Acetylation and contraction-mediated glucose uptake

乙酰化和收缩介导的葡萄糖摄取

• 批准号: 10490253
• 负责人: Simon Schenk
• 金额: $ 20.26万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-30 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10490253
• 关键词: 5' -AMP-activated protein kinase; Acetylation; Acetyltransferase; Acute; Acyltransferase; Address; Binding Proteins; Blood; Cell membrane; Chemicals; Clinical; Clinical Treatment; Contracts; Cyclic AMP-Responsive DNA-Binding Protein; Cytosol; Deacetylase; Development; EP300 gene; Enzymes; Exercise; Family member; GLUT 4 protein; Genetic Transcription; Glucose Transporter; Health; Human; Hyperglycemia; Immunoprecipitation; Intervention; Knowledge; Lysine; Maintenance; Mass Spectrum Analysis; Measures; Mediating; Mediator of activation protein; Modeling; Mus; Muscle; Muscle Contraction; Non-Insulin-Dependent Diabetes Mellitus; Oranges; Orthologous Gene; Outcome; Phosphorylation; Prevention; Production; Proteins; Regulation; Research; Rest; Role; Signal Transduction; Skeletal Muscle; Specificity; Strenuous Exercise; Testing; Thinking; Time; Translating; USP6 gene; Western Blotting; Work; base; directed differentiation; experimental study; glucose metabolism; glucose uptake; improved; inhibitor; insight; novel; protein function; protein transport; rac1 GTP-Binding Protein; response; trafficking

PROJECT SUMMARY Contraction-stimulated glucose uptake is important to the maintenance of ATP production during exercise, especially exercise of high-intensity. It is also a cornerstone for the treatment and prevention of clinical hyperglycemia and the development of type 2 diabetes. Thus, understanding the regulation of contraction- stimulated glucose uptake is important for the development of strategies to optimize skeletal muscle glucose metabolism. The long-term objective of this research is to elucidate the mechanisms that regulate contraction- stimulated glucose uptake. The fundamental premise of this application is that lysine acetylation of GLUT4- trafficking proteins is necessary for contraction-stimulated glucose uptake. Accordingly, in this application our primary objective is to elucidate the importance of the acetyltransferases, p300 (E1A binding protein p300) and CBP (cAMP response element-binding protein binding protein) to contraction-stimulated glucose uptake, and to identify the GLUT4 trafficking proteins that are acetylated in response to contraction. Our central hypothesis is that p300 and CBP regulate contraction-stimulated glucose uptake through acetylation of GLUT4-trafficking proteins, and that they do so independent of their common role as transcriptional regulators. To address this hypothesis, we will measure basal and contraction-stimulated glucose uptake and plasma membrane GLUT4 abundance in mouse skeletal muscle in which p300 and CBP acetyltransferase activity is acutely regulated. Specifically, Aim #1 will investigate the contributions of p300/CBP to contraction-stimulated glucose uptake and plasma membrane GLUT4 translocation, including the importance of gene transcription to their regulatory effects. Aim #2 will define the GLUT4 trafficking proteins that are acetylated in response to contraction, including the contributions of p300/CBP. Altogether, these studies will provide insight into the contribution of p300/CBP and lysine acetylation to contraction-stimulated glucose uptake. Altogether, because of this work, an improved understanding of the signalling that regulates glucose uptake by skeletal muscle is anticipated, which by extension is expected to translate into tangible benefits to human health.

项目摘要 收缩刺激的葡萄糖摄取对于维持运动期间ATP的产生是重要的， 特别是高强度的运动。它也是治疗和预防临床 2型糖尿病的治疗方法因此，了解收缩的调节- 刺激葡萄糖摄取对于优化骨骼肌葡萄糖的策略的发展是重要的 新陈代谢.这项研究的长期目标是阐明调节收缩的机制- 刺激葡萄糖摄取。本申请的基本前提是GLUT 4-的赖氨酸乙酰化。 运输蛋白是收缩刺激的葡萄糖摄取所必需的。因此，在本申请中， 主要目的是阐明乙酰转移酶p300（E1 A结合蛋白p300）和 CBP（cAMP反应元件结合蛋白结合蛋白）对收缩刺激的葡萄糖摄取的作用，和 以鉴定响应收缩而乙酰化的GLUT 4运输蛋白。我们的核心假设 p300和CBP通过GLUT 4运输乙酰化调节收缩刺激的葡萄糖摄取 蛋白质，并且它们这样做独立于它们作为转录调节因子的共同作用。为了解决这个 假设，我们将测量基础和收缩刺激的葡萄糖摄取和质膜GLUT 4 在小鼠骨骼肌中的丰度，其中p300和CBP乙酰转移酶活性受到急性调节。 具体而言，目标#1将研究p300/CBP对收缩刺激的葡萄糖摄取的贡献， 质膜GLUT 4易位，包括基因转录对其调控的重要性， 方面的影响.目标#2将定义响应收缩而乙酰化的GLUT 4运输蛋白， 包括p300/CBP的贡献。总之，这些研究将提供深入了解的贡献， p300/CBP和赖氨酸乙酰化对收缩刺激的葡萄糖摄取的影响。总而言之，由于这项工作， 预期对调节骨骼肌葡萄糖摄取的信号传导有更好的理解， 通过推广，预计将转化为对人类健康的切实惠益。