The small nematode Caenorhabditis elegans has been used with great success as a model organism for the genetic analysis of programmed cell death. Our long term goal is to use the C. elegans germ line as a genetic model system to understand how apoptosis is regulated in response to various regulatory signals. We show in this application that germ cells respond to two distinct signals: 1. a physiological pathway that is used to limit germ cell numbers, and 2. a checkpoint pathway that activates the apoptotic program in response to DNA damage. To better understand the molecular basis of these two pathways, and how they regulate the common apoptotic effector machinery, we will: 1. Isolate and genetically characterize germ 1ine apoptosis (gla) mutants. 2. Clone and characterize three strong gla genes involved in physiological germ cell apoptosis. 3. Generate and characterize null alleles in five candidate DNA damage checkpoint genes. 4. Isolate and genetically characterize ard mutants that show an abnormal response to DNA damage. 5. Clone two strong ard genes by positional cloning and/or candidate gene approach. We expect that the work described in this application will shed considerable new light on how multiple pro death or pro survival signals can be integrated within a single cell. We also expect to obtain a much better understanding of the genetic pathway(s) that mediate DNA damage response in metazoans. Because mutations in this pathway are likely to alter the sensitivity of tumor cells to DNA damaging agents, we believe that our work has the potential to greatly impact our understanding of how and why tumors can develop resistance to radio and chemotherapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM052540-07
Application #
6386146
Study Section
Special Emphasis Panel (ZRG1-CDF-5 (02))
Program Officer
Greenberg, Judith H
Project Start
1995-05-01
Project End
2002-04-30
Budget Start
2001-05-01
Budget End
2002-04-30
Support Year
7
Fiscal Year
2001
Total Cost
$231,395
Indirect Cost
Name
Cold Spring Harbor Laboratory
Department
Type
DUNS #
065968786
City
Cold Spring Harbor
State
NY
Country
United States
Zip Code
11724
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Chung, S; Gumienny, T L; Hengartner, M O et al. (2000) A common set of engulfment genes mediates removal of both apoptotic and necrotic cell corpses in C. elegans. Nat Cell Biol 2:931-7
Hengartner, M O (1999) Programmed cell death in the nematode C. elegans. Recent Prog Horm Res 54:213-22;discussion 222-4
Fraser, A G; James, C; Evan, G I et al. (1999) Caenorhabditis elegans inhibitor of apoptosis protein (IAP) homologue BIR-1 plays a conserved role in cytokinesis. Curr Biol 9:292-301

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