Programmed cell death (apoptosis) is a gene-directed process responsible for the widespread and deliberate elimination of cells during animal development. Aberrant regulation apoptosis is firmly established in the etiology of some human cancers and also implicated in the progression of acquired immune deficiency syndrome (AIDS), neurodegenerative disorders and aging. The cytological features of apoptotic cell deaths are strikingly similar in all metazoans and several lines of evidence suggest that central molecular components required for this process may be highly conserved. The long-term goal of our research is to understand the molecular physiology of programmed cell death during the course of normal development. Our previous work has led to the identification of a complex genomic interval required for all naturally-occurring cell deaths in the Drosophila embryo. At least two genes in this interval appear to mediate central apoptotic functions in this model system. One of these genes, reaper, restores cell death in transformation assays, is dramatically up- regulated when ectopic cell deaths are induced and may, in fact, precede the onset of apoptosis in cells that are committed to die. The reaper gene also contributes important functions during abnormal cell deaths provoked either by X-irradiation or by developmental defects. We propose experiments designed to further characterize the function and regulation of reaper. Using cell culture assays and transgenic strains we will determine whether the product of the reaper gene is sufficient to induce apoptosis. We shall also determine the precise subcellular distribution of this gene product by immunocytochemical methods and utilize reporter gene constructs to determine how the action of reaper is regulated in both normal and abnormal contexts. Finally, we also propose a novel approach that will permit us to isolate additional genes required for cell death in Drosophila. Our studies will provide fundamental insights into mechanisms that underlie apoptosis. This information, in turn, may provide novel rationales for the treatment of some human diseases and could offer valuable new targets for drugs that specifically activate or block the apoptosis pathway.
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