Programmed cell death plays an important role during animal development, and defects in this process result in a variety of human disorders including cancer and autoimmunity. Apoptosis and autophagic cell death are the two most prominent morphological forms of programmed cell death that occur during development. The regulation of apoptosis is relatively well understood, but little is known about the mechanisms that mediate autophagic programmed cell death. We are studying autophagic programmed cell death during development of the fruit fly Drosophila melanogaster using larval salivary gland cell death as a model. An increase in steroid triggers a genetic hierarchy that activates nearly synchronous cell death in salivary glands. These developmentally-regulated cell deaths utilize apoptosis genes, including caspase proteases, but inhibition of caspases and caspase mutations only partly inhibit salivary gland degradation. Salivary glands possess the morphology of cells that die by autophagic cell death, and autophagy is required for their complete degradation. While much is known about the function and regulation of autophagy in yeast, less is known about the mechanisms that regulate this fundamental process in animal cells, and little is known about the function of autophagy in programmed cell death. Our hypothesis is that the cell-specific use of autophagy in multicellular organisms involves specific regulatory mechanisms that integrate with core autophagy pathways that are conserved from yeast to humans. We have made the surprising discovery that engulfment genes are induced before autophagic cell death, and that the engulfment receptor drpr is required for tissue autonomous autophagy and degradation of salivary glands. Our goal is to characterize the engulfment factors that regulate autophagy, and investigate how their regulation is coordinated in the context of autophagy that participates in cell death during development. Here we propose to: (1) determine the function of engulfment genes in the regulation of autophagy and death of salivary glands, (2) investigate the regulation and function of engulfment receptors during autophagy, and (3) investigate the signaling downstream of Drpr and determine how Drpr regulates autophagy. The recent association of autophagy with neurodegenerative disorders and cancer indicates the importance of investigating the understudied process of autophagic programmed cell death.

Public Health Relevance

Programmed cell death plays an important role during animal development, and defects in this process are associated with a variety of human disorders including cancer and autoimmunity. We are studying the relationship between autophagy and programmed cell death during development. The recent association of autophagy with neurodegenerative disorders and cancer illustrates the importance of investigating the relationship between autophagy and cell death.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM079431-08
Application #
8415532
Study Section
Development - 1 Study Section (DEV1)
Program Officer
Maas, Stefan
Project Start
2007-02-01
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2014-01-31
Support Year
8
Fiscal Year
2013
Total Cost
$341,296
Indirect Cost
$133,821
Name
University of Massachusetts Medical School Worcester
Department
Biology
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Tracy, Kirsten; Velentzas, Panagiotis D; Baehrecke, Eric H (2016) Ral GTPase and the exocyst regulate autophagy in a tissue-specific manner. EMBO Rep 17:110-21
Lee, T V; Kamber Kaya, H E; Simin, R et al. (2016) The initiator caspase Dronc is subject of enhanced autophagy upon proteasome impairment in Drosophila. Cell Death Differ 23:1555-64
Lindqvist, L M; Simon, A K; Baehrecke, E H (2015) Current questions and possible controversies in autophagy. Cell Death Discov 1:
Anding, Allyson L; Baehrecke, Eric H (2015) Autophagy in Cell Life and Cell Death. Curr Top Dev Biol 114:67-91
Zhang, Hong; Baehrecke, Eric H (2015) Eaten alive: novel insights into autophagy from multicellular model systems. Trends Cell Biol 25:376-87
Anding, A L; Baehrecke, E H (2015) Vps15 is required for stress induced and developmentally triggered autophagy and salivary gland protein secretion in Drosophila. Cell Death Differ 22:457-64
Nelson, Charles; Ambros, Victor; Baehrecke, Eric H (2014) miR-14 regulates autophagy during developmental cell death by targeting ip3-kinase 2. Mol Cell 56:376-88
Nelson, Charles; Baehrecke, Eric H (2014) Eaten to death. FEBS J 281:5411-7
Nelson, Charles; Baehrecke, Eric H (2014) Autophagy and cell death in the fly. Methods Enzymol 545:181-99
Mariño, Guillermo; Niso-Santano, Mireia; Baehrecke, Eric H et al. (2014) Self-consumption: the interplay of autophagy and apoptosis. Nat Rev Mol Cell Biol 15:81-94

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