Pivotal Role of Mitochondrial Telomerase in Regulation of Vascular Tone and Redox Homeostasis

线粒体端粒酶在血管张力和氧化还原稳态调节中的关键作用

• 批准号: 9307494
• 负责人: Andreas M Beyer
• 金额: $ 41.25万
• 依托单位: MEDICAL COLLEGE OF WISCONSIN
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9307494
• 关键词: Address; Age of Onset; Aging; Animals; Attenuated; Blood Vessels; Cardiovascular Diseases; Cardiovascular system; Cause of Death; Cell Aging; Cell Culture Techniques; Cell Nucleus; Cell Proliferation; Chronic; Coronary; Coronary Arteriosclerosis; Cytosol; DNA Damage; Data; Development; Dilatation - action; Dilator; Disease; Dominant-Negative Mutation; Endothelial Cells; Endothelium; Environment; Exclusion; Generations; Genetic; Genetic Transcription; Goals; Health; Homeostasis; Human; Hydrogen Peroxide; Impairment; In Vitro; Individual; Malignant Neoplasms; Measures; Mediating; Mediation; Mediator of activation protein; Microcirculation; Microvascular Dysfunction; Mitochondria; Mitochondrial DNA; Modeling; Molecular; Mus; Nitric Oxide; Nuclear; Oxidation-Reduction; Oxidative Stress; Pathologic; Pathway interactions; Patients; Peptides; Pharmacology; Phenotype; Physiological; Play; Positioning Attribute; Prevention; Production; Publishing; RNA Splicing; RNA-Directed DNA Polymerase; Reactive Oxygen Species; Regulation; Resistance; Ribonucleoproteins; Role; Secondary to; Stress; TERT gene; Telomerase; Telomerase inhibition; Telomere Shortening; Testing; Up-Regulation; Variant; Vasodilation; Western World; arteriole; disease phenotype; endothelial dysfunction; experimental study; inhibitor/antagonist; mouse model; new therapeutic target; novel; nucleocytoplasmic transport; prevent; protective effect; restoration; telomere; tool; tumor progression

Project Abstract Telomerase a ribo-nucleoprotein that counteracts telomere shortening has recently been shown by our investigative team to have a non-canonical role in attenuating formation of mitochondrial reactive oxygen species (mtROS) in coronary arterioles from subjects with coronary artery disease (CAD). We demonstrated that activation of TERT can reverse the mechanism of flow-induced endothelium-dependent dilation from H2O2- to NO, restoring the phenotype to one observed in subjects without CAD. In this proposal, we aim to investigate the role of mitochondrial specific effects of telomerase activity and whether the dominant negative splice variant β del TERT is critical in this phenotypic change in dilator mechanism. Our central hypothesis is that mitochondrial DNA damage is one of the underlying causes that leads to increase in ROS production. mtROS is known to promote development of arteriolosclerosis and endothelial dysfunction predisposing individuals to vascular complications. NO has a well-known inhibitory effect on mtROS generation and has also been demonstrated to increase telomerase. Whether nuclear or mitochondrial telomerase activity contributes to cardiovascular protection is not defined. We developed novel inhibitors of nuclear (nucTERT) or mitochondrial (mitoTERTi) telomerase activity to differentiate the roles of nuclear and mitochondrial telomerase in mediating vascular protective phenotypes. We will identify the role of mitochondrial telomerase in this change of mechanism from health (NO mediation) to disease (H2O2 mediation) in mouse and human resistance vessels. We hypothesize that mitochondrial telomerase plays a protective role by preventing mtDNA damage in normal conditions, while expression of β del TERT in disease suppresses this protective effect and elevates vascular cellular oxidative stress, and induces the conversion from NO to H2O2 as the mediator of FMD. This will be tested by addressing two specific aims. First, we will determine whether mitochondrial localization of TERT is necessary and sufficient to maintain NO rather than mtH2O2 as the mediator of flow-induced dilation in the human microcirculation. Second, we will investigate whether the mechanism by which CAD elicits a switch from NO to H2O2 as the mediator of FMD and impairs mitochondrial function involves accumulation of β-del TERT. We will use existing pharmacological and genetic tools that will lead to strategies for restoration of microvascular function in disease. This novel hypothesis has important translational potential, identifying new therapeutic targets for moderating the pathological changes associated with microvascular disease.

项目摘要 端粒酶一种抵抗端粒缩短的核糖核蛋白最近已被我们的 调查小组在衰减线粒体活性氧的形成中具有非经典作用 （MTROS）在患有冠状动脉疾病（CAD）受试者的冠状动脉动脉中。我们证明了这一点 TERT的激活可以逆转流动诱导的内皮依赖性解释的机理，从H2O2-到 不，将表型恢复到没有CAD的受试者中观察到的表型。在此提案中，我们旨在调查 端粒酶活性线粒体特异性效应的作用以及显性负剪接变体是否存在 βdel tert在扩张器机制的这种表型变化中至关重要。我们的中心假设是线粒体 DNA损伤是导致ROS产生增加的根本原因之一。 Mtros已知 促进动脉粥样硬化和内皮功能障碍的发育诱发血管 并发症。 NO对MTROS的产生有众所周知的抑制作用，并且也已证明 增加端粒酶。核或线粒体端粒酶活性是否有助于心血管 没有定义保护。我们开发了核（Nuctert）或线粒体（Mitoterti）的新型抑制剂 端粒酶活性以区分核和线粒体端粒酶在介导血管中的作用 保护表型。我们将确定线粒体端粒酶在这种机制变化中的作用 对小鼠和人类抗性血管中疾病（H2O2介导）的健康（无调解）。 我们假设线粒体端粒酶通过防止mtDNA损害在 正常条件，而疾病中βdel tert的表达抑制了这种受保护的作用并升高 血管细胞氧化应激，并诱导从NO到H2O2的转化为FMD的介体。这会 通过解决两个具体目标来测试。 首先，我们将确定TERT的线粒体定位是否需要且足以维持 没有而非MTH2O2作为人类微循环中流动诱导字典的介体。第二，我们会的 调查CAD的机制是否引起从NO转换为H2O2作为FMD的介体和 损害线粒体功能涉及β-DEL TERT的积累。我们将使用现有的药物和 遗传工具将导致恢复疾病中微血管功能的策略。这个新颖的假设 具有重要的翻译潜力，确定了新的治疗靶标，以缓解病理变化 与微血管疾病有关。