Apoptosis is a physiological cell suicide process. It plays essential roles in development, tissue homeostasis, and protection against viral infection and formation of cancer. Apoptosis is controlled by a cell intrinsic death pathway, at the core of which are a group of aspartic acid specific cysteine proteases termed caspases. Caspases normally exist in the cytoplasm as inactive precursors and are activated during apoptosis through proteolytic processing. Once activated, caspases cleave various cellular proteins, which leads to dismantling of cells. The conversion of caspase precursors to mature caspases is a key regulatory step in apoptosis, and is subject to intricate regulation by other anti and proapoptotic proteins. In this proposal, we will investigate three interrelated aspects of caspase activation: 1) the mechanism by which caspases are activated, 2) the inhibition of caspase activation by a family of apoptosis inhibitors termed IAPs, and 3) the regulation of the caspase activator Apaf1 and CED4. These studies would lead to an improved understanding of the regulation of apoptosis and may identify new therapeutic targets for the treatment of related diseases, ranging from cancer and autoimmune disorders to neurodegenerative diseases, immunodeficiency, and ischemic injury.
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