Cytochrome oxidase inhibition in septic heart

描述（由申请人提供）： 该提案旨在扩大Levy博士的经验，并通过直接指导来磨练基本的科学技能。通过这个过程，目的是让初级研究员变得更容易与实验室技能，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，具有巨大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）是外科危重患者死亡的最常见原因。心功能不全常见于脓毒症患者。脓毒症的一个标志是细胞病变性缺氧，其中细胞不能使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，在脓毒症早期竞争性抑制，发展到不可逆的抑制，后来在脓毒症的低动力期。氧化磷酸化中的这种特定缺陷可能导致细胞病变性缺氧。在这项提案中，我们的目标是通过使用MRI技术精确测量心内容积来精确表征脓毒症相关的心功能不全，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，并评估一个潜在影响;启动线粒体凋亡途径。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的工作，使利维博士成熟为一个称职的，独立的研究人员。沿着初步的数据，这个提议将允许初级研究者发展一个专注于线粒体功能障碍、细胞病变性缺氧和脓毒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.