Differentiation of mitochondrial vs. nuclear function of telomerase

端粒酶线粒体与核功能的区分

• 批准号: 8681115
• 负责人: Andreas M Beyer
• 金额: $ 19.13万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-21 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8681115
• 关键词: Ablation; Acute; Affect; Aging; Animals; Arteries; Automobile Driving; Biochemical; Biological Availability; Biological Models; Blood Vessels; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cell Culture Techniques; Cell Nucleus; Cells; Chronic; Coronary Arteriosclerosis; Data; Defect; Development; Diabetes Mellitus; Disease; Endothelial Cells; Endothelium; Environment; Enzymes; Evaluation; Event; Exclusion; Flow Cytometry; Generations; Genomics; Goals; Health; Heart Mitochondria; Homeostasis; Hour; Human; Hydrogen Peroxide; Hypertension; Imaging Techniques; Inflammatory; Knock-out; Lead; Length; Link; Malignant Neoplasms; Measures; Mediating; Mediator of activation protein; Membrane Potentials; Methods; Microvascular Dysfunction; Mitochondria; Mitochondrial DNA; Modeling; Modification; Molecular; Mus; Neurodegenerative Disorders; Nuclear; Nucleoproteins; Oxidation-Reduction; Oxidative Stress; Pathogenesis; Pathologic Processes; Pathway interactions; Patients; Phenotype; Physiological; Play; Production; Proteins; Rattus; Reactive Oxygen Species; Regulation; Relaxation; Reporting; Research Personnel; Resistance; Respiratory Chain; Role; Southern Blotting; Telomerase; Telomerase inhibition; Telomere Shortening; Testing; Tissues; Transcription Coactivator; adverse outcome; improved; innovation; mitochondrial dysfunction; mitochondrial membrane; mouse model; mutant; novel; novel therapeutic intervention; nuclease; protective effect; public health relevance; senescence; stressor; telomerase reverse transcriptase; telomere

DESCRIPTION (provided by applicant): Telomerase, a ribo-nucleoprotein that counteracts telomere shortening, has recently been suggested as having a telomere independent survival function. A protective effect of telomerase on mitochondrial function under conditions of oxidative stress has been described, yet the exact mechanism and phenotype linked to mitochondrial or nuclear TERT (catalytic subunit of telomerase) is not clearly identified. We have shown that in the presence of coronary artery disease or acute vascular stressors, there is a shift in the mechanism of flow mediated dilation (FMD) from NO to H2O2. The current study aims to differentiate the role of nuclear TERT vs. mitochondrial TERT in the development of cardiovascular (CV) disease. In our central hypothesis, mitochondrial TERT plays a critical and previously undiscovered role in reducing mitochondrial reactive oxygen species (ROS) thus protecting against CV disease and other ROS associated disorders. This study will focus on CV health and use FMD and its mechanism and redox environment as physiological markers. The conceptual paradigm shift tested is that mitochondrial TERT decreases mitochondrial ROS production by improving mitochondrial respiratory chain activity. This contributes to maintaining normal NO levels, thereby preserving physiological regulation of FMD in the microvasculature. Conversely, we postulate that reduced mitochondrial TERT results in increased mitochondrial ROS, driving microvascular dysfunction by changing the mediator of FMD from NO to H2O2 thereby creating a pro-inflammatory milieu. We will be using state of the art methods to evaluate vascular reactivity alongside molecular evaluation of the redox environment to characterize the role of telomerase in regulating cellular and mitochondrial ROS levels. This novel hypothesis and the models generated have important translational potential and will be extremely useful for investigators studying varying diseases and in multiple fields.

描述（由申请人提供）：端粒酶是一种抵消端粒缩短的核糖核蛋白，最近被认为是具有端粒独立生存函数。已经描述了端粒酶对氧化应激条件下线粒体功能的保护作用，但尚未清楚地鉴定出与线粒体或核TERT（催化亚基）相关的确切机制和表型。我们已经表明，在存在冠状动脉疾病或急性血管应激源的情况下，流动介导的扩张（FMD）的机理从NO到H2O2发生了变化。当前的研究旨在区分核TERT与线粒体TERT在心血管疾病发展中的作用。在我们的中心假设中，线粒体TERT在减少线粒体活性氧（ROS）中起着至关重要的，以前未被发现的作用，因此可以预防CV疾病和其他与ROS相关的疾病。这项研究将集中于简历健康，并使用FMD及其机制和氧化还原环境作为生理标记。测试的概念范式转移是线粒体TERT通过改善线粒体呼吸链活性来降低线粒体ROS的产生。这有助于维持正常的NO水平，从而保留了微脉管系统中FMD的生理调节。相反，我们假设减少线粒体TERT会导致线粒体ROS增加，从而通过将FMD的介体从NO变为H2O2，从而驱动微血管功能障碍，从而创建促炎的环境。我们将使用最先进的方法与氧化还原环境的分子评估一起评估血管反应性，以表征端粒酶在调节细胞和线粒体ROS水平的作用。这个新颖的假设和产生的模型具有重要的翻译潜力，对于研究不同疾病和多个领域的研究人员将非常有用。