Genetic Regulation of Autophagic Cell Death

Univ Of Massachusetts Med Sch Worcester, Worcester MA

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Abstract

? DESCRIPTION (provided by applicant): 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 recently identified an immune signaling pathway, including the complement molecule Mcr, as being required for autophagy in salivary glands. Our goal is to characterize the immune signaling 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 how Mcr regulates salivary gland degradation, (2) investigate the relationship between Mcr and the engulfment receptor Drpr, and (3) investigate the relationship between Mcr and calcium in the regulation of autophagy. The recent association of autophagy with neurodegenerative disorders and cancer indicates the importance of investigating the understudied process of autophagic programmed cell death.