Cytochrome oxidase inhibition in septic heart

描述(由申请人提供)： 这项建议旨在通过直接指导，扩大利维博士的经验，磨练基本的科学技能。通过这个过程，目的是让初级研究员在实验室技能、科学写作、研究设计和实验方法论方面变得更加熟练。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，拥有丰富的专业知识和多样性。多学科协作每天都在发生，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)是外科危重患者最常见的死亡原因。心功能不全常见于败血症患者。脓毒症的一个特征是细胞病理性缺氧，即细胞无法利用分子氧产生能量。这种缺陷可能是败血症相关器官功能障碍的原因。最初的研究表明，心肌细胞色素c氧化酶是电子传递链的末端氧化酶，在脓毒症早期被竞争性抑制，在脓毒症的低动力阶段进展到不可逆转的抑制。氧化磷酸化的这种特殊缺陷可能导致细胞病理性缺氧。在这项建议中，我们的目标是通过使用MRI技术精确测量心内容量来准确地表征脓毒症相关的心功能障碍，评估不可逆的细胞色素氧化酶抑制的一个潜在原因；线粒体转录失败，并评估一个潜在的影响：线粒体凋亡途径的启动。这项建议的长期目标是确定一个可能适合治疗干预的特定区域。这项研究的设计将为利维博士成长为一名称职的独立研究员奠定基础。与初步数据一起，这项建议将允许初级研究员发展专注于线粒体功能障碍、细胞病理性低氧和败血症相关的心肌抑制的研究生涯。

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.