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

申请人为华盛顿大学医学院内分泌、代谢与脂质研究学部新聘教员，本计划书旨在为申请人提供职业发展机会。首席研究员（PI）曾在肌肉和运动生理学领域接受过博士培训，并在克莱·塞门科维奇博士的指导下获得了三年的博士后奖学金，克莱·塞门科维奇博士是生理学和代谢领域公认的领导者，拥有培养成功科学家的记录。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。该项目还将利用华盛顿大学广泛的资源。本研究旨在确定新生磷脂酰乙醇胺（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先前已经生成并表征了骨骼肌特异性脂肪酸合成酶缺失的小鼠，并提供了新生成的脂肪酸有助于肌浆网（SR） PE合成的证据。SR PE似乎影响钙通量，改变肌肉胰岛素敏感性和强度。PI现在已经培养出骨骼肌特异性缺失胆碱/乙醇胺磷酸转移酶-1 （CEPT1）的小鼠，CEPT1是新生PE生物合成的末端酶。PI将在没有从头合成PE的情况下研究骨骼肌，这种情况从未出现过。细胞培养的初步证据表明，CEPT1和FAS一样，有助于SR - PE含量改变钙通量。在本应用中，PI将验证通过CEPT1缺失影响肌肉PE生物合成将引发SR钙通量改变并调节肌肉胰岛素敏感性和强度的假设。

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.