This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Apoptosis is a fundamental process in metazoan development. It is a central component of countless events during animal development that serve to sculpt and shape structures, eliminate obsolete tissues, and closely control cell number. Apoptosis also plays a critical role throughout the life of an organism for the maintenance of tissue architecture and homeostasis. Defects in apoptosis are associated with a several debilitating conditions including cancer, autoimmune disorders, and neurodegenerative diseases. An in-depth understanding of the mechanisms and regulation of apoptosis is central to the development of new, more effective therapies for these conditions. We propose to advance understanding of apoptotic mechanisms through study of the recently identified Drosophila morgue gene. morgue encodes an F-box protein that suppresses levels of Drosophila IAP-1 (DIAP1) to promote apoptosis in developing tissues. Our preliminary findings have shown Morgue to be a key regulator of mitochondrial membrane depolarization during apoptosis, and to be required for organelle breakdown and cell surface phosphatidylserine display. Loss of Morgue results in failure to commit to apoptosis and prolonged survival of corpse-like cells in vivo. Thus, proper regulation of Morgue activity is central to the progression of apoptosis in Drosophila.
The specific aims of this project are to a) characterize the influence of sumoylation and phosphorylation on Morgue activity, and b) characterize additional genes required for PS display and organelle breakdown. We will use a multidisciplinary approach to these experiments that will include classical genetic studies, as well as molecular and biochemical approaches.
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