SKELETAL MUSCLE DE NOVO LIPOGENESIS AND THE GLUCOSE-FATTY ACID CYCLE

描述(由申请人提供)：本提案旨在为申请人提供职业发展机会，他是华盛顿大学医学院内分泌学、代谢和血脂研究部的一名新聘教员。首席研究员(PI)此前接受过肌肉和运动生理学领域的博士培训，并在Clay Semenkovich博士的指导下获得了为期三年的博士后奖学金。Clay Semenkovich博士是生理学和新陈代谢领域的公认领导者，曾培训过成功的科学家。拟议的培训计划将不断完善PI的科学技能，并帮助他过渡到一个独立的实验室。PI还将利用华盛顿大学巨大的资源广度。这项拟议的研究试图确定从头开始的磷脂酰乙醇胺(PE)脂质生物合成在骨骼肌“葡萄糖-脂肪酸循环”中的潜在作用。PI以前已经产生并表征了骨骼肌特异性脂肪酸合成酶缺失的小鼠，并提供了证据表明从头生成的脂肪酸有助于肌浆网(SR)的PE合成。SR PE似乎影响钙流动，并改变肌肉的胰岛素敏感性和强度。PI现在已经产生了骨骼肌特异性缺失胆碱/乙醇胺磷酸转移酶-1(CEPT1)的小鼠，CEPT1是PE从头合成的终端酶。PI将在没有从头合成PE的情况下研究骨骼肌，这是永远不可能的情况。在细胞培养中的初步证据表明，CEPT1和Fas一样，促进了SR PE的含量，从而改变了钙流。在这一应用中，PI将检验这样一个假设，即通过CEPT1缺失影响肌肉PE的生物合成，将触发SR钙通量的改变，并调节肌肉的胰岛素敏感性和强度。

DESCRIPTION (provided by applicant): 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.