The overall goal of this K01 application is to provide the candidate with a mentored research experience that will facilitate their development into an independent researcher. The overall career goal of the candidate is to pursue a research career in the field of metabolic regulation as it relates to the development of diabetes and obesity with the ability to understand and investigate metabolic regulation from the genomic to organismic level. To facilitate the candidates' career goals both formal training and research are proposed. Formal training will occur in advanced molecular biology methods and a course in research ethics. The research proposed in this application will be conducted under the tutelage of Drs. Michael Pagliassotti and Jacob Friedman, with additional opportunities to interact with other scientists. The general theme of the research addressed in this application is to understand the process of lipid accumulation in skeletal muscle. In liver and adipose tissue this process is mediated by the transcription factor SREBP-1c. Although, it has been demonstrated that SREBP-1c is present in skeletal muscle, the regulation and function of SREBP-1c in skeletal muscle has not been extensively studied. Therefore, the specific aims of the research proposed are 1) To determine the roles of glucose, insulin and fatty acids in the regulation of SREBP-1c mRNA, protein content and nuclear localization in skeletal muscle in vivo, 2) To determine the role of SREBP-1c in skeletal muscle lipid partitioning and, 3) determine whether SREBP-1c binds to the acetyl-CoA-carboxylase a (ACCa) and glycerol-3-phosphate acyltransferase (GPAT) promoters. It is hypothesized that insulin and glucose will increase SREBP-1c, and decreased by fatty acids in skeletal muscle. Adenovirus mediated overexpression of SREBP-1c will increase the flux of lipid into the glycerol-lipid pool and decrease lipid oxidation. This partitioning of lipid will occur in part from the binding of SREBP-1c to regions of the ACCa and GPAT gene promoters. This research experience will provide the candidate training in several new methodologies including sophisticated in vivo methodologies, adenovirus generation and gene promoter analysis. Importantly, it will provide novel information pertaining to the basic regulation of skeletal muscle lipid metabolism. This research experience will allow the candidate to compete for R01 funding and establish an independent research career.
| Bizeau, Michael E; MacLean, Paul S; Johnson, Ginger C et al. (2003) Skeletal muscle sterol regulatory element binding protein-1c decreases with food deprivation and increases with feeding in rats. J Nutr 133:1787-92 |
