Acetylation and contraction-mediated glucose uptake

乙酰化和收缩介导的葡萄糖摄取

基本信息

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
项目类别：
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&apos -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

项目摘要

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.

项目概要收缩刺激的葡萄糖摄取对于运动期间维持 ATP 产生很重要，尤其是高强度的运动。它也是临床治疗和预防的基石高血糖和 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制定优化骨骼肌葡萄糖的策略很重要代谢。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。该应用的基本前提是 GLUT4- 的赖氨酸乙酰化运输蛋白质对于收缩刺激的葡萄糖摄取是必要的。因此，在这个应用程序中我们的主要目的是阐明乙酰转移酶 p300（E1A 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，以及鉴定响应收缩而乙酰化的 GLUT4 运输蛋白。我们的中心假设 p300 和 CBP 通过 GLUT4 运输的乙酰化调节收缩刺激的葡萄糖摄取蛋白质，并且它们的作用独立于它们作为转录调节因子的共同作用。为了解决这个问题假设，我们将测量基础和收缩刺激的葡萄糖摄取和质膜 GLUT4 小鼠骨骼肌中 p300 和 CBP 乙酰转移酶活性受到强烈调节的丰度。具体来说，目标 #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影响。目标 #2 将定义响应收缩而乙酰化的 GLUT4 运输蛋白，包括 p300/CBP 的贡献。总而言之，这些研究将深入了解 p300/CBP 和赖氨酸乙酰化导致收缩刺激的葡萄糖摄取。总而言之，由于这项工作，预计将加深对调节骨骼肌葡萄糖摄取的信号传导的理解，这推而广之，预计将转化为对人类健康的切实好处。