AMPK-SIRT1 Signaling in the Adaptive Metabolic Response

适应性代谢反应中的 AMPK-SIRT1 信号传导

• 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
• 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' -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

 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（由适用提供）：临床研究报告说，在60岁以上的患者中，心肌梗死，冠状动脉血管成形术或心脏手术后，缺血性心脏病和死亡率的较高事件与内在的心肌耐受性损伤的抗性下降有关。导致与年龄相关的缺血性intlerance的机制尚不完全理解，并且与缺血/再灌注有关的细胞反应涉及的信号传导途径在很大程度上尚不清楚。我们最近报道说，与衰老相关的AMP激活蛋白激酶（AMPK）信号传导的降低是重要的因素，从而导致通过调节葡萄糖转运蛋白（GLUT4）翻译的敏感性增加了对缺血应力的敏感性。有趣的是，长寿蛋白的Sirtuin 1（SIRT1）是 作为心脏病涉及的下游靶标的潜在AMPK。因此，假设老年心脏中受损的AMPK-SIRT1信号级联反应有助于肠道内部的缺血性损伤。我们将检验这一假设，以研究SIRT1信号传导在老年心脏对缺血性损伤的敏感性中的重要性。目标1：表征缺血/再灌注期间老年心脏中的SIRT1激活； AIM 2：确定SIRT1在缺血 - 再灌注胁迫期间控制心脏功能中的作用；目标3：评估小分子AMPK或SIRT1激动剂的能力，以改善老年心脏的缺血/再灌注诱导的适应性反应。通过这种方式，我们将提高人们对响应缺血性压力的心脏SIRT1信号通路的衰老相关改变背后的机制的理解。此外，我们提出了一种新型的治疗策略，该策略可能会上调心脏SIRT1信号传导，从而预防这一人群中缺血引起的心脏损伤。