Functional aspects of SREBP1c in intact skeletal muscle

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DESCRIPTION (provided by applicant): Dr. MacLean has trained in the areas of muscle physiology, lipid metabolism, and the regulation of gene expression in skeletal muscle. This proposal includes didactic training, research skill development, and a mentored research project, that will foster his development into an independent academic scientist. The research plan is focused on studying the regulation of skeletal muscle lipid metabolism in an in vivo model of adenoviral gene delivery. In the liver, mammary, and adipose tissue, there is evidence to suggest that sterol response element binding proteins (SREBPs), a family of transcription factors, mediate the nutritional regulation of the expression of genes involved in cholesterol, triglycerides, and carbohydrate metabolism. One particular isoform, SREBP1c, has been implicated in regulating gene expression in such a manner as to promote an enzymatic profile that would promote the accumulation of lipids. Because of this link to lipid accumulation, it has been hypothesized that the dysregulation of SREBP1c may be contributing to the lipid abnormalities commonly found with tissues in the metabolic syndrome. SREBP1c is also expressed in skeletal muscle, but its regulation and function in this tissue have not been elucidated. The work in the mentored research project will further characterize a novel in vivo approach to study gene function in skeletal muscle and employ it to examine the gene targets and physiological effects of SREBP1c in this tissue. First, a model of adenoviral gene delivery to skeletal muscle will be characterized with respect to the immediacy and duration of transduction, the titer requirements for transduction efficacy, and the time course of the accompanying immune response. Second, adenoviral vectors containing expression cassettes for the dominant positive or dominant inhibitory forms of SREBP1c will be used with the model to identify the genes that are sensitive to SREBP1c regulation. Third, the same adenoviral vectors will be used with the model to examine the effects of SREBP1c on muscle lipid metabolism. Having a better understanding of the function and interaction of genes expressed in skeletal muscle may lead to novel therapeutic strategies of muscle-related diseases. This award will provide: 1) the means to apply new techniques to his research program; 2) a formal plan for interaction with well-established, successful investigators; and 3) an opportunity for him to mature his research, teaching, and administrative skills, in an excellent research environment.