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，申请人是华盛顿大学医学院内分泌、代谢和脂质研究部的新任命教员。首席研究员（PI）之前曾在肌肉和运动生理学领域接受过博士培训，并在Clay Semenkovich博士的指导下获得了为期三年的博士后研究金，Clay Semenkovich博士是生理学和代谢领域公认的领导者，在培训成功的科学家方面有着良好的记录。拟议的培训计划将提供PI的科学技能的不断完善，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广泛的资源。拟开展的研究旨在确定磷脂酰乙醇胺（PE）脂质从头生物合成在骨骼肌“葡萄糖-脂肪酸循环”中的潜在作用。PI先前已经产生并表征了具有骨骼肌特异性脂肪酸合酶缺失的小鼠，并提供了新产生的脂肪酸有助于肌浆网（SR）PE合成的证据。SR PE似乎影响钙流并改变肌肉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（CEPT 1）的小鼠，CEPT 1是从头PE生物合成中的末端酶。PI将在不存在从头合成PE的情况下研究骨骼肌，这种情况从未发生过。细胞培养中的初步证据表明，CEPT 1与FAS一样，有助于SR PE含量改变钙通量。在本申请中，PI将检验以下假设：通过CEPT 1缺失影响肌肉PE生物合成将触发SR钙通量的改变并调节肌肉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.