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

线粒体靶向抗氧化剂补充剂可改善老年人与年龄相关的血管功能障碍：循环因子的作用

• 批准号: 10606926
• 负责人: Kevin Owen Murray
• 金额: $ 7.2万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2025-03-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10606926
• 关键词: Adult; Age; Age Years; Aging; Antioxidants; Aorta; Back; Biological Availability; Biomedical Research; Blood; Blood Vessels; Cardiovascular Diseases; Cause of Death; Cell physiology; Chronic; Circulation; Clinical Trials; Crossover Design; Data; Development; Double-Blind Method; Elderly; Endothelial Cells; Endothelium; Exposure to; Extramural Activities; Funding; Future; Human; International; Intervention; LOX gene; Laboratories; Learning; Low Density Lipoprotein Receptor; Mediating; Mediator; Mentors; MicroRNAs; Mitochondria; Molecular; Molecular and Cellular Biology; Morphology; Nitric Oxide; Phase; Physiology; Placebos; Plasma; Positioning Attribute; Postdoctoral Fellow; Production; Randomized; Reactive Oxygen Species; Recording of previous events; Research; Research Personnel; Research Project Grants; Research Training; Risk Reduction; Role; Sampling; Scientist; Small Interfering RNA; Source; Supplementation; Training; United States National Institutes of Health; Vascular Diseases; Vascular Endothelium; Woman; age related; brachial artery; cardiovascular disorder risk; cardiovascular risk factor; endothelial dysfunction; experience; extracellular vesicles; improved; in vivo; insight; men; middle age; novel; novel strategies; oxidized low density lipoprotein; pilot trial; receptor-mediated signaling; seal; skills; vascular endothelial dysfunction

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.

项目摘要/摘要 该F32申请的目的是支持凯文·默里博士（Kevin Murray） 在道格拉斯·海豹博士的实验室中，进行原始研究并接受科学培训 准备他成为转化血管领域的独立，外部资助的研究者 生理学旨在确定新的干预措施，以改善衰老和 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 培训进行临床试验。他提出的研究项目将利用他的主要赞助商 NIH资助的R01资助的临床试验旨在建立靶向线粒体的效率 抗氧化剂MITOQ用于改善老年人血管内皮功能的抗氧化剂，以确定（AIM 1）是否是否 3个月以后，Mitoq慢性治疗后，循环环境的变化改善了内皮细胞 通过从Mitoq或 安慰剂治疗。他还将确定（AIM 2）如果氧化的低密度脂蛋白（OXLDL）减少 通过改善OXLDL刺激，遵循MITOQ处理介质改进内皮细胞功能 线粒体裂变。最后，他还将探索（AIM 3）与细胞外蔬菜（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是否改变 与电动汽车的miRNA含量的改变有关。与年龄有关的内皮功能障碍在很大程度上是 由于过量而导致的一氧化氮（NO）降低了生物利用度 活性氧（ROS）的产生。线粒体功能障碍随着年龄的增长而增加，并且是主要的 脉管系统中过量ROS（MTROS）的来源。 mitoq是一种靶向线粒体的抗氧化剂，我们的 实验室先前表明，老年人的6周补充剂改进了未介导的 内皮依赖性词典。 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没有增加生物利用度，并减少了MTROS Haecs ex Vivo中的生物活性，扩大了Mitoq补充改善的作用机制 内皮功能。在这些强大的初步数据的指导下，默里博士将旨在建立变更 循环环境作为一种作用机制，通过这种机制，mitoq治疗可以通过 在其主要赞助商持续的NIH资助R01中，利用受试者收集的等离子样品 临床试验。主要赞助商是国际公认的NIH资助的科学家，有着悠久的历史 在翻译的生物医学研究中成功进行了心理。在他的指导下以及他的心理团队的指导下 默里博士将能够成功完成拟议的研究和培训计划，并为他做好准备 成功地成为了翻译血管生理学的独立研究者。