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.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 1956年首次提出的“自由基衰老理论”可能是衰老生物学中最被广泛接受的理论。与衰老相关的自由基积累或氧化应激已被证明是导致衰老器官损伤和寿命的原因。这一理论为“线粒体衰老理论”的现代概念铺平了道路，后者认为线粒体是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的心脏收缩功能中起着至关重要的作用。然而，氧化应激和线粒体功能在心脏衰老中的确切作用机制仍然不清楚。我们实验室的证据表明，抗氧化剂金属硫蛋白和过氧化氢酶对衰老引起的心脏损伤具有保护作用，延长寿命。我们的实验室已经证明，心脏特异表达胰岛素样生长I(IGF-1)可以在不影响寿命的情况下改善高龄患者的心脏收缩功能。因此，我们的中心假设是，随着年龄的增加，氧化应激是细胞凋亡增强和心功能障碍的最终原因，其机制是Akt磷酸化减少，Forkhead转录因子Akt依赖的失活减少，以及FasL介导的细胞凋亡。在年轻、中年和老年心脏特异性过表达抗氧化剂金属硫蛋白、超氧化物歧化酶和IGF-1的转基因小鼠模型中，将评估心肌细胞和超声心动图功能、心脏形态、心脏兴奋收缩偶联、心肌收缩蛋白表达、氧化损伤、线粒体功能、DNA损伤和细胞凋亡。氧化应激诱导剂百草枯和BSO将被用来检验氧化应激诱导是否模仿心脏衰老。