In the post-genomic world, it is possible to harness the power of the new technologies (genomics, proteomics, bioinformatics, and other tools) to address fundamental mechanisms of human disease. Traditional grants, intended to support hypothesis-driven research, still have a major and important role to play. Under the aegis of this proposal, however, we will emphasize the practice of discovery-based research, applying the new technologies to ask and answer very broad questions in appropriate model systems. We are confident that the data developed through our efforts will present challenging new hypotheses to be pursued by ourselves and by the scientific community at large. This will occur by direct and timely communication of information to the at-large research community via the consortium's web site.

RESEARCH TEAM

To accomplish our long-term goals, investigators with expertise in many distinct areas of basic science will be required. Below is a list of the principals involved who are committed to make certain that we achieve the goals delineated here. The primary focus will be on the expertise needed to achieve our goals and the specific role that each investigator will play. Publication details, honors and awards and participation with journals, review groups etc are found in the biosketches included herein. Each of the members of this team is an internationally recognized expert in his or her field of research and/or clinical experience.

RICHARD ULEVITCH, Ph.D. Dr. Richard Ulevitch will serve as the Program Director. For more than two decades, his research has focused on basic research with a long-term goal of defining the pathogenic mechanisms operative in septic shock. His laboratory has produced a number of seminal discoveries that have provided new paradigms to understand septic shock. He has participated in nearly all aspects of the research; this includes the most basic molecular biology approaches to identifying new genes, discovery and structure/function characterization of key proteins (LPS binding protein, CD14, the p38 MAP kinase family and pathway, etc), development of animal models relevant to septic shock and extension of basic studies into potentially new therapeutics. His broad scientific background from his Ph.D. training in enzyme mechanisms through his nearly 30 years of experience in the field of innate immune responses to infection make him ideally suited to direct the program outlined in the Phase II grant.

ALAN ADEREM, Ph.D. Dr. Aderem is an internationally recognized immunologist and cell biologist who headed the Laboratory of Signal Transduction at The Rockefeller University in New York before moving to the Department of Immunology at the University of Washington in 1996. He is one of the founding members of the Institute for Systems Biology, as well as Professor and Associate Director. His early research, in biophysics, dealt with the manner in which cells convert energy into work. In 1982 he moved to The Rockefeller University in New York, where he began a classical series of studies investigating the function of macrophages as innate immune effector cells. Dr. Aderem has worked on the communication networks within the cell that are involved in the internalization and killing of pathogens and the coordination of the ensuing inflammatory response. In addition, he has worked on the mechanism by which LPS stimulates macrophages for almost twenty years. More recently Dr. Aderem has focused on the establishment of high throughput, single-cell, assays of macrophage function. He will serve on the GLUE grant steering committee, ensure the efficient running of the Genomics core, and direct a bridging project dealing with macrophages responses to bacterial products.

RUEDI AEBERSOLD, Ph.D. Dr. Aebersold is a Professor and founding member of the Institute for Systems Biology. He is internationally recognized for his work in analytical protein biochemistry and proteomics, and is actively involved in developing new technologies for the comprehensive analysis of regulated biological systems. Dr. Aebersold will direct the proteomics core.

BRUCE BEUTLER, M.D., Ph.D. Dr. Beutler has contributed major, seminal discoveries in field of innate immunity. These include the role of TNF-a as a key mediator of the innate immune response, cutting edge molecular genetic approaches as evidenced by his identification of mutations in murine TLR4 using positional cloning to identify Lps gene, development of novel anti-inflammatory therapies and studies of polymorphisms in human disease. Dr. Beutler combines a medical background with proven expertise in molecular biological and genetic approaches to understand human disease. Dr. Beutler will also assume key supervisory/administrative roles as head of Molecular Biology Core and Steering Committee.

TIMOTHY GALITSKI Ph.D. Dr. Timothy Galitski, Ph.D., is a Burroughs Welcome Fund Career Awardee in the Biomedical Sciences and an Assistant Professor at the Institute for Systems Biology. His research spans the areas of genetics, microbiology, functional genomics, and computational biology. Dr. Galitski's accomplishments include the identification of mechanisms of adaptive mutation in bacteria, the discovery of gene regulation by ploidy, the development of genomic data-mining utilities, and the development of methods to compute predictive models of the global modular structure of complex biological systems.

LEROY HOOD, M.D., Ph.D. Dr. Hood is President, Director, and Professor of the Institute for Systems Biology, of which he is a founding member, and an affiliate professor of Molecular Biotechnology and Immunology at the University of Washington school of Medicine. He is an internationally recognized expert in the development and application of new technology for the analysis of biological systems. It is also important to recognizing his pioneering work defining developmental aspects of adaptive immunity. Indeed he received the Lasker Award for studies of immune diversity. Dr. Hood will serve as co-director of the Genomics core and as a member of the Steering Committee.

JOHN MATHISON, Ph.D. Dr. Mathison received his Ph.D. training in the Department of Pathology at the University of Alabama in Birmingham. Dr. Mathison has been associated with the Principle Investigator for more than 20 years. He has been directly involved in seminal observations with Dr. Ulevitch and colleagues including the discovery of the function of CD14. He has a strong background in pathology, animal model studies and development, production of monoclonal antibodies as well as large-scale purification and development/implementation of immunoassays for biologicals. Dr. Mathison Ph.D. has also agreed to become the Phase II Glue Grant Administrative Manager. He is ideally suited for this position since during the past decade he has served in this capacity in the laboratory of Dr. Ulevitch overseeing much of the daily operations. He will coordinate communication among various sites including web site management, organization of video conferencing, monitoring of budgets, etc. Most importantly, as an ex officio member of the Steering Committee he will assist Dr. Ulevitch with preparation of reports so that the Steering monitor can appropriately monitor progress (goals and milestones) and evaluate actual progress versus what is desired according to the written plans.

ROBERT MUNFORD, M.D. Dr. Munford, who holds the Bromberg Chair in Internal Medicine at UT Southwestern Medical Center, is a physician-scientist whose investigative career has focused on host mechanisms for detoxifying bacterial LPS. His laboratory identified, purified, cloned, and characterized the only known animal enzyme that detoxifies LPS, acyloxyacyl hydrolase. In another arena he pioneered in the use of inflammation-regulated promoter-enhancer systems to control the production of anti-inflammatory recombinant proteins in vivo ("physiologically-responsive gene therapy"). His scientific experience and his clinical expertise in infectious diseases and sepsis will be valuable assets for this collaborative group. He will serve as a member of the Steering Committee.

JEFFREY RAVETCH MD, Ph.D. Dr. Jeffrey Ravetch holds the Theresa and Eugene M. Lang Chair, The Rockefeller University where he heads the Laboratory of Molecular Genetics and Immunology. Dr. Ravetch's accomplishments include the isolation and characterization of the chemokine, IP-10; the cloning and physical mapping of the first malarial parasite chromosome; the cloning of the first Fc receptor and the molecular definition of the family of immunoglobulin Fc receptors; the identification of the mechanism of the Arthus reaction; the definition of the inhibitory immunoreceptor motif (ITIM) and its mechanism of modulating ITAM activation; the discovery of the role of immunoglobulin receptors in mediating antibody triggered inflammation in vivo; and the mechanism of immunosuppression by IVIG. Dr. Ravetch will study the interface between adaptive and innate immunity during bacterial infection. He will also serve on the Glue steering committee.

JONATHAN SPRENT MD, Ph.D. Dr. Sprent is a Professor in the TSRI Immunology Department. He is an internationally recognized expert in the developmental aspects of acquired immunity (a member of the Royal Society to name one of international awards and honors). His views of the interactions between the innate and acquired immune system may be considered unique since Dr. Sprent is among the few immunologists who view the immune system as interacting organs and/or tissues rather than in the context of isolated cells. This perspective will be crucial in maintenance of the focus of this program. Moreover he understands the needs of complex organizational structures having been a key person in setting policies of the American Association of Immunologists; he is a recent past president of this group. Dr. Sprent will be a member of the Steering Committee and perhaps more importantly will be available for consultation with the Program PI, Dr. Ulevitch, on an as needed basis since their offices are nearby at TSRI.

RALPH STEINMAN M.D., Ph.D. Dr. Ralph Steinman is the Henry G. Kunkel Professor, head of the Laboratory of Cellular Physiology and Immunology and Director of the Christopher H. Browne Center for Immunology and Immune Diseases. Dr. Steinman investigates the fundamental mechanisms of cellular immunity, including studies aimed at developing immune-based therapies to fight tumors and designing treatments for infectious diseases such as AIDS and tuberculosis. He discovered dendritic cells and is responsible for many of the seminal studies on the function of these professional antigen-presenting cells. Dr. Steinman will study the interaction of dendritic cells with microbial pathogens, and serve on the Glue steering committee.

LUC TEYTON M.D., Ph.D. Dr. Teyton received his scientific training in immunology and virology. His clinical training includes internal medicine and infectious disease with a specialty in infectious diseases with a board certification in Rheumatology. Dr. Teyton has been at TSRI for more than 10 years. During this time he has developed a high level of expertise in recombinant protein expression, purification and crystallization. Moreover his knowledge of biophysical techniques and plasmon resonance is invaluable in developing studies to probe protein-protein and ligand-protein interactions. Included in his background is the use of many biophysical methods applicable to biology such as analytical ultracentrifugation, microcalorimetry, FRET. He has played a key role in determining the complete structure of key cell surface receptors of the innate immune system and is currently working on solving the structure of human CD14. He will be director of the Biological Reagent Core.

DAVID UNDERHILL, Ph.D. Dr. Underhill is a Senior Research Scientist at the Institute for Systems Biology. He is a highly skilled cell and molecular biologist with a great deal of experience in a variety of fields related to this proposal. As a graduate student he worked on the assembly of the multi-subunit vacuolar H+-ATPase. During post-doctoral studies at The Rockefeller University and the University of Washington he developed high throughput systems to rapidly evaluate gene products with putative roles in macrophage function. In recent work Dr. Underhill has been responsible for key discoveries in the specificity of Toll-like receptors (TLRs) 2, 4, and 6 for their various ligands and has developed methods for macrophage transfection and dominant-negative protein expression that are being used by others in the field. Dr. Underhill will oversee the bridging project dealing with the signaling pathways of the TLRs.