Anti-aging and Stress Resistance by Sir2

Sir2 的抗衰老和抗压能力

• 批准号: 7139107
• 负责人: Junichi Sadoshima
• 金额: $ 31.88万
• 依托单位: UNIV OF MED/DENT OF NJ-NJ MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-15 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7139107
• 关键词: adenylate cyclase; aging; amidohydrolases; apoptosis; baroreflex; caloric dietary content; cardiac myocytes; catalase; cytoprotection; dietary restriction; gene induction /repression; genetically modified animals; heart failure; heart function; intermolecular interaction; laboratory mouse; longevity; myocardial ischemia /hypoxia; oxidative stress; pathologic process; phenotype; reperfusion; tissue /cell culture; transcription factor

DESCRIPTION (provided by applicant): Growing lines of evidence suggest that the life span of the organisms are regulated by defined molecular mechanisms, including silent information regulator2 (Sir2) family histone deacetylases (HDACs), anti- oxidants, such as catalase and superoxide dismutase, and Forkhead box, class O (FOXO) family transcription factors. These mechanisms are evolutionarily conserved and thus expected to regulate fundamental biological functions. These factors not only extend the maximum lifespan, but also retard aging process in a wide variety of animals. Importantly, the longevity factors in the lower organisms confer stress- resistance to the organism. However, it is unclear whether or not these regulators of longevity also affect aging and the stress resistance of individual post-mitotic organs, including the heart, in higher organisms. Yeast Sir2, an NAD+ dependent HDAC and a founding member of the HDAC class III family, functions in a wide array of cellular processes, including gene silencing, longevity, and DNA damage repair. We have reported that Sir2alpha, a mouse homologue, plays an essential role in mediating cell survival in cardiac myocytes in vitro. At present, however, very little is known about the function of Sir2alpha in mammals at the organ levels. In order to elucidate the in vivo function of Sir2alpha, we have recently generated both persistent and conditional transgenic mice with cardiac specific expression of Sir2alpha. Our central hypotheses in this study are that Sir2alpha mediates anti-aging as well as cell protective effects in the heart in vivo. We will: 1) Examine whether the known longevity factors, such as Sir2alpha, slow cardiac aging, 2) Examine whether the known longevity factors, including Sir2alpha, confer stress resistance to the heart, and 3) Identify the molecular mechanisms by which the longevity factors confer stress resistance to cardiac myocytes. Our study will elucidate the mechanisms regulating aging of cardiac myocytes and identify the effective method to make the heart stress-resistant. Knowledge obtained from this study should be useful not only for the development of novel modalities for treatment of ischemic heart diseases and congestive heart failure but also for the prevention of age-associated complications in the elderly.

描述（由申请人提供）：越来越多的证据表明，生物体的寿命受到明确的分子机制的调节，包括沉默信息调节因子 2 (Sir2) 家族组蛋白脱乙酰酶 (HDAC)、抗氧化剂，例如过氧化氢酶和超氧化物歧化酶和 Forkhead box，O 类 (FOXO) 家族转录因子。这些机制在进化上是保守的，因此有望调节基本的生物功能。这些因素不仅可以延长多种动物的最大寿命，而且可以延缓衰老过程。重要的是，低等生物体的长寿因素赋予生物体抗逆性。然而，目前尚不清楚这些长寿调节因子是否也会影响高等生物体中个体有丝分裂后器官（包括心脏）的衰老和应激抵抗力。 Yeast Sir2 是一种 NAD+ 依赖性 HDAC，也是 HDAC III 类家族的创始成员，在多种细胞过程中发挥作用，包括基因沉默、长寿和 DNA 损伤修复。我们报道了 Sir2alpha 是一种小鼠同源物，在体外介导心肌细胞存活中发挥着重要作用。然而目前，人们对Sir2alpha在哺乳动物器官水平上的功能知之甚少。为了阐明 Sir2alpha 的体内功能，我们最近培育了具有心脏特异性表达 Sir2alpha 的持续性和条件性转基因小鼠。我们在这项研究中的中心假设是 Sir2alpha 在体内介导抗衰老以及心脏细胞保护作用。我们将：1) 检查已知的长寿因素，如 Sir2alpha，是否可以减缓心脏衰老，2) 检查已知的长寿因素，包括 Sir2alpha，是否赋予心脏抗应激能力，以及 3) 确定长寿的分子机制因素赋予心肌细胞抗应激能力。我们的研究将阐明调节心肌细胞衰老的机制，并找到使心脏抵抗应激的有效方法。从这项研究中获得的知识不仅有助于开发治疗缺血性心脏病和充血性心力衰竭的新方法，而且有助于预防老年人与年龄相关的并发症。