Acyl-CoA Synthetase: Structure, Function and Regulation

描述（由申请人提供）：响应no - od -09-058: NIH宣布竞争性修订申请的恢复法案基金的可用性，我们提出对父资助DK 59935的竞争性修订：酰基辅酶a合成酶：结构，功能，调节。在下游代谢途径（如TAG合成、储存和脂蛋白分泌）中酰基辅酶a的使用增加，而在FA氧化途径中酰基辅酶a的使用减少，被广泛认为是肥胖、脂肪肝、动脉粥样硬化和糖尿病等营养失调的发生的基础。Parent Grant提议使用功能获得和功能丧失研究来分析主要ACSL亚型在脂肪组织、肝脏和心脏中的作用。我们发现，心脏和脂肪组织中ACSL1的缺失会导致脂肪酸用于氧化的严重损害。有了这个竞争性修订，我们现在建议将我们的研究扩展到骨骼肌，这是一个对胰岛素反应的主要组织。利用Acsl1Flox/Flox小鼠与肌原素- cre小鼠杂交，我们将制造出仅在骨骼肌中缺乏ACSL1的小鼠（Acsl1MusKO小鼠），并研究它们对饮食诱导的肥胖和胰岛素抵抗的反应性以及运动能力。我们预测Acsl1MusKO小鼠将具有高度胰岛素敏感性，而运动不会改善胰岛素敏感性。此外，高脂肪饮食会导致肥胖，但不会导致胰岛素抵抗，尽管如果高脂肪饮食导致肝脂肪变性，肝脏可能会产生胰岛素抵抗。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脂储存的影响与被认为是由FA氧化受损引起的胰岛素抵抗分开，并将阐明ACSL1在指导FA氧化中的作用。这一修订扩大了父母赠款的具体目标范围，允许我们探索与脂肪代谢和胰岛素抵抗作用相关的新想法。此外，此次修订将加快肌肉在胰岛素抵抗中的作用的科学研究的速度，并有助于创造就业机会。具体来说，它将允许我们额外雇用一名博士后和一名研究生。

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.