AGING AND VENTRICULAR DYSFUNCTION

衰老和心室功能障碍

• 批准号: 7720532
• 负责人: JUN REN
• 金额: $ 3.88万
• 依托单位: UNIVERSITY OF WYOMING
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2009-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7720532
• 关键词: Age; Aging; Antioxidants; Apoptosis; Biology of Aging; Buthionine Sulfoximine; Cardiac; Cardiac Myocytes; Computer Retrieval of Information on Scientific Projects Database; Contractile Proteins; Coupling; DNA Damage; Elderly; Equilibrium; Free Radicals; Funding; Grant; Growth; Institution; Insulin; Insulin-Like Growth Factor I; Laboratories; Longevity; Maintenance; Mediating; Metallothionein; Mitochondria; Morphology; Organ; Oxidants; Oxidative Stress; Oxidative Stress Induction; Paraquat; Performance; Phosphorylation; Play; Research; Research Personnel; Resources; Role; Source; Superoxide Dismutase; Transgenic Organisms; United States National Institutes of Health; Ventricular Dysfunction; age related; catalase; concept; forkhead protein; heart function; improved; mouse model; protective effect; protein expression; senescence; theories

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The "free radical theory of aging" first postulated in 1956 has been perhaps the most widely accepted theory for biology of aging. Aging-related accumulation of free radicals or oxidative stress has been demonstrated to be responsible for senescent organ damage and lifespan. This theory has paved its way to the modern concept of "mitochondrial theory of aging", which credits mitochondria as the main culprits for oxidative stress. Oxidant balance and mitochondrial function play crucial roles in the maintenance of normal cardiac contractile performance. Nevertheless, the precise mechanisms of action of oxidative stress and mitochondrial function in cardiac aging remain elusive. Evidence from our laboratory indicated that antioxidants metallothionein and catalase exert protective effects against aging-induced cardiac damage and prolong lifespan. Our lab has shown cardiac-specific expression of insulin-like growth I (IGF-1) improved cardiac contractile function in advanced age without compromising lifespan. Therefore, our central hypothesis is that oxidative stress with advanced age is the ultimate cause of enhanced apoptosis and ventricular dysfunction through a mechanism of reduced Akt phosphorylation, lessened Akt-dependent inactivation of Forkhead transcription factor and FasL-mediated apoptosis. Cardiomyocyte and echocardiographic function, heart morphology, cardiac excitation-contraction coupling, cardiac contractile protein expression, oxidative damage, mitochondrial function, DNA damage and apoptosis will be evaluated in transgenic mouse models with cardiac specific over-expression of antioxidants metallothionein, superoxide dismutase and IGF-1 in young, middle and old ages. Oxidative stress inducer paraquat and BSO will be used to examine if oxidative stress induction mimics cardiac aging.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 1956年首次假设的“自由基理论”也许是衰老生物学最广泛接受的理论。自由基或氧化应激的衰老相关积累已被证明是衰老器官损伤和寿命的原因。该理论已铺平了“衰老的线粒体理论”的现代概念，该概念将线粒体视为氧化应激的主要罪魁祸首。氧化剂平衡和线粒体功能在维持正常心脏收缩性能中起着至关重要的作用。然而，心脏衰老中氧化应激和线粒体功能的确切机制仍然难以捉摸。我们实验室的证据表明，抗氧化剂金属硫硫代蛋白和过氧化氢酶对衰老诱导的心脏损伤和延长寿命具有保护作用。我们的实验室表明，胰岛素样生长I（IGF-1）的心脏特异性表达在不影响寿命的情况下改善了高龄的心脏收缩功能。因此，我们的中心假设是，具有高级年龄的氧化应激是通过降低Akt磷酸化的机制增强凋亡和心室功能障碍的最终原因，从而减少了Akt依赖性依赖于Akt的转录因子的失活和Fasl介导的失活。心肌细胞和超声心动图功能，心脏形态，心脏激发偶联耦合，心脏收缩蛋白表达，氧化损伤，线粒体功能，DNA损伤和凋亡将在转基因小鼠模型中以抗氧化剂的心脏特异性过表达的抗氧化剂抗氧化剂和超级氧化剂的质量和Imigffimigffimfifectase评估。氧化应激诱导剂Paraquat和BSO将用于检查氧化应激诱导是否模仿心脏老化。