RTI ppt template

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Incorporating Genomics in Epidemiological
Research Examples from the Partnerships for
Genomics and Molecular Epidemiology Judith T.
Lessler March 18, 2005
RTI International is a trade name of Research
Triangle Institute
3040 Cornwallis Road P.O. Box 12194
Research Triangle Park, North Carolina, USA
27709
Phone [phone]
e-mail lessler_at_rti.org
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NIH Research

• Solving the puzzle of complex diseases, from
  obesity to cancer, will require a holistic
  understanding of the interplay between factors
  such as genetics, diet, infectious agents,
  environment, behavior, and social structures.
• Zerhouni SCIENCE VOL 302 October 3, 2003

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NIH Directions

• Focus on interdisciplinary teams to solve large
  scientific problems
• Provide a seed mechanism for high-risk research
• Create programs to forge public-private
  partnerships
• NIH Institutes focus on
• Genomics and gene-environment interactions
• Sharing of data public data resources

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NIMH and Mood Disorders

• Mood disorders (depression and bipolar disorder)
  are highly heritable
• Non-genetic factors, particularly stress are
  significant in triggering episodes of mood
  disorders
• Breaking Ground, Breaking Through The Strategic
  Plan for Mood Disorders Research, National
  Institutes of Mental Health, July 2002

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Influence of Life Stress on Depression (Caspi,
et. al, 2003)

• Prospective-longitudinal cohort study of stress
  and depression
• Functional polymorphism in the promoter region of
  the serotonin transporter (5-HTT) gene
• Individuals with the short allele of the 5-HTT
  promoter polymorphism exhibited more depressive
  symptoms, diagnosable depression, and suicidality
  in response to stress
• Caspi, A, et. al (2003) Influence of Life Stress
  on Depression, Science, Vol. 301, July 18, 2003

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Partnerships for Genomics and Molecular
Epidemiology (PGME)

• Goal Build a research program that would allow
  us to conduct complex research that illuminates
  the interaction between genetics and the
  environment
• Took a building block approach
• Development of internal capabilities and
  experience
• Partnering with universities and other
  organizations that have complementary capabilities

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Partnerships for Genomics and Molecular
Epidemiology (PGME)

• Bioinformatics
• Statistical Genetics
• Proteomics
• Public understanding of genetics/genomics
• Epidemiology

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Epidemiology a Core Competency that Binds
Disciplines
Laboratory Molecular Sciences
Health Sciences
Epidemiology
Biostatistics Informatics
Social and Behavioral Sciences
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PGME Bioinformatics

• Data management and data integration
• Data types clinical, biological assays, sequence
  data, gene expression, and protein expression
• Integration of external data sets on genes,
  proteins, biological pathways
• High performance computing
• 64-cpu Linux Cluster

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PGME Bioinformatics

•  

http//gdbwww.gdb.org/
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Statistical Genetics

• Data mining
• Mathematical modeling
• Statistical Genetics genetic linkage analysis,
  genetic association mapping, gene-environment
  interactions
• Analysis of microarray and proteomic data
• Statistical and data coordinating centers

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Proteomics

• Methodologies
• Tissue Protein Isolations
• 2-D Gel Separations
• Quantitative Image Analysis
• Immunological analyses
• Technologies
• Instrument development
• Alternative separations
• Protein characterization
• Quantitative analysis

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Proteomics

• Equipment
• TOF-TOF
• 2 Ion Traps (Linear and 3-D)
• 2-D gel electrophoresis platform
• Technology Development
• Shot-gun proteomics

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RTI Shotgun Proteomics
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Partnerships

• Expertise in sequencing and gene expression
• Clinical expertise immunology, vaccine response,
  drug and alcohol abuse, heart disease, pre-term
  labor, microbial systems, pulmonology, etc., high
  performance computing, software development
• Duke, UNC, NC State, East Carolina, IBM, SAS,
  Alpha-Gamma Inc, Virginia Commonwealth
  University, and from India Institute of
  Statistical Sciences, National Institute of
  Cholera and Enteric Diseases NICED and
  Institute of Molecular Medicine

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NIAID Program on Immunity to Vaccines/Infections

• The objective is to understand role of
  polymorphisms in genes of innate and adaptive
  immunity in modulating the response to vaccines
  for two gastrointestinal tract infections
  typhoid and cholera.
• RTI International
• Institute of Molecular Medicine
• National Institute of Cholera and Enteric
  Diseases
• Duke University

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Immunity to Vaccines/Infections

• Collect blood and saliva from 1000 participants
  for each vaccine in Kolkata, India, at days 0, 3,
  and 28
• Perform vaccine related immunological assays on
  all biospecimens and classify subjects as non-,
  poor-, and good responders using ELISA and
  vibrocidal antibody assays
• Discover and validate SNP polymorphisms and
  screen all participants DNA for SNPs to 14
  innate immunity genes and genome scans for
  adaptive immunity genes

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Immunity to Vaccines/Infections

• Protein/peptide expression of 11 protein
  mediators of innate/adaptive immunity and 22
  proteins involved in cell stimulation and signal
  transduction. Using LC/MS, immunoassay, and flow
  cytometry
• Also using 2-D gel MS/MS on 100-200 proteins,
  protein isoforms and protein fragments to
  determine more generalized effects of immune
  activation, signal transduction and general
  response to vaccination,
• Analysis if association between vaccine response
  and SNPs, haplotypes, or protein expression

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Immunity to Vaccines/Infections

• Data will be included in a NIAID sponsored data
  system that will integrate data from 5 other
  similar trials
• Bioinformatics Integration Support System (BISS)

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Opportunities Abound

• NC has many resources that can be used to develop
  partnerships
• Appreciate work that Donna Spoon and others have
  done to create opportunities for sharing
  information and developing partnerships

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PGME Team (partial)

• Diane Wagener, PhD, Director of Genetic
  Epidemiology and project director for the vaccine
  research project
• Jim Stephenson, PhD, Director of Proteomics Group
• Jamie Cuticchia, PhD, Director of Bioinformatics
• Georgiy Bobashev, PhD, Director of Statistical
  Genetics

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Partnerships for Genomics and Molecular
Epidemiology

• Partnership contacts
• Judy Lessler
• lessler_at_rti.org -- 919-541-6631
• Joe Pratt
• jpratt_at_rti.org 919-541-6463