Cytochrome oxidase inhibition in septic heart

脓毒症心脏中细胞色素氧化酶的抑制

• 批准号: 6907511
• 负责人: Richard J Levy
• 金额: $ 12.71万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 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/6907511
• 关键词: apoptosis; cytochrome oxidase; electrocardiography; enzyme activity; enzyme induction /repression; genetic transcription; heart function; intracardiac volume; laboratory mouse; magnetic resonance imaging; mitochondrial DNA; molecular pathology; myocardial ischemia /hypoxia; oxidative phosphorylation; septicemia; transcription factor

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）： 该提案旨在扩大 Levy 博士的经验并通过直接指导磨练基本科学技能。通过这个过程，目的是让初级研究者更加熟悉实验室技能、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智力丰富的环境，拥有各种各样的资源和人员，具有丰富的专业知识和多样性。多学科合作每天都在发生，机会几乎是无限的。脓毒症、全身炎症反应综合征（SIRS）和多器官功能障碍综合征（MODS）是危重外科患者最常见的死亡原因。心脏功能障碍常见于脓毒症患者。脓毒症的标志之一是细胞病变性缺氧，即细胞无法利用分子氧来产生能量。这种缺陷可能是脓毒症相关器官功能障碍的基础。初步研究表明，心肌细胞色素c氧化酶（电子传递链的末端氧化酶）在脓毒症早期受到竞争性抑制，在脓毒症低动力期后期发展为不可逆抑制。这种氧化磷酸化的特定缺陷可能导致细胞病变性缺氧。在本提案中，我们的目标是使用 MRI 技术精确测量心内容积来精确表征脓毒症相关的心脏功能障碍，评估不可逆细胞色素氧化酶抑制的一个潜在原因；线粒体转录失败，并评估一种潜在影响；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。研究设计将为利维博士成长为一名有能力的独立研究人员奠定基础。除了初步数据外，该提案还将允许初级研究者开展专注于线粒体功能障碍、细胞病变性缺氧和脓毒症相关心肌抑制的研究生涯。