Cell death is a fundamental process in animal development and homeostasis, and mis-regulation of cell death is associated with a large number of human diseases including cancer and neurodegenerative disorders. While much is known about mechanisms of apoptotic cell death, far less is known about non-apoptotic forms of cell death which contribute significantly to development and disease. Our research focuses on uncovering the mechanisms that control a non-apoptotic form of cell death that occurs naturally in the Drosophila ovary, a model system with powerful tools in genetics and cell biology. During late stages of oogenesis, germline- derived nurse cells undergo synchronous programmed cell death. In the prior grant periods, we determined that developmental nurse cell death can occur independently of apoptosis and autophagy genes, and nurse cell death displays hallmarks of necrosis. We recently discovered a transcription factor that inhibits nurse cell death more strongly that combined inhibition of apoptosis and autophagy. Furthermore, we have found that follicle cells, which surround the nurse cells, act non-cell-autonomously to promote nurse cell removal. We propose that nurse cell death involves collaboration between novel pathways acting autonomously in the germline and non-autonomously in the surrounding somatic follicle cells. This proposal aims to uncover the network acting in the nurse cells and follicle cells that culminates in nurse cell death. First, we will investigate the events occurring in follicle cells, nd how these coordinate with nurse cell death. Second, we will characterize the targets of transcription factors found to direct the cell- autonomous cell death pathway in nurse cells. Third, we will determine how the upstream activators of nurse cell death control specific nuclear events and interface with downstream effectors. Given the high degree of conservation of cell death mechanisms between Drosophila and mammals identified thus far, we expect that pathways that we uncover in the fly ovary will provide insight into the diversity of cell death mechanisms in humans. A complete understanding of the 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. Our research aims 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 #
2R01GM060574-10A1
Application #
8579129
Study Section
Cellular Signaling and Regulatory Systems Study Section (CSRS)
Program Officer
Maas, Stefan
Project Start
2001-09-01
Project End
2017-03-31
Budget Start
2013-08-15
Budget End
2014-03-31
Support Year
10
Fiscal Year
2013
Total Cost
$361,777
Indirect Cost
$140,777
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; Meehan, Tracy L; Gartmond, Tori D et al. (2013) Use of necrotic markers in the Drosophila ovary. Methods Mol Biol 1004:215-28
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
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
Tanner, Elizabeth A; McCall, Kim (2011) Mitochondrial regulation of cell death in the Drosophila ovary. Autophagy 7:793-4
Wonglapsuwan, Monwadee; Chotigeat, Wilaiwan; Timmons, Allison et al. (2011) RpL10A regulates oogenesis progression in the banana prawn Fenneropenaeus merguiensis and Drosophila melanogaster. Gen Comp Endocrinol 173:356-63
Tanner, Elizabeth A; Blute, Todd A; Brachmann, Carrie Baker et al. (2011) Bcl-2 proteins and autophagy regulate mitochondrial dynamics during programmed cell death in the Drosophila ovary. Development 138:327-38
McCall, Kimberly (2010) Genetic control of necrosis - another type of programmed cell death. Curr Opin Cell Biol 22:882-8
Pritchett, Tracy L; Tanner, Elizabeth A; McCall, Kimberly (2009) Cracking open cell death in the Drosophila ovary. Apoptosis 14:969-79
McCall, Kimberly; Peterson, Jeanne S; Pritchett, Tracy L (2009) Detection of cell death in Drosophila. Methods Mol Biol 559:343-56

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