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Our research focuses on understanding the molecular mechanism involved in the regulation of the immune system through programmed cell death (PCD). Two major PCD pathways, apoptosis and necrosis are of particular interest because they play critical roles in immune cell development, responses to pathogens, inflammatory diseases, and cancer. Apoptosis is considered a benign form of PCD, occurs at various stages during lymphocyte development and responses, and is essential for eliminating non-functional, cancerous, or self-reactive lymphocytes. Dysregulation of lymphocyte apoptosis may cause autoimmune diseases, leukemia, and lymphoma. Necrosis has long been considered unregulated cell death which leads to cell rupture, resulting tissue damage. Recent evidence demonstrates that some forms of necrosis including necropotsis are tightly controlled cell death process. We are searching, by molecular cloning and by proteomic approaches, for proteins that are involved in cell death-signaling network. Physiological functions of each protein will be studied using various in vitro cell line systems, and using whole animals by transgenics and gene targeting (knockout) in mice. Our long-term goal is to identify key regulatory steps during cell death process, that are potential targets for therapeutic intervention of various diseases. Current projects in our group are as follows. FADD-mediated apoptosis/necrosis. A number of related receptors, designated “Death Receptors (DR)”, initiate a potent cell death signal upon engagement with cognate ligands. Fas is essential for apoptosis of self-reactive lymphocytes. Several years ago, we isolated a Fas-Associated Death Domain (FADD) protein, which is a mediator of apoptotic signal transduction in at least five death receptor pathways, Fas, Tumor Necrosis Factor Receptor I (TNFR-I), DR3, 4, and 5. By FADD gene knockout studies in mice, we found that FADD not only is essential for apoptosis, but plays a role in cell proliferation as well. Future studies are aimed at understanding the molecular mechanisms in signal switching by FADD, between two drastically distinct pathways: apoptosis and necrosis.