The elimination of cells by programmed cell death (apoptosis) is a universal feature of development and aging in animals. Aberrant regulation of apoptotic cell death is also firmly established in the etiology and treatment of many human diseases including cancer, AIDS and neurodegenerative disorders. Our research seeks to understand the specification and execution of apoptosis in the genetic model, Drosophila. In this animal, three tightly linked genes, REAPER, GRIM and HID, are required for all programmed cell death in the embryo. Current evidence argues that in order to understand how these death activators elicit cell killing, we need to understand how they engage the action of caspases (cysteinyl aspartate-specific proteinases). To investigate this problem we propose complementary aims that focus on events proximal to caspase activation. One line of investigation will study an effector of REAPER, GRIM and HID that we recently discovered. This gene, referred to as DREDD, encodes a putative apical caspase that is acutely responsive to signaling by the death activators at both the protein and RNA levels. We propose biochemical and genetic studies to elucidate the precise role of DREDD in apoptosis and development. In a second line of investigation, we examine """"""""private"""""""" signaling pathways associated with the death activator, GRIM. Initial efforts will focus on GI-c, a GRIM-binding protein and probable effector of GRIM- induced apoptosis in the animal. These projects are expected to uncover significant and converging information on the molecular physiology of apoptosis in an important genetic model.
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