Toll-like receptors are critical sensors of microbial infection, responsible for the induction of the inflammatory, innate and adaptive immune responses. Over the past few years, significant progress has been made in elucidating the TLR signaling pathways. It has been defined that four signaling adapters: MyD88, TIRAP, TRIP and TRAM, are used by TLRs to induce distinct signaling pathways. While the role of these adapters has been clearly defined genetically, the biochemical and cell biological mechanisms of their functions are almost completely unknown. In this proposal, we plan to investigate the cell biology of TLR signaling, with the emphasis on the signaling adapters. Based on preliminary studies, our plan is to analyze the processes that control sub-cellular distribution of these adapter proteins, their mechanisms of recruitment to the receptors, and the engagement of the downstream signaling components. As the critical sensors of microbial infection capable of inducing powerful inflammatory responses, TLRs must combine the exquisite sensitivity to their ligands, with robust regulation to ensure the fidelity of the responses they induce. Elucidation of the cell biological principles of TLR signal transduction will help to understand the fundamental biology of the innate immune recognition.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI046688-10
Application #
7843706
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Palker, Thomas J
Project Start
1999-10-01
Project End
2011-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
10
Fiscal Year
2010
Total Cost
$351,160
Indirect Cost
Name
Yale University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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