The Role of PPARa in Cardiac Dysfunction in Sepsis

项目总结/摘要 脓毒症是一种严重的疾病，通常会导致危及生命的多器官功能障碍。这项建议 描述了一个为期5年的研究和培训计划，将允许博士斯蒂芬标准发展为一个 开展脓毒症临床相关、基础和转化研究的独立研究者 发病机制完成了儿科重症监护医学的奖学金培训， 脓毒症免疫学基础研究培训背景，申请人寻求发展新知识 以及研究代谢途径的调节如何影响脓毒症患者器官功能障碍的技能。 目的确定可能改善患者结局的关键机制和治疗干预措施。 该研究项目特别关注阐明PPARα如何影响心脏能量产生， 脓毒症患者的心脏功能过氧化物酶体增殖物激活受体α是一种核激素受体转录因子， 炎症和代谢过程。先前的研究表明，感染性休克的儿童 外周血白细胞中的PPARα表达显著下调。申请人的初步研究 表明，缺乏PPARα（Ppara-/-）的小鼠在实验性脓毒症中的死亡率要高得多， 用野生型小鼠的骨髓重建并不能挽救死亡表型，这表明了一个关键的 组织过氧化物酶体增殖物激活受体α在脓毒症中调节器官损伤和死亡率的作用脓毒症Ppara-/-小鼠具有升高的 严重心脏损伤的血浆和组织标志物，与野生型相比显示心脏功能降低 小鼠，发现与Ppara-/-组中较低的脂肪酸氧化有关。这些数据共同 支持总体假设，即PPARα通过激活脂肪酸保护脓毒症患者的心脏功能 氧化和增加心脏的过氧化物酶体增殖物激活受体α信号将改善生存。的具体目标 拟开展的研究包括：1）明确脓毒症患者心肌组织中PPARα表达在心功能和存活中的作用 使用一种新的转基因心脏特异性PPARα基因敲除小鼠和一种过表达 2）确定影响心脏中PPARα依赖性心脏功能的代谢途径， 通过测量心脏ATP产生和底物利用、组织基因表达和代谢产物 水平，并通过评估线粒体结构和功能;和3）确定是否药理学 PPARα激活可改善脓毒性心功能障碍并提高生存率。 这项工作是有意义的，具有很高的翻译潜力，因为PPARα信号是一个靶向的 FDA批准的激动剂已经上市。这里评估的假设挑战了 流行的范式，脓毒症的发病率和死亡率的结果，免疫失调和研究结果将有 有可能重新制定处理这一重大公共卫生问题的方法。

Project Summary/Abstract Sepsis is a severe condition that often results in life-threatening multiorgan dysfunction. This proposal describes a 5-year research and training program that will permit Dr. Stephen Standage to develop as an independent investigator conducting clinically relevant, basic and translational research in sepsis pathogenesis. Having completed fellowship training in pediatric critical care medicine and building on a background of basic research training in sepsis immunology, the applicant seeks to develop new knowledge and skills to investigate how regulation of metabolic pathways influences organ dysfunction in sepsis with an objective to identify key mechanisms and therapeutic interventions that may improve patient outcomes. This research project specifically focuses on elucidating how PPARα influences cardiac energy production and heart function in sepsis. PPARα is a nuclear hormone receptor transcription factor that regulates many inflammatory and metabolic processes. Previous research has demonstrated that children with septic shock have significant downregulation of PPARα in peripheral blood leukocytes. The applicant's preliminary studies demonstrated that mice lacking PPARα (Ppara-/-) have much higher mortality in experimental sepsis, but reconstitution with bone marrow from wild type mice did not rescue the mortality phenotype, indicating a critical role for tissue PPARα in regulating organ injury and mortality in sepsis. Septic Ppara-/- mice have elevated plasma and tissue markers of severe cardiac injury and show decreased heart function compared to wild type mice, findings that are associated with lower fatty acid oxidation in the Ppara-/- group. Collectively, these data support the overall hypothesis that PPARα preserves cardiac function in sepsis by activating fatty acid oxidation and that augmenting cardiac PPARα signaling will improve survival. The specific aims of the proposed investigations are to: 1) Define the role of PPARα expression in heart function and survival in sepsis using a novel transgenic, cardiac-specific PPARα knock-out mouse and a mouse strain that over-expresses PPARα in the heart; 2) Identify the metabolic pathways that influence PPARα dependent cardiac function in the heart by measuring cardiac ATP production and substrate utilization, tissue gene expression and metabolite levels, and by evaluating mitochondrial structure and function; and 3) Determine whether pharmacologic PPARα activation ameliorates septic cardiac dysfunction and improves survival. This work is significant and has high translational potential because PPARα signaling is a targetable mechanism with FDA approved agonists already on the market. The hypotheses evaluated here challenge the prevailing paradigm that sepsis morbidity and mortality result from immune dysregulation and findings will have the potential to reframe the approach to treating this significant public health problem.