
  • Total RNA isolated from lungs collected at days
    1, 3, and 5 p.i. (5 animals per group)
  • Determined relative viral mRNA expression in
    biological replicates by qRT-PCR
  • Compared 3 individual infected animals to a pool
    of 10 mock infected lung samples
  • Array data presented as
  • - Arrays on 3 individual animals (N4 each)
  • - Error-weighted in silico pool (N12)

40
Response to 1918 Influenza Infection on Day 1
Tx91
2/6Tx91
5/3Tx91
r1918
1 2 3 P
1 2 3 P
1 2 3 P
1 2 3 P
1072 genes 2x Plt0.01
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Future of Virology Article Looking Ahead
  • Biologists, Data Analysts, Computer Specialists
  • working closely together
  • Hybrid bioinformatics software
  • take validated low throughput wet lab results
  • make genome-wide functional predictions
  • Integration of emerging technologies
  • microarrays and proteomics
  • microRNA

42
What do we really want to accomplish?
  • To define the complete host response at the RNA
    and protein level to every virus infection
  • To identify impacted pathways in common
  • To identify unique pathways
  • To cure all virus infections (with one drug?)
  • To uncover links between virus infections and
    other diseases e.g. malignancy
  • Almost 6000 array experiments in our database

43
Breakout Group Questions
  • 1. Who are the intended and potential users of
    the new resource? What tasks are they performing
    and what are their needs, particularly in
    translational science?
  • 2. What are the characteristics of this new
    resource that will best serve the users needs?
  • 3. What framework for animal model systems is
    most appropriate to serve as the basis for this
    new resource that will also support later
    development? Possibilities might include one or
    more disease categories, body or organ systems or
    tissues, etc.
  • 4. How can currently available resources and
    distributed systems information technology
    projects be leveraged to develop the new shared
    infrastructure?
  • 5. What are the requirements of a
    cyberinfrastructure framework for animal model
    systems that are most critical in order to
    provide a foundation for this new resource that
    will also support rapid technological elaboration
    and expanded use?

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HONEY_at_U.WASHINGTON.EDU 1-206-732-6135
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