Apoptosis is a highly controlled process necessary for development and survival almost very multicellular organism. Apoptosis directly counteracts cell proliferation and these two processes are carefully balanced by external stimuli and internal cellular programs. An accumulation of knowledge has suggested that disregulation of apoptosis plays an important role in several human diseases such as cancer, neurodegenerative diseases and autoimmune diseases. In order to discover the molecular mechanisms regulating the cell death pathway, we are studying apoptosis in T cells. Apoptosis mediated by the T cell receptor (TCR) plays a pivotal role in the clonal deletion of self-reactive thymocytes and peripheral T cells. It is known that this process requires the de novo synthesis of sets of gene products. However, little is known about how apoptosis is induced and regulated upon TCR-stimulation. In an attempt to understand the signaling pathway of TCR-mediated apoptosis, we have devised a system involving the generation and characterization of several death-resistant mutant T cell hybridomas. From this study, we have identified a novel gene (TDAG51) which plays a critical role in TCR-mediated apoptosis by controlling Fas (CD95) expression, and two additional gene products (TDAG52 and TDAG53) whose expression correlated with the susceptibility of T cell hybridomas to anti-TCR induced apoptosis. We propose to extend these molecular genetic studies of TCR-mediated apoptosis by pursuing three specific aims; 10 Determine the molecular mechanisms of how TDAG51 controls apoptosis both in vitro and in vivo. 20 Investigate the role of TDAG52 and TDAG53 in TCR-mediated apoptosis by transfection experiments, 3) Characterize the death-resistant cell lines further to identify addition apoptosis-regulatory genes. The knowledge gained from studies in this application will provide important insight into the regulation of TCR- mediated cell death and may provide a basis for the design of new therapeutic strategies for various lymphomas, immunodeficiencies, and autoimmune diseases which may arise from improper control of cell death.
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