Regulated apoptosis is critical to T cell development in the thymus and controls T cell- dependent adaptive immunity in periphery. 2-catenin, a coactivator of T cell factor 1 (TCF-1), and retinoid-related orphan receptor gamma t (ROR3t) both regulate thymocyte survival via the up-regulation of anti-apoptotic Bcl-xL. In the process of studying ROR3t, we have identified 2- catenin/TCF-1 as a potential upstream pathway that controls ROR3t-mediated thymocyte survival. Deletion of TCF-1 resulted in thymocyte apoptosis and down-regulated ROR3t, whereas transgenic expression of a stabilized 2-catenin (2-catTg), which activated TCF-1 constitutively, led to enhanced thymocyte survival and up-regulated ROR3t. In contrast to its survival role in thymocytes, 2-catTg up-regulated pro-apoptotic Bid and surface Fas, and enhanced super-antigen staphylococcal enterotoxin B (SEB)-induced deletion of peripheral T cells by promoting activation-induced cell death (AICD). We thus hypothesize that the 2- catenin/TCF pathway utilizes distinct mechanisms in the regulation of apoptosis in developing T cells and peripheral mature T cells. In the first two aims of this study, we propose to elucidate the mechanisms responsible for 2-catenin/TCF-1-regulated apoptosis in thymocytes and peripheral T cells. In the last aim, we will determine whether we can control T cell-dependent allograft rejection by manipulating 2-catenin-regulated T cell survival. Public Health Relevance: This proposal is to study the mechanisms responsible for 2-catenin and ROR3t-regulated T cell apoptosis.
The use of gene therapy to enhance the expression of therapeutic genes shows great promise for future therapy in the heart, however, several hurdles remain. In this application, we will examine the newest generation of viral delivery vectors to enhance the delivery of these therapeutic proteins and to examine the mechanisms responsible for the cardioprotective effects. Moreover, we will take a major step towards translation of these findings into the clinical setting by examining their application in a porcine model.
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