The role of p300/CBP and acetylation towards skeletal muscle insulin action

p300/CBP 和乙酰化对骨骼肌胰岛素作用的作用

基本信息

批准号：
9975145
负责人：
Vitor Fernandes Martins
金额：
$ 5.05万
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：
2018
资助国家：
美国
起止时间：
2018-07-01 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9975145
关键词：
Acetylation Acetyltransferase Actins Address Adipocytes Alleles Binding Proteins Cell membrane Cell model Complication Consensus Cyclic AMP-Responsive DNA-Binding Protein Development EP300 gene F-Actin Flow Cytometry Fluorescence Microscopy Functional disorder Genetic Transcription Glucose Transporter Health Human Impairment Insulin Insulin Receptor Insulin Resistance Intuition Knock-out Knowledge Lead Left Link LoxP-flanked allele Lysine Measures Mechanics Mediating Metabolic Modeling Molecular Morbidity - disease rate Movement Mus Muscle Myoblasts Non-Insulin-Dependent Diabetes Mellitus Obesity Outcome Pharmacology Phosphatidylinositols Phosphorylation Phosphotransferases Protein Acetylation Proteins Proteomics Quality of life Regulation Research Role Signal Transduction Signaling Protein Skeletal Muscle Validation Work aged basal insulin base clinical care experimental study glucose transport glucose uptake imaging capabilities improved in vivo inhibitor/antagonist innovation insulin regulation insulin sensitivity insulin signaling mortality risk mouse model novel novel strategies novel therapeutics polymerization predictive modeling protein transport response therapy development trafficking

项目摘要

PROJECT SUMMARY Insulin resistance is a common metabolic complication in aged and obese skeletal muscle that is central to the pathophysiology of type 2 diabetes (T2D). In order to develop strategies to treat insulin resistance it is necessary to define the signaling transduction steps that lead to insulin-stimulated glucose uptake, particularly in skeletal muscle and adipocytes; remarkably, these steps have yet to be fully elucidated. Thus, the long-term objective of this research is to expand the knowledge of the molecular regulation of insulin-stimulated glucose transport. Currently, phosphorylation-based signaling from the insulin receptor through phosphoinositide 3- kinase (PI3K)-Akt, to Akt substrate of 160 kDa (AS160) and actin remodeling-related proteins, is considered the major mechanism regulating insulin-stimulated GLUT4 translocation to the plasma membrane and glucose uptake. In contrast to this `classical' model, herein this project proposes a new model in which lysine acetylation (in combination with phosphorylation-based signaling) of key insulin signaling and GLUT4 trafficking proteins is necessary for insulin-stimulated glucose uptake. Accordingly, the primary objective of this proposal is to elucidate the importance of the acetyltransferases (KATs), p300 (E1A binding protein p300) and CBP (cAMP response element-binding protein [CREB] binding protein), to insulin-stimulated glucose transport. The central hypothesis of this proposal is that acetylation, by p300 and/or CBP, of actin remodeling-related proteins are required for insulin-stimulated GLUT4 translocation and, therefore, the insulin-mediated increase in glucose uptake. To address this hypothesis, insulin-induced skeletal muscle glucose uptake, actin remodeling and GLUT4 translocation will be measured in murine and cell models in which p300 and CBP activity are manipulated. This proposal predicts that loss of both p300 and CBP activity will abolish insulin- stimulated actin reorganization, GLUT4 translocation and glucose transport. Specifically, in Aim #1 the necessity and redundancy of p300 and CBP for insulin-stimulated glucose uptake in skeletal muscle will be elucidated, whilst in Aim #2, the importance of p300/CBP to actin remodeling and polymerization, and GLUT4 translocation will be assessed. Overall, these studies will broaden the understanding of the contribution of p300, CBP and acetylation to skeletal muscle glucose uptake in response to insulin. Ultimately, knowledge gathered from this work is expected to manifest novel targets for the development of therapies to improve insulin sensitivity and treat type 2 diabetes, with enhancement of human health and quality of life being anticipated outcomes.

项目概要胰岛素抵抗是老年和肥胖骨骼肌中常见的代谢并发症，是骨骼肌健康的核心。 2 型糖尿病 (T2D) 的病理生理学。为了制定治疗胰岛素抵抗的策略有必要定义导致胰岛素刺激的葡萄糖摄取的信号转导步骤，特别是在骨骼肌和脂肪细胞中；值得注意的是，这些步骤尚未完全阐明。因此，长期这项研究的目的是扩大胰岛素刺激葡萄糖分子调节的知识运输。目前，胰岛素受体通过磷酸肌醇 3- 发出基于磷酸化的信号传导激酶 (PI3K)-Akt，160 kDa (AS160) 的 Akt 底物和肌动蛋白重塑相关蛋白，被认为是调节胰岛素刺激的 GLUT4 易位至质膜和葡萄糖的主要机制吸收。与这种“经典”模型相反，该项目提出了一种新模型，其中赖氨酸关键胰岛素信号传导和 GLUT4 的乙酰化（与基于磷酸化的信号传导相结合）运输蛋白质对于胰岛素刺激的葡萄糖摄取是必要的。因此，本次活动的首要目标是该提案旨在阐明乙酰转移酶 (KAT)、p300（E1A 结合蛋白 p300）和 CBP（cAMP 反应元件结合蛋白 [CREB] 结合蛋白），对胰岛素刺激的葡萄糖转运。该提案的中心假设是 p300 和/或 CBP 乙酰化与肌动蛋白重塑相关的蛋白质是胰岛素刺激的 GLUT4 易位所必需的，因此，胰岛素介导的增加在葡萄糖摄取中。为了解决这个假设，胰岛素诱导的骨骼肌葡萄糖摄取，肌动蛋白将在小鼠和细胞模型中测量重塑和 GLUT4 易位，其中 p300 和 CBP 活动受到操纵。该提案预测 p300 和 CBP 活性的丧失将废除胰岛素刺激肌动蛋白重组、GLUT4 易位和葡萄糖转运。具体来说，在目标#1中 p300 和 CBP 对于胰岛素刺激骨骼肌葡萄糖摄取的必要性和冗余性将是在目标 #2 中阐明了 p300/CBP 对肌动蛋白重塑和聚合以及 GLUT4 的重要性将评估易位。总体而言，这些研究将拓宽人们对以下贡献的理解： p300、CBP 和乙酰化对胰岛素反应中骨骼肌葡萄糖摄取的影响。最终，知识从这项工作中收集的数据预计将揭示出用于开发治疗方法的新目标，以改善胰岛素敏感性并治疗 2 型糖尿病，从而提高人类健康和生活质量预期结果。