Nuclear receptors (NRs) and their coregulators act in concert to regulate the expression of myriad target genes involved in maintenance of metabolic homeostasis. Over the past ten years of this PPG, we have shown that NRs (specifically COUP-TFII) and their attendant coactivators, in particular the Steroid Receptor Coactivators (SRCs), have evolved as primary regulators of metabolic pathways in fat, liver and skeletal muscle tissues. This phase of the PPG will extend these observations by focusing our investigations on the molecular, cellular and physiological metabolic contributions of SRC-2 in tissues that contribute to the development of Metabolic Syndrome (MS). Our overarching hypothesis is that SRC-2 is a 'Master Genetic Regulator'for organs affected by MS. Specifically, Project 1 will focus on the hepatic functions of the AMPK/SRC-2 signaling axis as it pertains to dietary fat absorption and whole body energy accretion. This project will be dovetailed with Project 2, which is focused on defining the physiological role of SRC-2 as a master circadian regulator that controls liver and adipose metabolism. Continuing with this theme, Project 3 is aimed at defining the role of SRC-2 as an essential mediator of the beneficial effects of LRH-1 activation that combat NASH induced by MS. Finally, Project 4 will dissect the functional interactions of SRC-2 and COUP-TFII in skeletal muscle energy metabolism. The realignment of these individual projects within this central hypothesis has created a PPG application that is both highly innovative and extensively integrated. These research efforts will be tightly coordinated with a centralized animal core (Core A) and administrative core (Core B) that will serve to expedite availability of animal resources and promote the free exchange of information generated from these research initiatives. Overall, these proposed studies will utilize state of the art technologies and methodologies to test our hypotheses, which utilize cell biology, biochemistry, bioinformatics, transgenic and traditional genetic animal models. When complete, this PPG will afford a much greater understanding of NR and coregulator biology and will help define novel therapeutic leverage points for intervention of diseases associated with MS.
Diabetes, obesity, and a host of associated co-morbidities develop from derangements in metabolic signaling. The combined efforts of the Projects and Cores outlined in this proposal will seek to establish new paradigms for our understanding of the molecular, cellular and physiological roles that coactivators like SRC-2 play in the homeostatic control of systems metabolism.
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