The Role of PPARa in Cardiac Dysfunction in Sepsis

项目摘要/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 描述了一项为期5年的研究和培训计划，该计划将使Stephen Standage博士能够发展成为 在脓毒症中进行临床相关性、基础性和转化性研究的独立研究员 发病机制。完成了儿科重症监护医学方面的团契培训，并在 败血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患有脓毒症的器官功能障碍的技巧 目的确定可能改善患者预后的关键机制和治疗干预措施。 这项研究项目专门致力于阐明PPARα如何影响心脏能量产生和 脓毒症患者的心功能。PPARα是一种核激素受体转录因子，调节许多 炎症和代谢过程。先前的研究表明，感染性休克的儿童 显著下调外周血白细胞中PPARα的表达。申请人的初步研究 证明缺乏PPARα的小鼠在实验性脓毒症中的死亡率要高得多，但 用野生型小鼠的骨髓重建并没有挽救死亡表型，表明 组织PPARα在脓毒症器官损伤和死亡率调节中的作用脓毒症Ppara-/-小鼠已升高 与野生型相比，严重心脏损伤的血浆和组织标志物显示心功能下降 这一发现与Ppara-/-组中较低的脂肪酸氧化有关。总的来说，这些数据 支持PPARα通过激活脂肪酸保护脓毒症患者心功能的总体假设 氧化和增强心脏PPARα信号将提高存活率。《公约》的具体目标 拟开展的研究包括：1)明确脓毒症患者PPARα表达在心功能和生存中的作用 使用一种新的转基因心脏特异性PPARα敲除小鼠和一种过度表达的小鼠品系 2)确定在心脏中影响PPARα依赖心功能的代谢途径 通过测量心脏ATP的产生和底物利用、组织基因表达和代谢物 水平，并通过评估线粒体的结构和功能；以及3)确定药理作用 激活PPARα可改善感染性心功能不全，提高存活率。 这项工作意义重大，具有很高的翻译潜力，因为PPARα信令是一种有针对性的 机制与FDA批准的激动剂已在市场上。这里评估的假设挑战了 脓毒症的发病率和死亡率是由免疫失调引起的流行范式，研究结果将 有可能重新制定治疗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.