Mitochondria-targeted antioxidant supplementation for improving age-related vascular dysfunction in older adults: the role of circulating factors

项目总结/摘要 这个F32应用程序的目的是支持凯文·默里博士，一个有前途的第一年博士后研究员 在道格拉斯西尔斯博士的实验室里，进行原创性研究，并接受科学培训， 准备他成为一个独立的，在转化血管领域的研究者， 生理学旨在确定改善血管功能的新型干预措施，随着年龄的增长和 相关的作用机制。默里博士将学习各种新的技术，概念和专业 技能，包括转化细胞和分子血管生理学研究的重点培训，此外， 进行临床试验的培训。他提出的研究项目将利用他的主要赞助商的 正在进行的NIH资助的R 01资助的临床试验，旨在确定靶向的抗肿瘤药物的疗效。 抗氧化剂MitoQ用于改善老年人的血管内皮功能，以确定（目的1）是否 MitoQ慢性治疗3个月后循环环境的变化改善了内皮细胞 通过用MitoQ或MitoQ后从受试者收集的血浆处理人主动脉内皮细胞（HAEC）来发挥功能 安慰剂治疗。他还将确定（目标2）氧化低密度脂蛋白（oxLDL）的减少是否 MitoQ治疗后，通过改善oxLDL刺激的内皮细胞功能， 线粒体分裂最后，他还将探索（目标3）细胞外囊泡（EV）变化的作用， MitoQ治疗介导内皮细胞功能的改善，以及这些潜在的变化是否 与EV中miRNA含量的改变有关。血管内皮功能障碍主要是 通过血管保护分子一氧化氮（NO）的生物利用度降低介导， 产生活性氧（ROS）。线粒体功能障碍随着年龄的增长而增加， 血管系统中过量ROS（mtROS）的来源。MitoQ是一种针对肾脏的抗氧化剂， 实验室先前表明，老年人补充MitoQ 6周可改善NO介导的 内皮依赖性舒张。Murray博士为此应用收集的初步数据表明， MitoQ治疗后循环环境的变化增加了NO的生物利用度并降低了mtROS 在HAEC中的离体生物活性，扩展了MitoQ补充改善的作用机制 内皮功能在这些强有力的初步数据的指导下，默里博士将致力于建立对 循环环境作为MitoQ治疗改善内皮功能的作用机制， 利用在其主要申办者正在进行的NIH资助的R 01期间从受试者中采集的血浆样本 临床试验主要申办者是一位国际公认的、NIH资助的科学家， 成功指导转化生物医学研究。在他和他的指导团队的指导下， 博士穆雷将能够成功完成拟议的研究和培训计划，为他做好准备 成功地作为一个在转化血管生理学的校外资助的独立研究者。

PROJECT SUMMARY/ABSTRACT The purpose of this F32 application is to support Dr. Kevin Murray, a promising first-year postdoctoral fellow in the laboratory of Dr. Douglas Seals, to conduct original research and receive scientific training that will prepare him to become an independent, extramurally funded investigator in the field of translational vascular physiology aimed at identifying novel interventions for improving vascular function with aging and the associated mechanisms of action. Dr. Murray will learn a variety of new technical, conceptual, and professional skills, including focused training in translational cellular and molecular vascular physiology research, in addition to training in conducting a clinical trial. His proposed research project will leverage his primary sponsor’s ongoing NIH-funded R01-funded clinical trial that seeks to establish the efficacy of the mitochondria-targeted antioxidant MitoQ for improving vascular endothelial function in older adults to determine (Aim 1) whether changes in the circulating milieu following 3 months of chronic treatment with MitoQ improves endothelial cell function by treating human aortic endothelial cells (HAECs) with plasma collected from subjects after MitoQ or placebo treatment. He will also determine (Aim 2) if reductions in oxidized low-density lipoprotein (oxLDL) following MitoQ treatment mediate improvements in endothelial cell function by ameliorating oxLDL-stimulated mitochondrial fission. Lastly, he will also explore (Aim 3) the role of changes in extracellular vesicles (EVs) with MitoQ treatment in mediating improvements in endothelial cell function and whether these potential changes are associated with alterations to miRNA content of EVs. Age-related endothelial dysfunction is largely mediated by reduced bioavailability of the vasoprotective molecule, nitric oxide (NO), as a result of excessive production of reactive oxygen species (ROS). Dysfunctional mitochondria increase with age and are a major source of excess ROS (mtROS) in the vasculature. MitoQ is a mitochondrial-targeted antioxidant and our laboratory previously showed that 6-weeks of MitoQ supplementation in older adults improved NO-mediated endothelium-dependent dilation. Preliminary data collected by Dr. Murray for this application suggest that changes to the circulating milieu following MitoQ treatment increase NO bioavailability and decrease mtROS bioactivity in HAECs ex vivo, extending the mechanisms of action by which MitoQ supplementation improves endothelial function. Guided by these strong preliminary data, Dr. Murray will aim to establish changes to the circulating milieu as a mechanism of action by which MitoQ treatment improves endothelial function by leveraging plasma samples collected from subjects during his primary sponsor’s ongoing NIH-funded R01 clinical trial. The primary sponsor is an internationally recognized, NIH-funded scientist with a strong history of successful mentoring in translational biomedical research. With his guidance, and that of his mentoring team, Dr. Murray will be able to successfully complete the proposed research and training plan, preparing him to succeed as an extramurally funded independent investigator in translational vascular physiology.