权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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指导临床科学家职业发展奖描述了一个为期五年的研究和培训主要研究者（PI）Fotios Spyropoulos博士的计划，这将使他能够过渡到独立的在氧化应激诱导的心脏代谢重编程和线粒体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病的影响。失败是越来越多地认识到的早产并发症，导致发病率和死亡率增加。 PI已经完成了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，PI的提案最初侧重于以下方面的表征：一个化学遗传性心力衰竭的成人模型，计划将从该奖项中获得的技能应用于未来新生儿心力衰竭模型的研究PI将使用新型转基因小鼠模型（DAAO-TGCar）这使得能够在细胞中以过氧化氢（H2O2）的形式稳定和特异性地产生氧化应激，心他的目标是描绘氧化应激在线粒体功能障碍和心脏病发展中的作用。失败他展示了新的初步数据，表明化学发生H2O2介导的Sirtuin 3（Sirt3）失活线粒体功能障碍的发展。为了检验这一假设，提出了以下具体目标： 1.表征DAAO-TGCar小鼠模型的心力衰竭表型，2.评估Sirt3氧化的作用对心脏氧化平衡和线粒体功能的影响，以及3.确定H2O2介导的调节心肌细胞生理学和能量学。本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发现预防和治疗这种疾病的新疗法。使人虚弱的状况PI将在Michel博士的共同指导下开展拟议工作，Michel博士是与心血管生物学和心力衰竭有关的氧化剂信号传导，活细胞成像和化学遗传学 Christou博士是血管生物学和心血管生理学方面的专家。PI将收到由资深科学家组成的奖学金监督委员会提供额外指导，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培训环境和PI机构提供的资源，布里格姆和妇女医院和哈佛医学院，是他职业发展的理想选择。保证PI> 75% 保护研究时间投入到拟议的K08计划。指导研究，教学课程，以及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。的pi 概述了完成拟议目标、撰写科学手稿和提交未来R01的时间轴应用程序.在该奖项结束时，PI将获得R01资金，并通过申请过渡到独立从该奖项获得的知识和概念，以未来的调查重点是确定的影响，氧化应激对新生儿心肌发育的影响。