Role of Sestrin2 in Prevention of Age-related Cardiomyopathy

Sestrin2 在预防年龄相关性心肌病中的作用

• 批准号: 8638216
• 负责人: Ji Li
• 金额: $ 23.04万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-06-01 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8638216
• 关键词: 5' -AMP-activated protein kinase; Acetylcysteine; Address; Affect; Age; Age-Years; Aging; American; Antioxidants; Autophagocytosis; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular Pathology; Cardiovascular system; Cell Death; Cells; Coronary Arteriosclerosis; Cytomegalovirus; Drosophila genus; Elderly; Embryo; Event; Exhibits; Fibroblasts; Functional disorder; Gene Deletion; Genes; Glucose; Goals; Grant; Health; Heart; Hypoxia; Impairment; In Vitro; Incidence; Individual; Injection of therapeutic agent; Injury; Intervention; Ischemia; Knock-out; Knockout Mice; Laboratories; Liver; Mammals; Measures; Mediating; Modeling; Molecular; Morbidity - disease rate; Mus; Myocardial; Myocardial Infarction; Myocardial Ischemia; Myocardial dysfunction; Myocardium; Necrosis; Outcome; Oxidative Stress; Pathway interactions; Patients; Performance; Phosphotransferases; Physiological; Population; Prevention; Protein Family; Proteins; Reactive Oxygen Species; Reperfusion Injury; Reperfusion Therapy; Research; Risk Factors; Role; STK11 gene; Signal Pathway; Signal Transduction; Stress; Testing; Therapeutic; Viral; adverse outcome; age related; aged; anti aging; base; biological adaptation to stress; deprivation; human FRAP1 protein; improved; in vivo; interdisciplinary approach; mortality; new therapeutic target; novel; novel therapeutics; particle; public health relevance; response; scaffold; senescence; stress tolerance

Project Summary/Abstract The overall goal is to elucidate the molecular and physiological mechanisms in the heart that promote cardioprotection against myocardial ischemia and ischemia/reperfusion (I/R) injury in the elderly. With aging, the ability of the myocardium to tolerate ischemic stress becomes compromised. Consequently, there is more morbidity and mortality in patients that are over 70 years of age receiving current interventions for myocardial infarction. Yet the mechanisms responsible for this age-related impairment in the adaptive response to I/R remains incompletely understood. Therefore, understanding the alteration of these mechanisms within the aging heart is fundamental for improving therapeutic strategies targeted against such cardiovascular pathologies. Our group and others have provided extensive evidence suggesting that activation of the AMP- activated protein kinase (AMPK) signaling pathway is highly advantageous to the heart. Moreover, we have recently demonstrated that during myocardial ischemia, AMPK activation is significantly impaired in the aged heart and that this is directly associated with increased myocardial infarction and cardiac dysfunction. However, how AMPK is activated during myocardial ischemia in addition to the endogenous mechanisms explaining the differences observed in impaired AMPK activation between young and aged hearts remains largely elusive. Recently, a novel group of proteins that lack kinase activity, known as the sestrins, particularly Sestrin2, have been demonstrated to increase the activation of AMPK in vitro and in vivo. Sestrin2 also limits cell death against hypoxic insults, limits oxidative stress, and increases the autophagic flux, all of which are important in age-related cardiac dysfunction. Accordingly, we hypothesize that Sestrin2 may be an integral part of the stress response that occurs during myocardial I/R and that its cooperation with the AMPK signaling pathway is altered with cardiac senescence. This hypothesis will be tested with two aims. First, we aim to define sestrin2 as a critical component of the adaptive response during I/R injury. Second, we aim to characterize how Sestrin2 is involved in the impaired AMPK signaling pathway during I/R in the aged heart. The proposed research takes an interdisciplinary approach encompassing physiologically relevant in vivo and ex vivo models of aging and I/R injury. In this manner, the proposed research will highlight new therapeutic targets and further our understanding about how specific stress-activated cardioprotective pathways are impaired with aging. PUBLIC HEALTH RELEVANCE: Ischemic heart disease, which affects approximately one million Americans each year, is most often caused by ischemic insults leading to myocardial damage. This grant seeks to understand the ways in which impaired cardioprotective signaling leads to a higher incidence of ischemic heart disease in the aged population, and has the potential to discover new therapeutic strategies to limit myocardial dysfunction in the elderly.

项目摘要/摘要 总体目标是阐明心脏中促进的分子和生理机制 老年人对心肌缺血和缺血/再灌注（I/R）损伤的心脏保护作用。随着衰老， 心肌耐缺血胁迫的能力受到损害。因此，还有更多 超过70岁的患者的发病率和死亡率接受心肌的当前干预措施 梗塞。然而，在对I/R的自适应反应中，导致这种与年龄相关的损害的机制 仍然不完全理解。因此，了解这些机制的改变 衰老的心脏对于改善针对这种心血管的治疗策略至关重要 病理。我们的小组和其他人提供了广泛的证据，表明激活AMP- 活化的蛋白激酶（AMPK）信号通路对心脏高度有利。而且，我们有 最近证明，在心肌缺血期间，AMPK激活在老年人中受到显着损害 心脏，这与心肌梗塞和心脏功能障碍的增加直接相关。 但是，除内源性机制外，在心肌缺血期间如何激活AMPK 解释在年轻心脏和老年心之间观察到的AMPK激活中观察到的差异仍然存在 在很大程度上难以捉摸。最近，一组缺乏激酶活性的新型蛋白质，称为sestrins，尤其是 已证明Sestrin2在体外和体内增加了AMPK的激活。 Sestrin2也限制 针对低氧损伤，限制氧化应激并增加自噬通量的细胞死亡，所有这些都是 与年龄相关的心脏功能障碍重要。因此，我们假设Sestrin2可能是不可或缺的 心肌I/R期间发生的压力反应的一部分，并且与AMPK信号的合作 心脏衰老改变了途径。该假设将以两个目标进行检验。首先，我们的目标是 将Sestrin2定义为I/R损伤期间自适应反应的关键组成部分。第二，我们的目标是 表征Sestrin2在老年心脏中I/R期间如何参与受损的AMPK信号通路。 拟议的研究采用了跨学科的方法，包括在体内与生理相关的方法 衰老和I/R损伤的体内模型。通过这种方式，拟议的研究将重点介绍新的治疗性 目标，进一步了解我们对特定压力激活的心脏保护途径的理解 衰老受损。公共卫生相关性：缺血性心脏病，会影响 每年一百万美国人通常是由缺血性损伤引起的，导致心肌损害。 该赠款试图了解受损的心脏保护信号导致更高的方式 老年人群中缺血性心脏病的发病率，并且有可能发现新的治疗性 限制老年人心肌功能障碍的策略。