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Proteomics in the Neurosciences Summary


Proteomics in the Neurosciences

National Institute of Neurological Disorders and Stroke
Wyndham Washington Hotel
Washington, D.C.

December 9-10, 2002

Meeting Summary

This workshop was convened by the National Institute of Neurological Disorders and Stroke for the purpose of reviewing the current status of proteomics, to engage scientists from various disciplines of proteomics and neuroscience in discussing issues to the study of the brain proteome, to identify the opportunities and requirements for the effective use of proteomics technologies in neuroscience research, and to determine the best proteomics tools and resources useful in the study of basic brain functions in normal and diseased states.

Proteomics is the systematic characterization of the complete set of proteins in a cell or tissue at a particular time. The levels of characterization may include various properties of the proteins such as its primary sequence, quantity, modification state, regulation, subcellular localization, structure, interaction partners and activity or cellular function that is performed in a large-scale fashion. Because of the immense datasets that can come from proteomic projects, robust bioinformatics and data management is a requisite for such studies. Proteomic approaches are useful in understanding the function of proteins, determining protein interaction partners (with other proteins, lipids, carbohydrates, metabolites), involvement in cellular pathways (such as signaling, metabolism, cell cycle, neuronal differentiation, apoptosis), profile changes through development and disease, for diagnosis and effects of treatment through monitoring of biomarkers and surrogate markers, and for target identification and drug discovery.

Proteomics is emerging as a powerful research tool in examining protein function, biochemical pathways and molecular networks. Separation-based approaches in proteomics may include high-resolution 2-D PAGE coupled with mass spectrometry (MS) and liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). On the other hand, nonseparation-based approaches may include direct MS in situ or the use of protein microarrays or other affinity-capture agents. Protein profiling can best be approached by differential isotope-labeling of test and control samples followed by MS. One of the major challenges for proteomic technologies is to increase the coverage of the proteome and have the capability to examine greater than 5000 proteins at a time. Being able to monitor post-translational modifications and to quickly ascertain where the proteins are inside the cell are also major challenges. Structural proteomics or the study of the 3-D structure of proteins by crystallography or NMR was not part of this workshop.

Neuroscience can benefit tremendously from the study of the proteome of the nervous system, and to be able to unravel its molecular organization and interactions, and cross talk between different cell types, various neurotransmitter receptors within the same synapse or across the synaptic cleft. This can be achieved at several different levels within the hierarchy of the nervous system which can be parsed with respect to the organization of the central and peripheral nervous systems, which by themselves can be further defined into various anatomical regions, such as cerebrum, cerebellum, hippocampus, and the local and distant circuits within those regions. Within those circuits are the various cell types (neurons, glia, oligodendrocytes) that may have their own subcellular compartments, synapses, axons and dendrites. This complex organization is flanked on one end by the phenotype and function, such as cognition, memory, learning, behavior, and on the other end by the molecules making up the genome, transcriptome, proteome and metabolonome that subsumes this organization and function.

The overall goal of the workshop was to critically assess the state and usefulness of proteomics as it applies to specific issues of the nervous system, and to identify areas where NINDS might play a role in facilitating the most effective use of proteomics in the neurosciences. The workshop addressed key issues regarding current and emerging technologies in proteomics, scientific and practical challenges germane to proteomics of the nervous system, integration and annotation of large protein databases, and how proteomic discoveries can be rapidly translated into prevention, treatment, and cures for neurological diseases. The following specific recommendations were made by the participants:

  • Recommendations for proteome analysis
    • Strategy
      • List of all brain proteins when technology permits
      • Functionally defined sets of proteins (e.g. apoptosis, signaling, GPCR, channels) as a good starting point
      • Subcellular compartments, e.g. synaptosome
      • Comparative analyses of model organisms
    • Resources
      • Access to appropriate platforms and training
      • Monoclonal antibody arrays
      • cDNA clones for expression into recombinant proteins
      • Tissue repositories
    • Technology innovations
      • Improved resolution and dynamic range
      • Isolation of individual cell types and subcellular fractionation, especially for low abundance proteins and membrane-bound proteins
      • Single cell proteomics
    • Neuroproteome alliance
      • Trans-NIH cooperation for common tasks
      • Promotion of centers and other collaborative efforts
      • International liaison and coordination of efforts
    • Recommendations for Databases
      • Central repository
      • Standards for data formatting to facilitate data comparison, exchange, verification and publication
      • Proteomic databases that will be interoperable with other databases, such as genomic and neuroscience-related databases, with interfaces to clinical information

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Agenda

Proteomics in the Neurosciences

Sponsored by NINDS, NIH
December 9-10, 2002

Wyndham Washington Hotel
1400 M Street, NW
Washington D.C. 20005
Phone: 202-429-1700

Chairs: Samir Hanash and Seth Grant
Co-Chairs: Danilo Tagle and Randall Stewart

December 9

8:00-8:45 AM Registration and breakfast
   
8:45-9:00 AM Welcome Remarks (Robert Baughman, Assoc. Director for Technology Development, NINDS)
Statement of workshop goals, Danilo Tagle, Program Director in Neurogenetics
   
9:00-10:00 AM Sam Hanash (U Michigan/ HUPO)- Overview of proteomics and its applications
Seth Grant (U Edinburgh) - Proteomics and the complexity of the nervous system
   
10:00-10:30 AM Break
   
10:30-12:40 PM Session 1 High-throughput technologies in Proteomics (Samir Hanash and Randall Stewart)
Gavin Macbeath (Harvard U) - Protein arrays for functional genomics and high throughput screening
Michael Snyder (Yale) - Global analysis of biochemical activities using proteome chips in yeasts
Richard Caprioli (Vanderbilt U) - Spatial analysis of proteins in tissue by MALDI-MS
Richard Smith (Batelle Pacific Northwest Labs) - Technology for nervous system proteome analysis
Norman Dovichi (U Washington) - Single cell proteomics
   
  Discussion (30 minutes) - 1) What are the strengths and weaknesses of these techniques in terms of their cost, capacity, resolution and usefulness of the data? 2) Do some of these techniques have special usefulness for studying tissue and cellular proteomics in the nervous system? 3) What are the special challenges in the large-scale study of proteins in the nervous system? 4) Are there emerging technologies that will provide major new capabilities?
   
12:40-1:40 PM LUNCH (sponsored by HUPO)
   
1:40-3:50 PM Session 2 Informatics (Samir Hanash and Randall Stewart)
   
  Helmut Meyer (Ruhr University, Germany) - The Human Brain Proteome Project
Cathy Wu (Georgetown U) - PIR protein knowledge base for functional proteomics
Edward Marcotte (U Texas Austin) - Integrating large scale biological data
Wen Yu (Diversa) - High-throughput data analysis platform for a large-scale proteomics project
Christian von Mering (EMBL) - Comparative assessment of large-scale data sets of protein-protein interactions
   
  Discussion (30 minutes) - 1) What is the status of collection, management and sharing of proteomics data at present? 2) What strategies for data management and sharing work best and what kind of data are most useful? 3) As projects scale up, what platform works is necessary for integrating various databases, such as protein profiles, gene expression changes, post-translational modifications, subcellular distribution, comparative protein changes across cell types, different species, etc..? 4) Do proteomics studies in neuroscience present any special data management problems?
   
3:50-4:20 PM Break
   
4:20-6:15 PM Session 3 Functional and Interaction Proteomics (Seth Grant and DaniloTagle)
 
   
  Seth Grant (U Edinburgh) - Proteomics of multiprotein complexes: The NMDA receptor
Joakim Klose (Humboldt University) - A theory of proteomics and the study of genetic defects in brain
Robert Qi (Singapore) - Proteomics of neuronal Cdk5 signaling complexes in brain
Edward Cooper (UCSF) - Proteomic dissection of M-channel phosphorylation
  Discussion (30 minutes) - 1) What are the best ways to dissect the functional states of a protein or protein complex? 2) How can one measure the specificity, stoichiometry, kinetics and affinity of protein interactions in a complex or pathway? 3) How might one track the proteomic changes from brain tissues or cells that are highly active, plastic and interconnected? 4) How might NINDS accelerate the analysis of various signaling and protein complexes in the brain?
   
  Adjourn
   
  December 10
   
8:00-8:30 AM Breakfast
 
   
8:30-10:20 AM Session 4 Expression Proteomics (Seth Grant and DaniloTagle)
   
  Kelvin Lee (Cornell U) - Proteome markers for Alzheimer's Disease Diagnosis (also BSE)
Garth Cooper (U Auckland) - Proteomic analysis of the brain in AD
Kevin Wang (U Florida) - Proteomics of trauma and acute CNS injury
Elisabetta Gianazza (U Milan) - Acute-phase proteins before cerebral ischemia in stroke-prone rats: identification by proteomics
 
   
  Discussion (30 minutes) - 1) How might proteomic technologies be applied or developed that will accelerate identification of proteins involved in pathogenesis or as biomarkers or drug targets for neurological disorders and brain injuries? 2) What is the best approach to integrate cross-platform approaches to the study of neurological diseases? 3) How might the identification of a disease proteome lead to translational research? 4) How might NINDS play a role in encouraging collaboration of academic and pharmaceutical enterprises such that large-scale proteomics efforts lead to meaningful clinical applications?
   
10:20-10:50 AM Break
 
   
10:50-1:00 PM Final Session:
Final Session: Recommendations
Future Research Priorities
Potential Collaborations
Funding Strategies
 

General questions for final session:

  1. What steps could NINDS take to facilitate the most effective use of proteomics approaches in neuroscience?
  2. How could the presently available facilities and access for neuroscientists be improved?
  3. What proteomics approaches show special promise in neuroscience?
  4. Is there a need to develop new proteomics technologies for unique applications in the neurosciences?
  5. In the neurosciences what are the pros and cons of distributed (individual labs) versus centralized (core center) proteomics resources for each of the major approaches?
  6. When core facilities are required, what are the pros and cons of supporting the use of existing university or commercial centers versus supporting the establishment of centers devoted to use by neuroscientists? Are the problems and techniques for working on the nervous system so unique that fostering a "neuroscience proteomics" community makes sense?
  7. Is there an argument for centralized data storage and sharing of neuroscience proteomics data? How can multiple large-scale efforts be integrated?
  8. What lessons from studies in bacteria, yeast, or other systems are useful in guiding proteomics research in the nervous system?

 

1:00 pm Box lunch (sponsored by HUPO)
 

Meeting ends

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Participants

List Of Speakers

Richard Caprioli, Ph.D.
Department of Biochemistry
Vanderbilt University

Edward Cooper, M.D., Ph.D.
Department of Neurology
University of Pennsylvania Medical Center

Garth Cooper, D.Phil.
School of Biological Sciences
University of Auckland

Norman Dovichi, Ph.D.
Department of Chemistry
University of Washington

Elisabetta Gianazza, Ph.D.
Dipartimento di Scienze Farmacologiche
Universita degli Studi di Milano, Italy

Seth Grant, M.D.
Division of Neuroscience
University of Edinburgh

Samir Hanash, M.D., Ph.D
Pediatrics Hematology Oncology
University of Michigan/HUPO

Joachim Klose, M.D., Ph.D.
Institute of Human Genetics
Humboldt-University Berlin,

Kelvin Lee, Ph.D.
Department of Chemical and Biomolecular Engineering
Cornell University

Gavin MacBeath, Ph.D.
Department of Chemistry and Chemical Biology
Harvard University

Edward Marcotte, Ph.D.
Department of Chemistry and Biochemistry
Institute for Cellular and Molecular Biology
University of Texas at Austin

Helmut Meyer, Prof., Dr.
Medical Proteom-Center
Head of MPC
Ruhr-Universitat-Bochum
Medizinisches Proteom-Center
Germany

Robert Qi, Ph.D. Department of Biochemistry
Hong Kong University of Science and Technology
Clear Water Bay, Kowloon, Hong Kong

Richard Smith, Ph.D.
Biological Sciences Division
Pacific Northwest National Laboratory

Michael Snyder, Ph.D.
Department of Molecular, Cellular and Developmental Biology
Department of Molecular Biophysics and Biochemistry
Yale University

Randall Stewart, Ph.D.
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Danilo Tagle, Ph.D.
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Christian Von Mering, Ph.D.
Computational and Structural Biology
European Molecular Biology Laboratory
Heidelberg, Germany

Kevin Wang, Ph.D.
Department of Psychiatry
McKnight Brian Institute
University of Florida

Cathy Wu, Ph.D.
Protein Information Resource
Georgetown University Medical Center

Wen Yu, M.S.
Department of Molecular Diversity
Diversa

List of Participants

Farid Ahmed, Ph.D.
Department of Neuroscience
Georgetown University

Rolf Apweiler, Ph.D.
European Bioinformatics Institute
Wellcome Trust Genome Campus
Hinxton, Cambridge, UK

Chiiko Asanuma, Ph.D.
National Institute of Mental Health
National Institutes of Health

Robert Baughman, Ph.D.
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Claudio Caamano, Ph.D.
Mental Health Research Institute
University of Michigan

Catherine Campbell, Ph.D.
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Mandeep Singh Chadha, M.D.
Pediatric Critical Care Medicine
Children's Hospital of Pittsburgh

Christine Colvis, Ph.D.
National Institute on Drug Abuse
National Institutes of Health

Mark Cookson, Ph.D.
National Institute on Aging
National Institutes of Health

Susan Daniels, Ph.D.
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Christopher Destache, Pharm. D
Center for Neurovirology and Neurodegenerative Disorders
University of Nebraska

Simone Di Giovanni, M.D.
Department of Neuroscience/Genetics
Georgetown University

Peter Dudley, Ph.D.
National Eye Institute
National Institutes of Health

Alan Faden, M.D.
Department of Neuroscience
Georgetown University

Yang Fann, Ph.D.
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Robert Finkelstein, Ph.D.
National Institutes of Health
National Institute of Neurological Disorders and Stroke

Nancy L. Freeman, Ph.D.
National Institute on Deafness and Other Communication Disorders
National Institutes of Health

Weimin Fu, M.D., Ph.D.
Department of Pharmacology
Weill Medical College of Cornell University

Meg Grab, Ph.D.
National Institute of Mental Health
National Institutes of Health

Katrina Gwinn-Hardy, M.D.
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Jack Harding, Ph.D
Division of Comparative Medicine
National Center Research Resources
National Institutes of Health

Ronald Hayes, Ph.D.
Department of Neuroscience
E.F. and W.L. McKnight Brain Institute
University of Florida

Henning Hermjakob, Dipl.-Inf.
European Bioinformatics Institute
Wellcome Trust Genome Campus
Hinxton, Cambridge, UK

Masaki Hosoya, Ph.D.
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Thomas Jacobs, Ph.D.
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Edward Jauch, M.D., M.S.
Department of Emergency Medicine
University of Cincinnati
Charles Jennings, Ph.D.
Editor, Nature Neuroscience

Dong-Won Kang, M.D., Ph.D.
Surgical Neurology Branch
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Julia Karow, D.Phil.
Editor, ProteoMonitor
GenomeWeb LLC

Christina King
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Susan Knoblach, Ph.D.
Department of Neuroscience
Georgetown University Medical Center

Alan Koretsky, Ph.D.
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Story Landis, Ph.D.
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Gabrielle Leblanc, Ph.D.
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Yuan Liu, Ph.D.
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Carlos Luciano, M.D.
Division of Neurology
University of Puerto Rico School of Medicine

Scott Mader, M.A.
Professional Education Department
Biosite, Inc.

Cynthia McCormick, M.D.
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Mary Ellen Michel, Ph.D.
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Sheldon Miller, Ph.D.
National Eye Institute
National Institutes of Health

Vilen Movsesyan, Ph.D.
Department of Neuroscience
Georgetown University

Thomas Neubert, Ph.D.
Skirball Institute of Biomolecular Medicine
New York University School of Medicine

Lisa Neuhold, Ph.D.
National Institute on Alcohol Abuse and Alcoholism
National Institutes of Health

John Park, M.D., Ph.D.
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Sussan Paydar, Ph.D.
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Carlos Pena, Ph.D.
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Peipei Ping, Ph.D.
Division of Cardiology
David Geffen School of Medicine
University of California at Los Angeles

Sandra Rossie, Ph.D.
Department of Biochemistry
Purdue University

Jeremy Schonhorn, Ph.D
Genzyme Diagnostics, Research and Development
Genzyme Corporation

Paul Sheehy, Ph.D.
National Institute of Neurological Disorders and Stroke
National Institutes of Health

Karen Skinner, Ph.D.
National Institute on Drug Abuse
National Institutes of Health

Min Song, Ph.D.
National Cancer Institute
National Institutes of Health

Howard Steinberg, Ph.D.
Division of Research Development
Northeastern University

Bogdan Stoica, M.D.
Department of Neuroscience
Georgetown University Medical School

Yang Tang, M.D., Ph.D.
Department of Neurology
University of Cincinnati

Ronald Taussig, Ph.D.
Department of Pharmacology
UT Southwestern Medical Center at Dallas

Kenneth Wagner, Ph.D.
University of Cincinnati College of Medicine
Veterans Affairs Medical Center

Bradley Wise, Ph.D.
National Institute on Aging
National Institutes of Health

Mary Wolpert, Ph.D.
National Cancer Institute
National Institutes of Health

Valerie Wojna, M.D.
Department of Neurology Service
University of Puerto Rico

Alexander Yakovlev, Ph.D.
Department of Neuroscience
Georgetown University

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Last updated April 8, 2011