C5a receptor on mast cells in inflammatory arthritis

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DESCRIPTION (provided by applicant): Inflammatory arthritis is a major national health care priority, yet the mechanisms of synovitis remain incompletely understood. Using a murine system with similarities to human rheumatoid arthritis, our laboratory has recently shown that mast cells are required for the genesis of synovitis. However, the mechanisms by which these cells become activated in the joint, and the effecter functions through they participate in synnovitis, remain obscure. We now present data demonstrating that mast cells deficient in the receptor for the complement fragment C5a (C5aR) or in Fc receptors for IgG (Fc gamma RIM) are incapable of mediating arthritis. Extending these experiments, the candidate proposes a series of in vitro studies to define pathways of mast cell activation and identify candidate mediators through which mast cells could promote inflammatory joint disease. Informed by these results, targeted in vivo experiments will explore the importance of selected pathways and mediators in murine arthritis. These experiments will advance our understanding of the basic biology of the mast cell and help to clarify the intriguing role of mast cells in synovitis, potentially assisting in the identification of novel targets of therapy in human inflammatory arthritis. Board certified in both pediatric and adult rheumatology, the candidate seeks the K08 Research Career Award to facilitate a transition from physician to physician-scientist. The research will be conducted under the coordinated guidance of Dr. Michael B. Brenner, a senior investigator with an established training record, and Dr. David M. Lee, a junior faculty member with an active research program and technical expertise at the bench. Through the skill of these mentors, as well as a rigorous program of formal instruction, the candidate aims to continue his professional development toward scientific independence. Ultimately, the candidate's goal is to join an academic faculty in order to pursue research focused on the pathogenesis of arthritis in childhood.