The control of growth and metabolism by effectors of the TOR signaling pathway

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DESCRIPTION (provided by applicant): Growth and metabolism are closely linked to nutrient availability. A key regulatory pathway that coordinates these processes is the nutrient-sensitive TOR pathway. Signaling through the TOR kinase promotes cellular growth through complex changes in cell metabolism, including a stimulation of general protein synthesis. At the same time, TOR increases fat stores and blocks autophagy, a process of 'self-digestion' by which cells mobilize nutrients under starvation conditions. TOR is controlled by both nutrients and insulin signaling, and thus integrates these inputs into a broader regulatory network that controls metabolism. Dysreglulation of the TOR pathway is associated with cancers, causes benign tumors (tuberous sclerosis), and has been linked to diabetes and obesity. However, the downstream effectors that mediate the effects of TOR on glucose and lipid metabolism are largely unknown. Recently, nuclear hormone receptors that function in metabolic control have emerged as promising candidates. This project aims at closing gaps in our knowledge of downstream mediators of TOR function. It will do this by (1) studying the integration of an evolutionarily conserved key regulator of lipid metabolism and obesity (Lipin) into the TOR signaling pathway, and (2) analyzing the functional interaction of Lipin with nuclear receptors. The project will use the genetic model organism Drosophila, which has made important contributions in the past to our understanding of TOR signaling in mammals including humans. The specific aims of the project are: (1) To characterize the interaction between Drosophila Lipin (dLipin) and TOR signaling in growth control. This will include assaying metabolic parameters (triglycerides, glucose, energy consumption etc.) under different nutritional conditions in animals lacking one or both of the two proteins. (2) To characterize the function of dLipin in autophagy. Preliminary data show that dLipin is strongly upregulated during autophagy, suggesting that it cooperates with TOR in the control of this important process. This hypothesis will be tested by analyzing markers of autophagy in animals in which the activities of dLipin, or both TOR and dLipin, were changed by genetic manipulation. (3) To identify nuclear receptors cooperating with dLipin in metabolic and growth control. Preliminary data suggest that dLipin, similar to mammalian Lipin1, is inducible by steroid hormone. In addition, Lipin1 has recently been shown to function, as least in part, by acting as a nuclear receptor co-regulator. dLipin-receptor interactions of functional relevance will be identified using a 'ligand sensor' system developed for the characterization of nuclear receptors in Drosophila. The project will thus pave the way for a better understanding of how TOR and steroid signaling pathways are interconnected. Obesity and diabetes have become a major challenge to public health in the United States and other industrialized nations. This project will examine how a key regulator of lipid metabolism and obesity cooperates with the nutrient and insulin-sensitive TOR signaling pathway. It will thus improve our under- standing of how nutrient sensing is linked to fat metabolism and help paving the way for treatments of obesity-related (type 2) diabetes and other diseases.