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

项目总结/摘要 这个F32应用程序的目的是支持博士扎卡里克莱顿，一个有前途的第一年博士后 研究员在实验室的博士道格拉斯海豹，进行原创性的研究和科学培训，将 准备他成为一个独立的，在翻译领域的校外资助调查员 心血管生理学旨在预防心血管疾病（CVD）。克莱顿医生将学习 各种新的技术，概念和专业技能，包括翻译方面的重点培训 临床前血管生理学研究。他提出的研究项目旨在（目标1）调查 最常用的蒽环类化疗药物多柔比星（DOXO） 药物介导血管内皮功能障碍，这是CVD发展中的关键病理生理步骤。 他还将确定（目标2），如果一个翻译的神经靶向抗氧化剂治疗， 甲磺酸盐（MitoQ®）可以恢复DOXO引起的血管内皮功能障碍： B）中年小鼠（在青春期用DOXO治疗），以“模拟”对 接受过DOXO治疗的中年儿童癌症幸存者内皮功能障碍通常由以下因素介导： 由于过量的内皮细胞，内皮衍生的扩张剂分子一氧化氮（NO）的生物利用度降低， 产生超氧化物，与NO反应。功能障碍的线粒体是总体代谢的主要来源 超氧化物生成，部分原因是抗氧化防御的补偿性增加不足。DOXO拥有 据报道，降低血管内皮功能，但潜在的机制和潜力， 治疗策略目前是未知的。在强有力的初步数据的指导下，克莱顿博士将调查 DOXO介导内皮功能障碍的机制，使用离体“药物解剖” 技术，特别关注线粒体超氧化物在降低NO生物利用度中的作用（目的 1）。此外，克莱顿博士将寻求建立初步（临床前）概念验证证据， 补充肾脏特异性抗氧化剂MitoQ可以减轻DOXO诱导的内皮细胞损伤， 功能障碍（目标2）。总体而言，拟议的研究有可能解决2个重要的战略问题， NHLBI的研究重点：1）确定降低血管发病率和死亡率的最佳策略， 血管事件风险增加的儿童癌症幸存者; 2）确定治疗靶点， 建立概念验证，并为研究性新药申请开发数据，以便尽早 将研究成果转化为临床应用。赞助商Seals博士是国际公认的 和NIH资助的科学家，在转化生物医学研究方面具有成功指导的悠久历史。 在他的指导下，以及咨询导师安东尼·多纳托博士、迈克尔·墨菲博士和朱迪思博士的指导下， 坎皮西，克莱顿博士将能够成功完成拟议的研究和培训计划，为 他成功地作为一个在转化心血管生理学的校外资助的独立调查员。

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.