Diabetes mellitus and obesity, major epidemics that affect more than 5-8% and 20-25% of the US population, respectively, are manifestations of dysregulated metabolism. A tissue prominently involved in these disorders is the liver which must adapt rapidly to large variations in macronutrient availability and the associated fluctuations in anabolic and catabolic hormones in order to act in coordination with other tissues of the body to maintain metabolic homeostasis. Adaptation by the liver to either an influx of nutrients or nutrient deprivation is accomplished by multiple biochemical processes mediated by transcriptional, translational, and posttranslational mechanisms. Of these, the least is presently known about translational mechanisms, i.e., the process of translating mRNA into protein, an area of research in which the expertise of the PI's laboratory is well-recognized. Therefore, the overall objective of the proposed project is to gain an understanding of how translational control mechanisms in the liver and the signaling pathways that regulate them respond to variations in macronutrients and the hormones insulin and glucagon, and in so doing provide insight into designing strategies for the treatment of disorders involving dysregulated metabolism. The general hypothesis to be tested is that nutrients and hormones activate both distinct and redundant cell signaling pathways in the liver, thus altering molecular mechanisms that mediate the regulation of mRNA translation, a process that contributes to the highly coordinated gene-expression patterns required to respond to fluctuations in the metabolic demands imparted on the tissue in a variety of physiological conditions. To test this hypothesis we propose the following specific aims: (1) identify the mechanisms that are responsible for mediating the action of glucagon to repress and the actions of free fatty acids and the branched-chain amino acid leucine to activate signaling through the mammalian target of rapamycin (mTOR) pathway to produce a change in the translational control of gene expression; (2) identify the mechanisms and signaling pathways that are responsible for producing a change in the translational control of gene expression in response to amino acid imbalance or unphysiologically low or high glucose concentrations; and (3) identify the molecular mechanism(s), the signaling pathways(s), and the nutritional and hormonal inputs through which translation of the albumin mRNA is derepressed in response to food intake. We expect to identify novel targets for therapeutic intervention under conditions in which the liver contributes to dysregulated metabolism. ? ?
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