This application is for a Clinical Investigator Award, to provide support during a period of transition from post doctoral training to a career as an mdependent investigator. In carrying out the proposed studies, the principal investigator in the short term will develop further training in Molecular biology, Immunology, Mouse Genetics and Mouse Pathology. The applicants career goals are to investigate the molecular mechanisms of T cell activation and immune disorders of the gastrointestinal tract. Despite the obvious centrality of the T cell receptor (TCR) signal transduction in IBD and other autoimmune diseases, relatively little is known about the cellular correlates of the organismic phenomena known as tolerance, anergy,clonal deletion and receptor activation. Receptors which induce immune system effector function bear similarites in receptor structure and respond to antigen recognition by tyrosine phosphorylation. In T cells specific kinases known to associate with the antigen receptor complex are Ick and zap 70. This proposal aims to build on recent data developed by the applicant to elucidate steps downstream from the activity of the nonreceptor tyrosine kinase zap70 in T lymphocytes. Tyrosine kinases act in sequence, with lck phosphorylating the signal transducing elements of the TCR complex leading to zap70 recruitment and activation. The events that take place after zap7O association with receptor complex are poorly understood. We have idenitified a novel adapter molecule Sam68 which when coupled to tyrosine kinase zap7O results in T cell activation. Overexpression of a mutant form of Sarn68 inhibits calcium mobilization triggered by TCR aggregation. At present downstream targets of Sam68 are unknown. To carry out this program we propose to define elements of Sam68 which participate in subsequent interactions, and to us,e genetic and biochemical tools to isolate downstream members of this pathway. I also propose to create ES cell lines bearing targeted disruption of the Sam68 locus to obtain in vivo functional insight into its action in T cell biology. The central relevance of this work to the study of IBD lies in its focus on understanding the mechanisms of physiological lymphocyte activation, providing potential new targets for pharmaceutical intervention as well as establishing elements of a pathway whose dysregulation may some day be recognized as pathognomonic for the inappropriately activated T cell.
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|Khokhlatchev, Andrei; Rabizadeh, Shahrooz; Xavier, Ramnik et al. (2002) Identification of a novel Ras-regulated proapoptotic pathway. Curr Biol 12:253-65|
|Xavier, R; Brennan, T; Li, Q et al. (1998) Membrane compartmentation is required for efficient T cell activation. Immunity 8:723-32|