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，一种核蛋白，抵消端粒缩短，最近被认为具有端粒独立的生存功能。在氧化应激条件下，端粒酶对线粒体功能的保护作用已被描述，但与线粒体或核TERT（端粒酶的催化亚基）相关的确切机制和表型尚未明确确定。我们已经证明，在冠状动脉疾病或急性血管应激源存在的情况下，血流介导的扩张（FMD）机制从NO转变为H2O2。目前的研究旨在区分核TERT和线粒体TERT在心血管（CV）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）中起着至关重要的作用，这是以前未被发现的，从而防止心血管疾病和其他ROS相关疾病。本研究将以心血管健康为研究重点，以FMD及其机制和氧化还原环境为生理指标。经测试的概念范式转变是，线粒体TERT通过改善线粒体呼吸链活性来减少线粒体ROS的产生。这有助于维持正常的一氧化氮水平，从而保持微血管中FMD的生理调节。相反，我们假设线粒体TERT的减少导致线粒体ROS的增加，通过将FMD的介质从NO改变为H2O2，从而产生促炎环境，从而驱动微血管功能障碍。我们将使用最先进的方法来评估血管反应性以及氧化还原环境的分子评估，以表征端粒酶在调节细胞和线粒体ROS水平中的作用。这一新的假设和模型具有重要的转化潜力，对研究不同疾病和多个领域的研究人员非常有用。