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在运动过程中维持ATP的生产很重要， 特别是行使高强度。它也是治疗和预防临床的基石 高血糖和2型糖尿病的发展。因此，了解收缩的调节 - 刺激的葡萄糖摄取对于开发优化骨骼肌葡萄糖的策略很重要 代谢。这项研究的长期目的是阐明调节收缩的机制 刺激的葡萄糖摄取。该应用的基本前提是Glut4-的赖氨酸乙酰化 运输蛋白对于收缩刺激的葡萄糖摄取是必需的。因此，在此应用程序中 主要目的是阐明乙酰基转移酶的重要性P300（E1A结合蛋白p300）和 CBP（cAMP响应元件结合蛋白结合蛋白）对收缩刺激的葡萄糖摄取，而 确定响应收缩的GLUT4运输蛋白。我们的中心假设 是P300和CBP通过乙酰化的GLUT4拖载来调节收缩刺激的葡萄糖摄取 蛋白质，并且他们这样做独立于他们作为转录调节剂的共同作用。解决这个问题 假设，我们将测量基础和收缩刺激的葡萄糖摄取和质膜Glut4 小鼠骨骼肌的丰度在其中P300和CBP乙酰转移酶活性受到严格调节。 具体而言，AIM＃1将研究P300/CBP对收缩刺激的葡萄糖摄取和 质膜GLUT4易位，包括基因转录对其调节的重要性 效果。 AIM＃2将定义GLUT4运输蛋白，这些蛋白因收缩而被乙酰化， 包括P300/CBP的贡献。总之，这些研究将为您提供有关的贡献 P300/CBP和赖氨酸乙酰化以刺激了葡萄糖的摄取。由于这项工作，总共 预计对调节骨骼肌摄取葡萄糖摄取的信号的理解得到了改善，这将是 预计将扩展将转化为人类健康的切实益处。