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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG012466-08
Application #
6509615
Study Section
Human Embryology and Development Subcommittee 1 (HED)
Program Officer
Sierra, Felipe
Project Start
1995-05-15
Project End
2004-04-30
Budget Start
2002-05-01
Budget End
2003-04-30
Support Year
8
Fiscal Year
2002
Total Cost
$333,989
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
Sang, Tzu-Kang; Li, Chenjian; Liu, Wencheng et al. (2005) Inactivation of Drosophila Apaf-1 related killer suppresses formation of polyglutamine aggregates and blocks polyglutamine pathogenesis. Hum Mol Genet 14:357-72
Chen, P; Ho, S-I; Shi, Z et al. (2004) Bifunctional killing activity encoded by conserved reaper proteins. Cell Death Differ 11:704-13
Salvesen, Guy S; Abrams, John M (2004) Caspase activation - stepping on the gas or releasing the brakes? Lessons from humans and flies. Oncogene 23:2774-84
Kauppila, Saila; Maaty, Walid S A; Chen, Po et al. (2003) Eiger and its receptor, Wengen, comprise a TNF-like system in Drosophila. Oncogene 22:4860-7
Sogame, Naoko; Kim, Misoo; Abrams, John M (2003) Drosophila p53 preserves genomic stability by regulating cell death. Proc Natl Acad Sci U S A 100:4696-701
Rodriguez, Antony; Chen, Po; Oliver, Holt et al. (2002) Unrestrained caspase-dependent cell death caused by loss of Diap1 function requires the Drosophila Apaf-1 homolog, Dark. EMBO J 21:2189-97
Christich, Anna; Kauppila, Saila; Chen, Po et al. (2002) The damage-responsive Drosophila gene sickle encodes a novel IAP binding protein similar to but distinct from reaper, grim, and hid. Curr Biol 12:137-40
Corey, D R; Abrams, J M (2001) Morpholino antisense oligonucleotides: tools for investigating vertebrate development. Genome Biol 2:REVIEWS1015
Brodsky, M H; Nordstrom, W; Tsang, G et al. (2000) Drosophila p53 binds a damage response element at the reaper locus. Cell 101:103-13
Chen, P; Abrams, J M (2000) Analysis of programmed cell death and apoptosis in Drosophila. Methods Enzymol 322:65-76

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