This proposal aims to provide career development opportunities for the applicant, a newly appointed faculty member in the Division of Endocrinology, Metabolism and Lipid Research in Washington University School of Medicine. The principal investigator (PI) has previously undergone PhD training in the field of muscle and exercise physiology and a three-year postdoctoral fellowship under the mentorship of Dr. Clay Semenkovich, a recognized leader in physiology and metabolism with a track record for training successful scientists. The proposed training plan will provide continual refinement of the PI's scientific skills and aid his transition into an independent laboratory. The PI will also take advantage of the enormous breadth of resources at Washington University. The proposed research seeks to identify the potential roles that de novo phosphatidylethanolamine (PE) lipid biosynthesis in skeletal muscle "glucose-fatty acid cycle". The PI has previously generated and characterized mice with skeletal muscle-specific deletion of fatty acid synthase and provided evidence that de novo-generated fatty acids contribute to PE synthesis at sarcoplasmic reticulum (SR). The SR PE appeared to affect calcium flux and alter muscle insulin sensitivity and strength. The PI has now generated mice with skeletal muscle-specific deletion of choline/ethanolamine phosphotransferase-1 (CEPT1), a terminal enzyme in de novo PE biosynthesis. The PI will study skeletal muscle in the absence of de novo synthesized PE, a situation that has never been possible. The preliminary evidence in cell culture suggests that CEPT1, like FAS, contributes to SR PE content to alter calcium flux. In this application, the PI will test the hypothesis that affecting muscle PE biosynthesis, by CEPT1 deletion, will trigger alteration of SR calcium flux and modulate muscle insulin sensitivity and strength.
Obesity and its associated co-morbidities are major public health problems affecting approximately 72.5 million individuals in United States alone. Findings from these studies may lead to novel therapeutic approaches to the treatment of the obesity-related diseases.