DESCRIPTION (provided by applicant): Defects in insulin signaling have impacts on both metabolic disease and cancer. Epidemiological studies confirm long time observations that obese individuals and type 2 diabetics with hyperinsulinimia are at higher risk for various types of cancers, but the link between these disorders are unclear. Hyperinsulinimia may directly increase growth of tumor with high levels of insulin receptor, or indirectly increase Insulin-like Growth Factor (IGF) levels, which activates a pathway with well-established links to colon, breast and thyroid cancers. The prevalence of Type 2 diabetes (T2D) is increasing rapidly in populations worldwide, but public programs to improve diet and nutrition have largely failed to reduce the problem and an urgent need exists to understand how the pathway is modulated during cancer progression. Trib family members have been linked to both metabolic defects and cancer formation. This family of proteins shares a conserved kinase line central domain and functions by binding key regulatory proteins - with targets that include transcription factors, kinases and enzymes - to link multiple cell signaling pathways regulating cell growth, proliferation and differentiation. In humans, Tribbles 3 (Trib3) levels are aberrantly high in sufferers of both insulin resistance and T2DM, and a Trib3 protein variant (Trib3Q/R85) has been linked to populations predisposed to metabolic disease. Several anticancer agents have been shown to promote cancer cell death via TRIB3 upregulation and a recent report shows that Trib3 knockout mice exhibit accelerated formation of premalignant lesions due to increased activity of the insulin signaling pathway. Model genetic organisms offer a powerful system to uncover the conserved genetic mechanisms that connect the insulin signaling to cell growth and tissue homeostasis and over the past fifteen years, Drosophila has been used to study the genetics of insulin-regulated metabolism and energy homeostasis. In Drosophila, Tribbles binds and block cdc25 phosphatase, a key trigger of cell proliferation and our recently published data shows that Trbl antagonizes insulin signaling by binding and inhibiting the activation of Akt kinase, a key mediator of the insulin response. Our identification of fly Trbl as a antagonist of insulin signaling puts us in the advantageous position to use the genetic tools available in this simple model organism to identify interacting genes, pathways and drug candidates that as well as the opportunity to carry out rapid dissection of genetic mechanisms, neither of which is feasible in higher model organisms. Here we propose to search for novel Trbl pathway components - including binding partners and pathway targets - combining a genetic screen with a molecular screens. This proposal also develops a computer-based tool which will serve as (1) a new framework for quantitative analysis of cell growth and proliferation, and (2) a versatile, modular, open-source toolbox of algorithms enabling the discovery of genetic pathways, chemical probes, and drug candidates via high-throughput screens in the whole organism with relevance to a variety of diseases. Our goals are to use this simpler model genetic system to identify new conserved Trbl pathway components regulating cell growth and proliferation. " |