The role of NALPs in innate immunity

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DESCRIPTION (provided by applicant): This proposal describes a 4 year training program for the development of an academic career in Infectious Diseases. The principal investigator has completed an M.D. and a Ph.D. in Immunology at Temple University, residency training in Internal Medicine at Yale University School of Medicine and is currently completing an Infectious Diseases fellowship at the same institute. This program will allow the candidate to expand on his previous scientific skills and to become proficient in the fields of innate immunity and host-pathogen interactions. Dr. Richard Flavell will mentor the principal investigator's scientific development. Dr. Flavell is a recognized leader in the field of innate immunity. Dr. Flavell is the Chairman of the Section of Immunobiology, and has successfully trained numerous postdoctoral fellows and graduate students. Research will focus on a newly discovered family of cytoplasmic molecules called NALPs, which serve as key elements in the formation of proinflammatory responses. We have previously demonstrated that NALP3 and ASC are required for the activation of caspase-1 in response to multiple inflammatory stimuli. We plan to examine how the NALP3/ASC/caspase-1 pathway is regulated, and will use loss of function mutagenesis to evaluate the physiologic role of NALP10 in this process. The specific aims include: 1) Determining if NALP10 can inhibit the NALP3/ASC/caspase-1 pathway and elucidating the mechanism by which such an inhibition occurs. 2) Determining how NALPS and IPAF can direct the activity of caspase-1 towards cytokine processing and/or cell death. 3) Examining if NALPS is necessary for the induction of joint inflammation in rheumatoid arthritis and if NALP10 can inhibit this process. Understanding the role the NALP family plays in innate immunity has many important health-related implications, ranging from fighting infections to understanding the mechanisms behind inflammatory disorders such as the periodic fever syndromes and rheumatoid arthritis. This K08 award will greatly assist the candidate's research into innate immunity and inflammation, and provide him with time and resources to develop into a skilled independent investigator.