PROJECT SUMMARY By governing growth and quiescence, nutrient-responsive pathways are central to cancer, diabetes and aging. The function of these pathways in starvation informs understanding of their dysfunction in disease, but their fundamental role in starvation is not well understood. The premise of this proposal is that multiple tumor sup- pressors are known to promote starvation resistance, but their regulatory relationships and effector mecha- nisms are unclear. The long-term goal of this project is to elucidate the genetic foundation and molecular mechanisms of starvation resistance in C. elegans as a model for human disease. Worms are an ideal model since they thrive in feast and famine with remarkable ability to endure starvation. Genes known to promote starvation resistance in C. elegans (eg, daf-18/PTEN, daf-16/FoxO, lin-35/Rb, hlh-30/TFEB and aak-2/AMPK) have conserved function in suppressing tumors, regulating metabolism, and promoting longevity. However, significant gaps in understanding remain. Preliminary studies show that inhibition of PI3K signaling does not account for the effect of DAF-18/PTEN on starvation resistance. They show that DAF-18/PTEN's protein- phosphatase activity promotes starvation resistance, and they identify a novel protein target. Preliminary re- sults also suggest that DAF-16/FoxO and LIN-35/Rb regulate histone variants to mediate nutritional control of chromatin structure and gene regulation. They also demonstrate the efficacy of an innovative population- sequencing approach for analysis of quantitative traits, and they identify novel genes affecting natural variation in starvation resistance. These include modifiers of insulin/IGF signaling and a conserved but uncharacterized transcription factor. The central hypothesis of this proposal is that a conserved network of tumor suppressors and proto-oncogenes governs starvation resistance through a variety of effector mechanisms. The objective of this proposal is to expand understanding of this network by identifying novel components, regulatory interac- tions, and effector mechanisms. The central hypothesis is supported by strong preliminary data and the litera- ture. It will be tested with the following three aims: 1) Identify DAF-18/PTEN targets that promote starvation resistance, 2) Identify gene regulatory mechanisms that mediate adaptation to starvation, and 3) Identify genes and mechanisms that contribute to natural variation in starvation resistance. Genetic, genomic and biochemical approaches will be used to complete these aims. This work is technically innovative for using population se- quencing to leverage the power of deep sequencing for statistical genetics, and for using gene expression as a high-dimensional trait for epistasis analysis. It is intellectually innovative for hypothesizing a novel regulatory relationship between clinically important tumor suppressors. The contributions of the proposed work will be identification of novel components...