AMPK-SIRT1 Signaling in the Adaptive Metabolic Response

适应性代谢反应中的 AMPK-SIRT1 信号传导

基本信息

批准号：
9243202
负责人：
Ji Li
金额：
$ 31.01万
依托单位：
UNIVERSITY OF MISSISSIPPI MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-15 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9243202
关键词：
5&apos -AMP-activated protein kinase Age-Years Aging Agonist Antidiabetic Drugs Attenuated Caloric Restriction Cardiac Cardiac Surgery procedures Cardiovascular Diseases Catabolic Process Clinical Research Cytomegalovirus Deacetylation Diet EP300 gene Echocardiography Elderly Exercise FOXO3A gene Gene Expression Gene Silencing Genetic Glucose Transporter HNF4A gene Heart Heart Diseases Impairment Incidence Individual Injection of therapeutic agent Injury Ischemia Knockout Mice Laboratories Lead Left Ventricular Dysfunction Longevity Measurement Measures Mediating Metabolic Metabolism Metformin Molecular Mus Muscle Fibers Myocardial Myocardial Infarction Myocardial Ischemia Myocardial dysfunction Myocardium Nutrient Orthologous Gene Outcome Oxidative Stress Performance Pharmacology Phosphotransferases Population Predisposition Prevention Process Protein Kinase Proteins Protocols documentation Regulation Reperfusion Injury Reperfusion Therapy Reporting Repression Resistance Role SIRT1 gene Signal Pathway Signal Transduction Sir2-like Deacetylases Sirtuins Stress System TP53 gene Tamoxifen Testing Thiazolidinediones Transgenic Mice Work Yeasts age effect age related aged coronary angioplasty improved in vivo mortality myocardial damage novel novel therapeutics older patient overexpression public health relevance response sensor small molecule transcription factor yeast protein

项目摘要

DESCRIPTION (provided by applicant): Clinical studies report a higher incidence of ischemic heart disease and mortality after myocardial infarction, coronary angioplasty, or cardiac surgery in patients older than 60 years of age, which appear to be related to a decline in intrinsic myocardial resistance to injury. The mechanisms responsible for age-related ischemic intolerance are incompletely understood and the signaling pathways involved in regulating cellular responses to ischemia/reperfusion remain largely unknown. We recently reported that an aging-associated reduction in AMP-activated protein kinase (AMPK) signaling is an important contributing factor leading to increased sensitivity to ischemic stress via modulation of the glucose transporter (GLUT4) translocation. Intriguingly, Sirtuin 1 (SIRT1), a longevity protein, is emerging as a potential AMPK downstream target involved in heart disease. Therefore, it is hypothesized that the impaired AMPK-SIRT1 signaling cascade in the aged heart contributes to intolerance to ischemic insults in the elderly. We will test this hypothesis to investigate the importance of SIRT1 signaling in the susceptibility of the aged heart to ischemic insults. Aim 1: To characterize the SIRT1 activation in the aged heart during ischemia/reperfusion; Aim 2: To determine the role of SIRT1 in regulating cardiac function during ischemia-reperfusion stress; Aim 3: To evaluate the capability of a small-molecule AMPK or SIRT1 agonist to improve ischemia/reperfusion-induced adaptive response in the aged heart. In this manner, we will advance our understanding of the mechanisms behind aging-associated alterations in cardiac SIRT1 signaling pathways in response to ischemic stress. Furthermore, we propose a novel therapeutic strategy that might up-regulate cardiac SIRT1 signaling and thus protect against ischemia- induced cardiac injury in this segment of population.

描述（由申请人提供）：冠状动脉临床研究报告显示，60 岁以上患者在心肌梗塞、血管成形术或心脏手术后，缺血性心脏病和死亡率较高，这似乎与内在心肌阻力下降有关与年龄相关的缺血不耐受的机制尚不完全清楚，并且参与调节细胞对缺血/再灌注反应的信号通路仍然很大程度上未知。与衰老相关的 AMP 激活蛋白激酶 (AMPK) 信号传导减少是通过调节葡萄糖转运蛋白 (GLUT4) 易位导致对缺血应激的敏感性增加的一个重要因素。因此，老年人心脏中 AMPK-SIRT1 信号级联受损会导致老年人对缺血性损伤的不耐受。我们将检验这一假设，以研究 SIRT1 的重要性。目标 1：表征衰老心脏在缺血/再灌注过程中的 SIRT1 激活；目标 2：确定衰老心脏对缺血损伤易感性的信号传导。 SIRT1 在缺血再灌注应激期间调节心脏功能的作用；目标 3：评估小分子 AMPK 或 SIRT1 激动剂改善衰老心脏缺血/再灌注诱导的适应性反应的能力。增进我们对心脏 SIRT1 信号通路因缺血应激而发生衰老相关改变的机制的理解此外，我们提出了一种可能上调心脏 SIRT1 信号传导和治疗的新治疗策略。从而防止这部分人群因缺血引起的心脏损伤。