Autophagy, a cellular process of cytoplasmic degradation and recycling, is an ancient starvation survival pathway found in all eukaryotes. Recent advances in understanding the roles of autophagy call for future therapeutic uses, as besides promoting cellular homeostasis, stress resistance, and longevity, autophagy also plays important roles in cancer, cell death, myopathies, neurodegeneration diseases, and immunity. About 20 conserved core proteins of autophagy are known from yeast studies, and various signaling pathways were shown to regulate the rate of this process. I will undertake three large-scale projects to identify the genes involved in autophagy, using fruit flies. Drosophila is an excellent genetic model organism, and displays very high levels of autophagy in response to starvation or during normal development, so it is ideally suited for my purposes. First, a whole-genome transgenic RNA interference screen will identify genes that are required for starvation-induced autophagy, as well as inhibitors of autophagy, whose silencing activates this process even without starvation. Second and third, transcription profiling and proteomic analysis of gene expression changes and post-translational modifications will be analyzed during autophagy. These studies together will hopefully isolate numerous novel factors involved in autophagy, potentially including drug targets for the above diseases associated with misregulated autophagy.