Differentiation of mitochondrial vs. nuclear function of telomerase

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，最近被认为具有端粒非依赖性生存功能。已经描述了端粒酶在氧化应激条件下对线粒体功能的保护作用，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鉴定。我们已经表明，在冠状动脉疾病或急性血管紧张性刺激的存在下，有一个流动介导的扩张（FMD）的机制从NO到H2O2的转变。目前的研究旨在区分核TERT与线粒体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）从而保护免受CV疾病和其他ROS相关疾病方面起着关键且先前未发现的作用。本研究将以心血管健康为重点，以FMD及其机制和氧化还原环境作为生理指标。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降低线粒体ROS产生。这有助于维持正常的NO水平，从而保持微血管系统中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的介体从NO改变为H2O2从而产生促炎环境来驱动微血管功能障碍。我们将使用最先进的方法来评价血管反应性，同时对氧化还原环境进行分子评价，以表征端粒酶在调节细胞和线粒体ROS水平中的作用。这种新的假设和生成的模型具有重要的转化潜力，对于研究不同疾病和多个领域的研究人员来说非常有用。

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.