Oxidative Stress and Mitochondrial Dysfunction in Chemogenetic Heart Failure

化学遗传性心力衰竭中的氧化应激和线粒体功能障碍

基本信息

批准号：
10643012
负责人：
Fotios Spyropoulos
金额：
$ 16.82万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-01 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10643012
关键词：
Acetylation Acute Adult Affect Alanine Amino Acids Animal Model Animals Antioxidants Applied Skills Award Bioenergetics Biological Assay Biology Blood Vessels Bypass Calcium Cardiac Cardiac Myocytes Cardiovascular Physiology Cardiovascular system Cell Respiration Chronic Clinical Clinical Investigator Award Complex Complication D-Amino Acid Dehydrogenase Data Deacetylase Death Rate Dependence Development Disease Dyes Environment Enzymes Equilibrium Experimental Models Fluorescent Probes Functional disorder Funding Future Generations Genetic Goals Heart Heart failure Hospitals Human Hydrogen Peroxide Immunoprecipitation Impairment In Vitro Injury Institution Investigation K-Series Research Career Programs Knowledge Laboratories Lead Link Manuscripts Measures Mediating Medical Membrane Potentials Mentors Mentorship Messenger RNA Metabolic Mitochondria Modeling Modification Molecular Morbidity - disease rate Mus Myocardium Neonatal Organ Oxidants Oxidative Stress Oxidative Stress Induction Pathway interactions Pattern Persons Phenotype Physiology Predisposition Premature Birth Premature Infant Prevention Prevention therapy Principal Investigator Protein Acetylation Proteins Quality of life Reactive Oxygen Species Recombinants Regulation Research Resources Role SOD2 gene Scholarship Scientist Senior Scientist Signal Transduction Sirtuins Superoxides Testing Time Tissues Training Training Programs Transgenic Mice Vascular blood supply Viral Vector Virus Western Blotting Woman Work Writing Yeasts career development experience extracellular fluorescence imaging heart function hemodynamics improved in vivo insight live cell imaging medical schools meetings mitochondrial dysfunction mortality mouse model new therapeutic target novel novel therapeutics oxidant stress oxidation perinatal medicine premature pressure release of sequestered calcium ion into cytoplasm response timeline

项目摘要

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.

这个K08指导的临床科学家职业发展奖描述了五年的研究和培训首席研究员（PI）的计划Fotios Spyropoulos博士将使他的过渡到独立氧化应激诱导的心脏代谢重编程和线粒体的科学研究功能障碍。过早的婴儿特别容易受到氧化物胁迫诱发的损伤和早期心脏的影响失败是早产的越来越多的并发症，导致发病率和死亡率增加。 PI已经完成了新生儿 - 周期医学的研究生培训，他的长期目标是确定早产与心力衰竭之间的联系。这是PI的提议最初着重于一个成人的化学心力衰竭模型，并计划将从该奖项中获得的技能应用于未来调查新生儿心力衰竭模型。 PI将使用新型的转基因小鼠模型（DAAO-TGCAR）这样可以以过氧化氢（H2O2）的形式实现强大而特定的氧化应激心。他旨在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。他显示了新型的初步数据隐式化学生成H2O2介导的Sirtuin 3（SIRT3）的失活在线粒体功能障碍的发展中。为了检验该假设，提出了以下特定目标： 1。表征DAAO-TGCAR小鼠模型的心力衰竭表型，2。评估SIRT3氧化的作用关于心脏氧化剂平衡和线粒体功能，以及3。确定H2O2介导的机制心肌细胞生理和能量学调节。这项研究具有重要意义，因为了解氧化物压力引起的线粒体损伤可能会发现预防和治疗的新疗法衰弱的状况。 PI将根据Michel博士的委托书进行拟议的工作，专家与心血管生物学和心力衰竭，活细胞成像和化学发生有关的氧化剂信号传导应用程序，以及Christou博士，是血管生物学和心血管生理学专家。 PI会收到他的奖学金监督委员会的额外指导委员会由高级科学家组成心脏血流动力学和生物能学，线粒体生物学和心脏实验模型方面的专业知识失败。培训环境和PI机构，Brigham和妇女提供的资源医院和哈佛医学院是他专业发展的理想选择。 PI保证> 75％受保护的研究时间，以致力于拟议的K08计划。指导的研究，教学课程和在科学会议上的演讲都是详细的职业发展和培训计划的一部分。 pi 概述了完成拟议目标，编写科学手稿并提交未来R01的时间表应用。在该奖项结束时，PI将通过申请获得R01的资金和过渡到独立性从该奖项获得的知识和概念到未来的调查，重点是确定对新生儿心肌发展的氧化应激。