Mitochondrial oxidative stress: a target for treatment of doxorubicin-associated vascular endothelial dysfunction

线粒体氧化应激：治疗阿霉素相关血管内皮功能障碍的靶点

• 批准号: 10403420
• 负责人: Zachary S. Clayton
• 金额: $ 2.41万
• 依托单位: UNIVERSITY OF COLORADO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-09 至 2021-07-08
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10403420
• 关键词: Acetylcholine; Address; Adolescence; Aftercare; Age; Anthracycline; Antioxidants; Arteries; Atherosclerosis; Biological Availability; Biomedical Research; Blood Vessels; C57BL/6 Mouse; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Carotid Arteries; Cessation of life; Clinical; Consult; Coronary Arteriosclerosis; Coupled; Data; Development; Dilator; Dissection; Doxorubicin; Endothelial Cells; Endothelium; Event; Extramural Activities; Failure; Funding; Future; Health; Human; Impairment; International; Investigational New Drug Application; Laboratories; Learning; Malignant Childhood Neoplasm; Malignant Neoplasms; Measures; Mediating; Mentors; Mesylates; Mitochondria; Modeling; Morbidity - disease rate; Mus; NG-Nitroarginine Methyl Ester; National Heart, Lung, and Blood Institute; Nitric Oxide; Nitric Oxide Synthetase Inhibitor; Oxidative Stress; Patients; Peripheral arterial disease; Pharmaceutical Preparations; Physiology; Placebos; Postdoctoral Fellow; Production; Reactive Oxygen Species; Recording of previous events; Reporting; Research; Research Personnel; Research Priority; Research Project Grants; Research Training; Risk; Role; SOD2 gene; Scientist; Solid; Source; Stroke; Superoxide Dismutase; Superoxides; Supplementation; Techniques; Testing; Therapeutic; Toxic effect; Training; Translational Research; United States National Institutes of Health; Up-Regulation; Vascular Endothelium; Wild Type Mouse; anti-cancer; antioxidant enzyme; antioxidant therapy; base; cardiovascular disorder prevention; cardiovascular disorder risk; chemotherapy; childhood cancer survivor; clinical application; drinking water; efficacy testing; emerging adult; endothelial dysfunction; improved; insight; leukemia/lymphoma; middle age; mortality; mouse model; novel; oral supplementation; overexpression; pre-clinical; premature; seal; skills; therapeutic target; vascular endothelial dysfunction; young adult

PROJECT SUMMARY/ABSTRACT The purpose of this F32 application is to support Dr. Zachary Clayton, a promising first-year postdoctoral fellow in the laboratory of Dr. Douglas Seals, to conduct original research and scientific training that will prepare him to become an independent, extramurally-funded investigator in the field of translational cardiovascular physiology aimed at the prevention of cardiovascular diseases (CVD). Dr. Clayton will learn a variety of new technical, conceptual and professional skills, including focused training in translational preclinical vascular physiology research in mice. His proposed research project seeks to (Aim 1) investigate the mechanism(s) by which doxorubicin (DOXO), the most commonly used anthracycline-chemotherapy drug, mediates vascular endothelial dysfunction, a key pathophysiological step in the development of CVD. He also will determine (Aim 2) if a translational mitochondrial-targeted antioxidant therapy, Mitoquinol Mesylate (MitoQ®), can restore vascular endothelial dysfunction caused by DOXO in: a) young adult mice soon after treatment; and b) middle-aged mice (treated with DOXO in adolescence) to “model” effects on middle-aged DOXO-treated childhood cancer survivors. Endothelial dysfunction is typically mediated by reduced bioavailability of the endothelium-derived dilator molecule, nitric oxide (NO), as a result of excessive production of superoxide, which reacts with NO. Dysfunctional mitochondria are a major source of overall superoxide production, due in part to inadequate compensatory increases in antioxidant defenses. DOXO has been reported to decrease vascular endothelial function, but the underlying mechanisms and potential therapeutic strategies are currently unknown. Guided by strong preliminary data, Dr. Clayton will investigate the mechanism(s) by which DOXO mediates endothelial dysfunction, using ex vivo “pharmaco-dissection” techniques, specifically focusing on the role of mitochondrial superoxide in decreasing NO bioavailability (Aim 1). Furthermore, Dr. Clayton will seek to establish initial (preclinical) proof-in-concept evidence that oral supplementation of a mitochondrial-specific antioxidant, MitoQ, can mitigate DOXO-induced endothelial dysfunction (Aim 2). Overall the proposed research has the potential to address 2 important strategic research priorities of NHLBI: 1) determine the best strategy for reducing vascular morbidity and mortality in childhood cancer survivors who are at enhanced risk of vascular events; 2) identifying therapeutic targets, establishing proof of concept, and developing data for investigational new drug applications to enable early translation of research findings to clinical applications. The sponsor, Dr. Seals, is an internationally recognized and NIH funded scientist with a strong history of successful mentoring in translational biomedical research. With his guidance, and the guidance of consulting mentors Drs. Anthony Donato, Michael Murphy and Judith Campisi, Dr. Clayton will be able to successfully complete the proposed research and training plan, preparing him to succeed as an extramurally-funded independent investigator in translational cardiovascular physiology.

项目摘要/摘要 该F32申请的目的是支持扎卡里·克莱顿（Zachary Clayton）博士，这是一个有前途的一年级博士后 Douglas Seals博士实验室的研究员进行了原始的研究和科学培训 准备他成为翻译领域的独立，外在资助的调查员 旨在预防心血管疾病（CVD）的心血管生理学。克莱顿博士将学习一个 各种各样的新技术，概念和专业技能，包括翻译的重点培训 小鼠的临床前血管生理研究。他提出的研究项目试图（目标1）调查 阿伐霉素（doxo）是最常用的蒽环类化学疗法的机制 药物，介导血管内皮功能障碍，这是CVD发展的关键病理生理步骤。 他还将确定（AIM 2）是否翻译的线粒体靶向抗氧化剂治疗，mitoquinol 梅赛酸盐（Mitoq®），可以恢复由Doxo引起的血管内皮功能障碍：a）年轻成年小鼠 治疗后不久； b）中年小鼠（在青少年中用doxo处理），以“模型”对 中年DOXO治疗的儿童癌症存活。内皮功能障碍通常由 由于多余 产生超氧化物，该氧化物反应不。线粒体功能障碍是总体的主要来源 超氧化物产生，部分原因是抗氧化剂防御剂的补偿性增加不足。 Doxo有 据报道会降低血管内皮功能，但潜在的机制和潜力 目前未知治疗策略。在强大的初步数据的指导下，克莱顿博士将调查 Doxo使用离体“ Pharmaco-DiStection”的机制介导内皮功能障碍的机制 技术，特别关注线粒体超氧化物在降低无生物利用度中的作用（AIM 1）。此外，克莱顿博士将寻求建立口头概念的初始（临床前）证据证据 补充线粒体特异性抗氧化剂mitoq可以减轻DOXO诱导的内皮 功能障碍（AIM 2）。总体而言，拟议的研究有可能解决2个重要策略 NHLBI的研究优先级：1）确定降低血管发病率和死亡率的最佳策略 儿童癌症的存活率增加了血管事件的风险； 2）确定治疗靶标， 建立概念证明，并为研究性新药物应用开发数据，以提早 将研究结果转换为临床应用。赞助商海豹博士是国际公认的 NIH在翻译生物医学研究方面拥有成功的心理历史的科学家。 在他的指导下以及咨询导师Drs的指导。安东尼·多纳托，迈克尔·墨菲和朱迪思 Campisi，Clayton博士将能够成功完成拟议的研究和培训计划，准备 他成功地成为翻译心血管生理学的外部资助的独立研究者。

项目成果

Anthracycline chemotherapy, vascular dysfunction and cognitive impairment: burgeoning topics and future directions.

蒽环类化疗、血管功能障碍和认知障碍：新兴话题和未来方向。

• DOI: 10.2217/fca-2022-0086
• 发表时间: 2023
• 期刊: Future cardiology
• 影响因子: 1.7
• 作者: Maurer,GraceS;Clayton,ZacharyS
• 通讯作者: Clayton,ZacharyS

Senolysis induced by 25-hydroxycholesterol targets CRYAB in multiple cell types.

• DOI: 10.1016/j.isci.2022.103848
• 发表时间: 2022-02-18
• 期刊: iScience
• 影响因子: 5.8
• 作者: Limbad C;Doi R;McGirr J;Ciotlos S;Perez K;Clayton ZS;Daya R;Seals DR;Campisi J;Melov S
• 通讯作者: Melov S

Lifelong physical activity attenuates age- and Western-style diet-related declines in physical function and adverse changes in skeletal muscle mass and inflammation.

终生体育活动可以减轻与年龄和西式饮食相关的身体机能下降以及骨骼肌质量和炎症的不利变化。

• DOI: 10.1016/j.exger.2021.111632
• 发表时间: 2022
• 期刊: Experimental gerontology
• 影响因子: 3.9
• 作者: Clayton,ZacharyS;Gioscia-Ryan,RachelA;Justice,JamieN;Lubieniecki,KaraL;Hutton,DavidA;Rossman,MatthewJ;Zigler,MelanieC;Seals,DouglasR
• 通讯作者: Seals,DouglasR