DESCRIPTION (provided by applicant): Programmed cell death and phospholipid asymmetry are two vitally important, distinct, and interconnected biological processes essential for normal cell functions and animal development. Defects in these two processes can cause various pathological conditions and human disease, including neurodegenerative disease, autoimmune disorders, and cancer. In this proposed work, we will carry out molecular genetic, reverse genetic, biochemical, cell biological, biophysical, and functional genomic analyses to decipher basic mechanisms that regulate apoptosis and phospholipid asymmetry during animal development. For the study of apoptosis, we hope to understand the regulatory mechanisms and signaling pathways that control the release of mitochondrial apoptogenic factors during apoptosis and identify new targets and downstream pathways of the cell death proteases that execute highly organized cell disassembly and rapid removal of the dying cells. For the study of phospholipid asymmetry, we plan to identify the molecular components and regulatory machineries that generate, maintain, and alter phospholipid asymmetry, focusing on understanding phosphatidylserine (PS) asymmetry. We will decipher the functions and roles of specific phospholipids to a cell and reveal the physiological and pathological consequences of altered phospholipid asymmetry to the cell and the animals. These studies should reveal novel mechanisms, pathways, and genes that control these two fundamental biological processes, and ultimately, provide new targets, ideas, and strategies to facilitate treatment of numerous human diseases caused by abnormalities in these two important processes.