Programmed cell death plays a central role in development and in many diseases. The long term goal of our research is to understand the mechanisms of programmed cell death in the Drosophila ovary, a model system with unique advantages in genetics and cell biology. The cell death genes identified thus far in Drosophila are generally homologous to the genes controlling cell death in mammals. The vast majority of cells that undergo cell death in Drosophila use a common pathway that is increasingly well-understood. However, cell death in the ovary occurs by distinct genetic pathways. This proposal aims to uncover the mechanisms controlling two types of cell death that occur in the fly ovary: developmental cell death of nurse cells, and stress-induced death of entire follicles. Stress-induced cell death requires caspases, whereas caspases are only partially required for developmental nurse cell death. Recent findings indicate that autophagy and mitochondrial morphological changes are occurring during both forms of cell death. The proposal aims to uncover the contribution of autophagy and mitochondria to cell death in the ovary. Additionally a genetic screen will be carried out to identify genes that function in ovarian cell death, perhaps in a pathway that acts in parallel to the caspases. Nutrition and the insulin signaling pathway are known to control egg chamber progression through oogenesis. Components of the insulin signaling pathway will be investigated for their effects on both autophagy and apoptosis in the ovary. Given the high conservation of cell death mechanisms between Drosophila and mammals identified thus far, we expect that pathways that we uncover in the fly ovary will be conserved in humans. A complete understanding of the diverse mechanisms controlling cell death may reveal new therapeutic targets for diseases with excessive or insufficient cell death such as neurodegenerative disorders and cancer. Public Health Relevance: Programmed cell death plays a central role in development and in many diseases. The long term goal of our research is to understand the mechanisms of programmed cell death in the Drosophila ovary, a model system with unique advantages in genetics and cell biology. A complete understanding of the diverse mechanisms controlling cell death may reveal new therapeutic targets for diseases with excessive or insufficient cell death such as neurodegenerative disorders and cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM060574-08
Application #
7778872
Study Section
Development - 1 Study Section (DEV1)
Program Officer
Zatz, Marion M
Project Start
2001-09-01
Project End
2012-02-29
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
8
Fiscal Year
2010
Total Cost
$392,721
Indirect Cost
Name
Boston University
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
049435266
City
Boston
State
MA
Country
United States
Zip Code
02215
Timmons, Allison K; Mondragon, Albert A; Meehan, Tracy L et al. (2017) Control of non-apoptotic nurse cell death by engulfment genes in Drosophila. Fly (Austin) 11:104-111
Klionsky, Daniel J (see original citation for additional authors) (2016) Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition). Autophagy 12:1-222
Timmons, Allison K; Mondragon, Albert A; Schenkel, Claire E et al. (2016) Phagocytosis genes nonautonomously promote developmental cell death in the Drosophila ovary. Proc Natl Acad Sci U S A 113:E1246-55
Meehan, Tracy L; Yalonetskaya, Alla; Joudi, Tony F et al. (2015) Detection of Cell Death and Phagocytosis in the Drosophila Ovary. Methods Mol Biol 1328:191-206
Perkins, Lizabeth A; Holderbaum, Laura; Tao, Rong et al. (2015) The Transgenic RNAi Project at Harvard Medical School: Resources and Validation. Genetics 201:843-52
Peterson, Jeanne S; Timmons, Allison K; Mondragon, Albert A et al. (2015) The End of the Beginning: Cell Death in the Germline. Curr Top Dev Biol 114:93-119
Peterson, Jeanne S; McCall, Kimberly (2013) Combined inhibition of autophagy and caspases fails to prevent developmental nurse cell death in the Drosophila melanogaster ovary. PLoS One 8:e76046
Timmons, Allison K; Meehan, Tracy L; Gartmond, Tori D et al. (2013) Use of necrotic markers in the Drosophila ovary. Methods Mol Biol 1004:215-28
Jenkins, Victoria K; Timmons, Allison K; McCall, Kimberly (2013) Diversity of cell death pathways: insight from the fly ovary. Trends Cell Biol 23:567-74
Pritchett, T L; McCall, K (2012) Role of the insulin/Tor signaling network in starvation-induced programmed cell death in Drosophila oogenesis. Cell Death Differ 19:1069-79

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