Oxidative Stress and Mitochondrial Dysfunction in Chemogenetic Heart Failure

这个K08临床科学家导师职业发展奖描述了一个为期五年的研究和培训 首席调查员(PI)Fotios Spyropoulos博士的计划，将使他能够过渡到独立 氧化应激诱导的心脏代谢重编程和线粒体领域的科学研究 功能障碍。早产儿特别容易受到氧化应激引起的损伤和早期心脏 失败是早产的一种日益公认的并发症，会导致发病率和死亡率的增加。 PI已经完成了新生儿-围产期医学的研究生培训，他的长期目标是确定 早产和心力衰竭之间的联系。因此，国际和平研究所的建议最初侧重于 一个化学性心力衰竭的成人模型，并计划将从这个奖项中获得的技能应用到未来 新生儿心力衰竭模型的研究。PI将使用一种新的转基因小鼠模型(DAAO-TGCar) 这使得在体内能够以过氧化氢(H_2O_2)的形式产生强烈和特定的氧化应激 心。他的目标是描述氧化应激在线粒体功能障碍和心脏发展中的作用 失败了。他展示了新的初步数据，涉及化学发生的过氧化氢介导的Sirtuin 3(SIRT3)失活 在线粒体功能障碍的发展过程中。为了验证这一假设，提出了以下具体目标： 1.鉴定DAAO-TGCar小鼠模型的心力衰竭表型；2.评价SIRT3氧化的作用 对心脏氧化平衡和线粒体功能的影响；3.确定过氧化氢介导的机制 心肌细胞生理学和能量学的调节。这项研究对于认识氧化剂具有重要意义 应激诱导的线粒体损伤可能会找到预防和治疗这种损伤的新疗法 使人虚弱的状况。国际和平协会将在米歇尔博士的共同指导下执行拟议的工作，米歇尔博士是 氧化信号与心血管生物学和心力衰竭、活细胞成像和化学发生有关 和克里斯图博士，他是血管生物学和心血管生理学的专家。PI将收到 来自他的奖学金监督委员会的额外指导，该委员会由资深科学家组成，具有补充 心脏血流动力学和生物能量学、线粒体生物学和心脏实验模型方面的专业知识 失败了。培训环境和由PPI的机构、Brigham和妇女机构提供的资源 医院和哈佛医学院，是他职业发展的理想选择。PI有保证&gt；75% 受保护的研究时间，以致力于拟议的K08计划。有指导的研究，授课的课程，以及 在科学会议上的陈述都是详细的职业发展和培训计划的一部分。《少年派》 概述了完成建议目标、撰写科学手稿和提交未来R01的时间表 申请。在本奖项结束时，PI将获得R01资金，并通过申请向独立过渡 从这一奖项中获得的知识和概念将用于今后的调查，重点是确定 氧化应激对新生儿心肌发育的影响

This K08 Mentored Clinical Scientist Career Development Award describes a five-year research and training program of the principal investigator (PI), Dr. Fotios Spyropoulos, that will enable his transition to independent scientific investigation in the field of oxidative stress-induced cardiac metabolic reprogramming and mitochondrial dysfunction. Premature infants are particularly susceptible to oxidative stress-induced injury and early heart failure is an increasingly recognized complication of preterm birth leading to increased morbidity and mortality. The PI has completed post-graduate training in neonatal-perinatal medicine and his long-term goal is to identify the link between prematurity and heart failure. Thus, the PI’s proposal initially focuses on the characterization of an adult model of chemogenetic heart failure with a plan to apply the skills gained from this award to future investigation of neonatal heart failure models. The PI will use a novel transgenic mouse model (DAAO-TGCar) that enables robust and specific generation of oxidative stress, in the form of hydrogen peroxide (H2O2), in the heart. He aims to delineate the role of oxidative stress in the development of mitochondrial dysfunction and heart failure. He shows novel preliminary data implicating chemogenetic H2O2 mediated inactivation of Sirtuin 3 (Sirt3) in the development of mitochondrial dysfunction. To test this hypothesis the following specific aims are proposed: 1. Characterize the heart failure phenotype of the DAAO-TGCar mouse model, 2. Assess the role of Sirt3 oxidation on cardiac oxidant balance and mitochondrial function, and 3. Determine the mechanisms of H2O2 mediated regulation of cardiomyocyte physiology and energetics. This research has significance, as understanding oxidant stress-induced mitochondrial damage may identify new therapies for the prevention and treatment of this debilitating condition. The PI will perform the proposed work under the co-mentorship of Dr. Michel, expert in oxidant signaling pertaining to cardiovascular biology and heart failure, live-cell imaging, and chemogenetic applications, and Dr. Christou, an expert in vascular biology and cardiovascular physiology. The PI will receive additional guidance from his scholarship oversight committee composed of senior scientists with complementary expertise in cardiac hemodynamics and bioenergetics, mitochondrial biology, and experimental models of heart failure. The training environment and the resources provided by the PI’s institutions, Brigham and Women's Hospital and Harvard Medical School, are ideal for his professional development. The PI is guaranteed >75% protected research time to devote to the proposed K08 program. Mentored research, didactic coursework, and presentations at scientific meetings are all part of a detailed career development and training plan. The PI outlines a timeline for completing the proposed aims, writing scientific manuscripts, and submitting a future R01 application. At the end of this award, the PI will obtain R01 funding and transition to independence by applying the knowledge and concepts gained from this award to future investigations focused on identifying the effects of oxidative stress on the development of the neonatal myocardium.