Genetic regulation of autophagic cell death

Univ Of Massachusetts Med Sch Worcester, Worcester MA

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Abstract

DESCRIPTION (provided by applicant): Cell growth, division, and death are determinants of tissue and animal size, and defects in these fundamental cellular processes result in a variety of human disorders including cancer. The mechanistic relationship between growth and cell death is poorly defined in the context of normal animal development even though they have been the focus of many studies. Apoptosis and autophagic cell death are the two most prominent morphological forms of programmed cell death that occur during development. We are studying steroid-activated 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 salivary glands also possess the morphology of cells that die-by autophagic cell death. Mutations in caspases only partially inhibit salivary gland cell death, and our recent studies suggest an important relationship between steroid signaling, growth that is regulated by phosphoinositide 3 kinase (PI3K), and death of this tissue. Here we propose to: (1) determine the relationship between salivary gland growth and autophagic cell death during development, (2) determine how PI3K-induced growth influences steroid signaling and cell destruction mechanisms in dying salivary glands, and (3) identify new genes that function in autophagic cell death. The recent association of autophagic cell death with neurodegenerative disorders and cancer indicates the importance of investigating this understudied form of programmed cell death.