GTP-BINDING PROTEIN RHO IN T CELL SIGNALING PATHWAYS

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Having been clinically trained in Internal Medicine and Infectious Diseases. I have long been intrigued by the biological responses to disease. My interest in Infectious Diseases and the basic processes that govern immune responses led me to the study of signal transduction pathways in leukocytes. Over the last several years. I have devoted the majority of my time to developing an understanding of the molecular biology and biochemistry of lymphocyte signalling and particularly the importance of small G proteins in this process. Building upon this foundation, my goal is to make the transition from a postdoctoral researcher to an independent investigator with an expertise in basic signal transduction in leukocytes. The T cell receptor complex (TCR) mediated signalling processes that are necessary for activation and proliferation of lymphocytes during immune responses. Ligation of the TCR by antigenic stimuli drives cellular responses that include upregulation of cytokine gene expression, and, ultimately, T cell activation. In addition, ligation of the TCR leads to remodeling of the action cytoskeleton; interactions between the TCR and this action cytoskeleton are crucial for effective T cell activation. Members of the Rho subfamily of GTPases are likely candidates to function as regulators of TCR-mediated signal transduction pathways. The role of Rho in lymphocytes, however, has received little attention. Studies in other systems suggest that Rho likely coordinates intracellular signalling pathways regulating both cytoskeletal remodeling and protein kinase-activated gene expression. The overall objective of this work is to investigate the hypothesis that Rho proteins coordinate such dual signal transduction pathways in lymphocytes, specifically those pathways emerging from TCR engagement and leading to effective T cell activation. Our study aims will be to 1) establish the role of Rho during classic T cell activation pathways, and to 2) characterize the function of Rho in the interaction between the TCR and early signalling events occurring at the plasma membrane. Using a transient expression system based on Sindbis virus we will express Rho proteins, including constitutively active and dominant negative mutants. Inlyphocytes; in addition, we will express C3 exoenzyme a specific inhibitor of Rho function. These tools will allow us to carefully delineate the role of Rho during T cell activation as assessed by both downstream cytokine gene expression and by alterations in early TCR signalling events at the plasma membrane. The environment in which I will complete this project is ideal. Experts in the areas of immunology. G protein signalling and protein biochemistry are committed to my efforts and will provide a rigorous academic milieu in which I can develop my skills effectively. Advocates within the Beirne Carter Center for Immunology and the Departments of Medicine and Microbiology will insure that I receive excellent training as I make the transition to an independent investigator.