Cytochrome oxidase inhibition in septic heart

脓毒症心脏中细胞色素氧化酶的抑制

基本信息

批准号：
7209078
负责人：
Richard J Levy
金额：
$ 12.71万
依托单位：
NEW YORK MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-04-01 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7209078
关键词：
Animals Apoptosis Apoptotic Area Basic Science Cardiac Cardiac Output Cardiac Volume Caspase Cell Hypoxia Cells Collaborations Condition Critical Illness Cytochromes Cytosol DNA Binding Daily Data Defect EFRAC Electrocardiogram Electron Transport Environment Enzymes Etiology Experimental Models Figs - dietary Functional disorder Gene Expression Genetic Transcription Goals Heart Hour Human Resources Hypoxia Imaging technology Invasive Investigation Knowledge Laboratories Lead Ligation Magnetic Resonance Imaging Measurement Measures Mentorship Methodology Mitochondria Mitochondrial DNA Molecular Mus Myocardial Myocardial dysfunction Myocardium Operative Surgical Procedures Organ Oxidases Oxidative Phosphorylation Oxygen Pathogenesis Pathway interactions Patients Pediatric Hospitals Pennsylvania Phase Philadelphia Process Production Proteins Puncture procedure Research Research Design Research Personnel Resources Sepsis Sepsis Syndrome Stroke Volume Syndrome Techniques Testing Therapeutic Intervention Transcription Elongation Universities Water Work Writing career cohort cytochrome c cytochrome c oxidase design experience mitochondrial dysfunction mortality programs septic skills transcription factor

项目摘要

DESCRIPTION (provided by applicant): This proposal is designed to broaden Dr. Levy's experience and hone basic science skills with direct mentorship. Through this process, the aim is for the junior investigator to become more facile with laboratory skills, scientific writing, research design, and experimental methodology. Both the Children's Hospital of Philadelphia and the University of Pennsylvania are intellectually rich environments with a wide variety of resources and personnel with tremendous expertise and diversity. Multi-disciplinary collaboration occurs daily and the opportunities are almost limitless. Sepsis, the systemic inflammatory response syndrome (SIRS), and multiple organ dysfunction syndrome (MODS) are the most common causes of mortality in critically ill surgical patients. Cardiac dysfunction occurs commonly in septic patients. One hallmark of sepsis is cytopathic hypoxia, where cells are unable to use molecular oxygen for energy production. Such a defect could underlie sepsis-associated organ dysfunction. Initial studies demonstrate that myocardial cytochrome c oxidase, the terminal oxidase of the electron transport chain, is competitively inhibited early in sepsis, progressing to irreversible inhibition later during the hypodynamic phase of sepsis. This specific defect in oxidative phosphorylation may lead to cytopathic hypoxia. In this proposal, we aim to precisely characterize sepsis-associated cardiac dysfunction with precise measurement of intracardiac volumes using MRI technology, evaluate one potential cause of irreversible cytochrome oxidase inhibition; failed mitochondrial transcription, and evaluate one potential effect; initiation of the mitochondrial apoptotic pathway. The long term goal of this proposal is to identify a specific area that may be amenable to therapeutic intervention. The research design will lay ground work allowing Dr. Levy to mature into a competent, independent researcher. Along with preliminary data, this proposal will allow the junior investigator to develop a research career focused on mitochondrial dysfunction, cytopathic hypoxia, and sepsis-associated myocardial depression.

描述（由申请人提供）：该建议旨在通过直接指导扩大Levy博士的经验和基础科学技能。通过这一过程，目的是使初级研究人员更加专注于实验室技能，科学写作，研究设计和实验方法。费城儿童医院和宾夕法尼亚大学都是知识上丰富的环境，拥有各种各样的资源和人员，具有巨大的专业知识和多样性。每天发生多学科合作，机会几乎是无限的。败血症，系统性炎症反应综合征（SIR）和多个器官功能障碍综合征（MOD）是重症手术患者死亡率最常见的原因。心脏功能障碍通常发生在化粪池患者中。败血症的一个标志是细胞质缺氧，细胞无法将分子氧用于能量产生。这样的缺陷可能是败血症相关器官功能障碍的基础。最初的研究表明，心肌细胞色素C氧化酶是电子传输链的末端氧化酶，在败血症的早期被竞争性抑制，在败血症的性能阶段后期发展为不可逆的抑制作用。氧化磷酸化的这种特异性缺陷可能导致细胞性缺氧。在此提案中，我们旨在精确地表征与败血症相关的心脏功能障碍，并使用MRI技术精确测量心脏内体积，评估一个潜在的不可逆细胞色素氧化酶抑制的可能原因。线粒体转录失败，并评估一个潜在效果；线粒体凋亡途径的启动。该提案的长期目标是确定可能适合治疗干预的特定领域。研究设计将奠定基础工作，使Levy博士成为一名有能力的独立研究人员。除了初步数据外，该提案将允许初级研究者开发针对线粒体功能障碍，细胞病缺氧和败血症相关的心肌抑郁症的研究职业。