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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Program Projects (P01)
Project #
2P01DK059820-11A1
Application #
8334179
Study Section
Special Emphasis Panel (ZDK1-GRB-D (M1))
Program Officer
Margolis, Ronald N
Project Start
2001-07-01
Project End
2017-06-30
Budget Start
2012-09-14
Budget End
2013-06-30
Support Year
11
Fiscal Year
2012
Total Cost
$1,828,135
Indirect Cost
$655,970
Name
Baylor College of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Mo, P; Zhou, Q; Guan, L et al. (2015) Amplified in breast cancer 1 promotes colorectal cancer progression through enhancing notch signaling. Oncogene 34:3935-45
Tang, Ke; Tsai, Sophia Y; Tsai, Ming-Jer (2015) COUP-TFs and eye development. Biochim Biophys Acta 1849:201-9
Gibbs, Julie; Ince, Louise; Matthews, Laura et al. (2014) An epithelial circadian clock controls pulmonary inflammation and glucocorticoid action. Nat Med 20:919-26
Dasgupta, Subhamoy; O'Malley, Bert W (2014) Transcriptional coregulators: emerging roles of SRC family of coactivators in disease pathology. J Mol Endocrinol 53:R47-59
Reineke, Erin L; Benham, Ashley; Soibam, Benjamin et al. (2014) Steroid receptor coactivator-2 is a dual regulator of cardiac transcription factor function. J Biol Chem 289:17721-31
Qin, Jun; Lee, Hui-Ju; Wu, San-Pin et al. (2014) Androgen deprivation-induced NCoA2 promotes metastatic and castration-resistant prostate cancer. J Clin Invest 124:5013-26
Stashi, Erin; Lanz, Rainer B; Mao, Jianqiang et al. (2014) SRC-2 is an essential coactivator for orchestrating metabolism and circadian rhythm. Cell Rep 6:633-45
Motamed, Massoud; Rajapakshe, Kimal I; Hartig, Sean M et al. (2014) Steroid receptor coactivator 1 is an integrator of glucose and NAD+/NADH homeostasis. Mol Endocrinol 28:395-405
Wang, Ying; Lonard, David M; Yu, Yang et al. (2014) Bufalin is a potent small-molecule inhibitor of the steroid receptor coactivators SRC-3 and SRC-1. Cancer Res 74:1506-17
Lin, Shih-Chieh; Li, Yo-Hua; Wu, Meng-Hsing et al. (2014) Suppression of COUP-TFII by proinflammatory cytokines contributes to the pathogenesis of endometriosis. J Clin Endocrinol Metab 99:E427-37

Showing the most recent 10 out of 123 publications