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

骨骼肌从头脂肪生成和葡萄糖-脂肪酸循环

基本信息

批准号：
9061671
负责人：
Katsuhiko Funai
金额：
$ 13.79万
依托单位：
EAST CAROLINA UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2017-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9061671
关键词：
Actins Affect Anabolism Artificial Membranes Ca(2+)-Transporting ATPase Calcium Calcium Signaling Cell Culture Techniques Choline Coin Comorbidity Contracts Data Doctor of Philosophy Eating Endocrinology Endoplasmic Reticulum Enzymes Ethanolamines Euglycemic Clamping Exercise Physiology Exhibits Faculty Fatty Acids Fatty-acid synthase Fellowship Generations Glucose Glucose Clamp Health High Fat Diet Human In Situ Individual Insulin Insulin Resistance Knock-out Laboratories Lead Lecithin Link Lipids Liver Mammals Mass Spectrum Analysis Measurement Mediating Mentorship Metabolic Metabolism Modification Mus Muscle Muscle Fibers Muscle Weakness Muscle relaxation phase Obesity Obesity associated disease Pathogenesis Pathway interactions Phenotype Phosphatidylethanolamine Phospholipids Phosphotransferases Physiology Postdoctoral Fellow Principal Investigator Property Public Health Reaction Relaxation Reporting Research Resources Role Sarcomeres Sarcoplasmic Reticulum Scientist Signal Transduction Site Skeletal Muscle Stress Techniques Testing Training United States Universities Washington career development clay exercise capacity exercise intolerance feeding glucose metabolism glucose uptake improved in vivo insulin sensitivity knock-down lipid biosynthesis lipid metabolism medical schools member metabolic phenotype muscle strength novel therapeutic intervention release of sequestered calcium ion into cytoplasm signal processing skeletal skills uptake

项目摘要

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.

描述（由申请人提供）：该提案旨在为申请人提供职业发展机会，该申请人是华盛顿大学医学院内分泌学，代谢和脂质研究部新任命的教职员工。首席研究员（PI）先前在肌肉和运动生理学领域接受过博士学位培训，并在Clay Semenkovich博士的指导下进行了为期三年的博士后研究金，这是一位公认的生理学和代谢领域的领导者，并获得了训练成功科学家的追踪记录。拟议的培训计划将不断地完善PI的科学技能，并帮助他过渡到独立实验室。 PI还将利用华盛顿大学的大量资源。拟议的研究旨在确定从头磷脂酰乙醇胺（PE）脂质生物合成在骨骼肌“葡萄糖脂肪酸周期”中的潜在作用。 PI先前已经用脂肪酸合酶的骨骼肌特异性缺失产生并表征了小鼠，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似乎会影响钙通量并改变肌肉胰岛素的敏感性和强度。现在，PI已经产生了胆碱/乙醇胺磷酸转移酶-1（CEPT1）的骨骼肌特异性缺失的小鼠，这是一种从头pe生物合成中的末端酶。 PI将在没有从头综合的PE的情况下研究骨骼肌，这种情况永远是不可能的。细胞培养中的初步证据表明，CEPT1（例如FAS）有助于SR PE含量改变钙通量。在此应用中，PI将检验以下假设，即通过CEPT1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的敏感性和强度。