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.

项目概要/摘要 总体目标是阐明心脏中促进心脏功能的分子和生理机制。 老年人心肌缺血和缺血/再灌注（I/R）损伤的心脏保护作用。随着年龄的增长， 心肌耐受缺血应激的能力受到损害。因此，有更多 接受当前心肌干预措施的 70 岁以上患者的发病率和死亡率 梗塞。然而，导致这种与年龄相关的 I/R 适应性反应损伤的机制 仍然不完全理解。因此，了解这些机制的变化 衰老的心脏是改善针对此类心血管疾病的治疗策略的基础 病理学。我们的小组和其他人提供了广泛的证据表明 AMP 的激活 活化蛋白激酶（AMPK）信号通路对心脏非常有利。此外，我们还有 最近证明，在心肌缺血期间，老年人中 AMPK 的激活显着受损 心脏，这与心肌梗塞和心脏功能障碍的增加直接相关。 然而，除了内源性机制之外，AMPK在心肌缺血期间是如何被激活的 解释年轻心脏和老年心脏之间 AMPK 激活受损的差异仍然存在 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被称为 sestrins，特别是 Sestrin2 已被证明可以在体外和体内增加 AMPK 的激活。 Sestrin2 也限制 针对缺氧损伤的细胞死亡、限制氧化应激并增加自噬通量，所有这些都是 在与年龄相关的心脏功能障碍中具有重要意义。因此，我们假设 Sestrin2 可能是一个积分 心肌 I/R 期间发生的部分应激反应及其与 AMPK 信号传导的配合 通路随着心脏衰老而改变。该假设将通过两个目标进行检验。首先，我们的目标是 将 sestrin2 定义为 I/R 损伤期间适应性反应的关键组成部分。其次，我们的目标是 描述 Sestrin2 如何参与老年心脏 I/R 期间受损的 AMPK 信号通路。 拟议的研究采用跨学科方法，涵盖生理相关的体内和 衰老和 I/R 损伤的离体模型。通过这种方式，拟议的研究将突出新的治疗方法 目标并进一步了解特定压力激活的心脏保护途径的作用 随着年龄的增长而受损。公共卫生相关性：缺血性心脏病，影响大约 每年有一百万美国人最常因缺血性损伤而导致心肌损伤。 这笔赠款旨在了解受损的心脏保护信号传导如何导致更高的 老年人群中缺血性心脏病的发病率，并有可能发现新的治疗方法 限制老年人心肌功能障碍的策略。