Acyl-CoA Synthetase: Structure, Function and Regulation

酰基辅酶 A 合成酶：结构、功能和调节

• 批准号: 7812133
• 负责人: Rosalind Anne Coleman
• 金额: $ 51.02万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-15 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7812133
• 关键词: Acyl Coenzyme A; Adenoviruses; Adipocytes; Adipose tissue; Atherosclerosis; Attention; Award; Cardiomyopathies; Cell physiology; Cells; Coenzyme A Ligases; Complex; Cultured Cells; Data; Defect; Development; Diabetes Mellitus; Diet; Exercise; Family; Fatty Acids; Fatty Liver; Fatty acid glycerol esters; Funding; Genes; Glucose; Heart; Hepatic; Hepatocyte; Impairment; Insulin; Insulin Resistance; Knock-out; Lipids; Lipoproteins; Liver; Mediating; Metabolic Pathway; Mus; Muscle; Myogenin; Nuclear; Nutrition Disorders; Obesity; Occupations; Pathway interactions; Phospholipids; Play; Postdoctoral Fellow; Protein Isoforms; Recovery; Regulation; Research; Role; Skeletal Muscle; Structure; Tissues; Triglycerides; United States National Institutes of Health; fatty acid metabolism; fatty acid oxidation; feeding; gain of function; glucose metabolism; graduate student; improved; insulin sensitivity; lipid metabolism; loss of function; muscle metabolism; novel; overexpression; oxidation; parent grant; prevent; public health relevance; response; small hairpin RNA; transcription factor

DESCRIPTION (provided by applicant): In response to NOT-OD-09-058: NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications, we propose a Competitive Revision to the Parent Grant DK 59935: Acyl-CoA synthetases: Structure, function, regulation. Increased use of acyl-CoAs in downstream metabolic pathways such as TAG synthesis, storage, and lipoprotein secretion and decreased acyl-CoA use in FA oxidation pathways are widely believed to underlie the development of nutritional disorders such as obesity, fatty liver, atherosclerosis and diabetes. The Parent Grant proposed to use gain-of function and loss-of function studies to analyze the roles of the major ACSL isoforms in adipose tissue, liver and heart. We found that loss of ACSL1 in heart and adipose tissue results in a profound impairment in the use of fatty acids for ¿-oxidation. With this Competitive Revision, we now propose to extend our studies to skeletal muscle, a major tissue responsive to insulin action. Using Acsl1Flox/Flox mice crossed with myogenin-Cre mice, we will create mice deficient in ACSL1 solely in skeletal muscle (Acsl1MusKO mice) and study their responsiveness to diet-induced obesity and insulin resistance and their ability to exercise. We predict that Acsl1MusKO mice will be highly insulin-sensitive, and that exercise will not improve insulin sensitivity. Further, the high fat diet will induce obesity but not insulin resistance, although the liver may become insulin resistant if the high fat diet induces hepatic steatosis. We also predict that these mice will have severely impaired ability to exercise. These studies will allow us to separate the effects of muscle lipid storage from the insulin resistance believed to be induced by impaired FA oxidation and will clarify the role of ACSL1 in directing FA towards ¿-oxidation. This revision expands the scope of the specific aims of the Parent Grant by allowing us to explore novel ideas related to the role of fat metabolism and insulin resistance. In addition, the revision will both accelerate the tempo of scientific research on muscle's role in insulin resistance, and it will allow for job creation. Specifically, it will allow us to hire an additional postdoctoral fellow and an additional graduate student. PUBLIC HEALTH RELEVANCE: This revision expands the scope of the specific aims of the Parent Grant by allowing us to explore novel ideas related to the role of fat metabolism and insulin resistance. In addition, the revision will both accelerate the tempo of scientific research on muscle's role in insulin resistance, and it will allow for job creation. Specifically, it will allow us to hire an additional postdoctoral fellow and an additional graduate student.

描述（由应用程序提供）：响应于NOT-OD-09-058：NIH宣布为竞争性修订申请提供恢复ACT资金，我们建议对父母赠款DK 59935进行竞争性修订：酰基-COA合成酶：结构，功能，功能，法规。人们普遍认为，在下游代谢途径（例如TAG合成，储存和脂蛋白分泌）等下游代谢途径中使用的使用增加了，并且在FA氧化途径中的使用改善被认为是肥胖，脂肪肝脏，动脉粥样硬化和动脉粥样硬化和糖尿病等营养疾病的发展。父母的赠款提议利用功能和功能丧失研究来分析主要ACSL同工型在脂肪组织，肝脏和心脏中的作用。我们发现，心脏和脂肪组织中ACSL1的损失会导致使用脂肪酸进行``氧化）的严重损害。通过这种竞争性修订，我们现在建议将研究扩展到骨骼肌，这是对胰岛素作用有反应的主要组织。使用ACSL1FLOX/FLOX小鼠与肌蛋白蛋白-CRE小鼠交叉，我们将创建仅在骨骼肌（ACSL1MUSKO小鼠）中缺乏ACSL1的小鼠，并研究其对饮食诱导的肥胖症和胰岛素抵抗和运动能力的反应。我们预测ACSL1MUSKO小鼠对胰岛素的敏感性将高度敏感，并且该运动不会提高胰岛素敏感性。此外，高脂肪饮食将诱发肥胖，但不能诱导胰岛素抵抗，尽管如果高脂饮食会影响肝脂肪变性，则肝脏可能会耐胰岛素。我们还预测，这些小鼠的运动能力将严重受损。这些研究将使我们能够将肌肉脂质储存的作用与被认为是由FA氧化受损引起的胰岛素抵抗的作用，并将阐明ACSL1在将FA指向FA氧化方面的作用。这项修订通过允许我们探索与脂肪代谢和胰岛素抵抗的作用相关的新思想来扩大父母赠款的特定目的的范围。此外，修订既可以加快肌肉在胰岛素抵抗中的作用的科学研究的节奏，并且将允许创造就业机会。具体来说，它将允许我们聘请其他博士后研究员和另外一名研究生。 公共卫生相关性：这项修订通过允许我们探索与脂肪代谢和胰岛素抵抗的作用相关的新思想来扩大父母赠款的特定目标的范围。此外，修订既可以加快肌肉在胰岛素抵抗中的作用的科学研究的节奏，并且将允许创造就业机会。具体来说，它将允许我们聘请其他博士后研究员和另外一名研究生。