The Role of PPARa in Cardiac Dysfunction in Sepsis

PPARa 在脓毒症心脏功能障碍中的作用

• 批准号: 10226912
• 负责人: Stephen Wade Standage
• 金额: $ 16.2万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-10 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10226912
• 关键词: Adult; Agonist; Basic Science; Bone Marrow; Cardiac; Cardiovascular system; Cell Compartmentation; Cessation of life; Child; Childhood; Clinical; Critical Care; Data; Data Set; Down-Regulation; Evaluation; Experimental Models; Expression Profiling; FDA approved; Failure; Fellowship; Functional disorder; Gene Expression; Genes; Genetic Transcription; Heart; Heart Injuries; Histologic; Hormones; Immune; Immune response; Immunology; Impairment; Inflammation; Inflammatory; Investigation; Knockout Mice; Knowledge; Lead; Leukocytes; Life; Ligands; Measures; Medicine; Mentors; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Morbidity - disease rate; Mouse Strains; Multiple Organ Failure; Mus; Myocardial; Myocardial dysfunction; Nuclear; Nuclear Hormone Receptors; Nuclear Receptors; Organ; Organ failure; PPAR alpha; Pathogenesis; Pathway Analysis; Patient-Focused Outcomes; Pharmacology; Phenotype; Plasma; Play; Process Measure; Production; Public Health; Regulation; Research; Research Personnel; Research Project Grants; Research Training; Role; Savings; Sepsis; Septic Shock; Severity of illness; Signal Pathway; Signal Transduction; Statistical Methods; Structure; Syndrome; Testing; Therapeutic Intervention; Tissues; Training; Training Programs; Transgenic Organisms; Translational Research; Transplantation; Troponin; Wild Type Mouse; Work; cecal ligation puncture; clinically relevant; experimental study; fatty acid oxidation; gain of function; genome-wide; heart function; heart preservation; improved; insight; lipid metabolism; loss of function; mRNA Expression; metabolomics; mortality; myocardial damage; novel; organ injury; peripheral blood; preclinical study; reconstitution; septic; skills; transcription factor; treatment strategy; uptake

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.

项目概要/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。这个提议 描述了一项为期 5 年的研究和培训计划，该计划将使 Stephen Standage 博士能够发展成为一名 独立研究者进行脓毒症的临床相关、基础和转化研究 发病。完成了儿科重症监护医学进修培训并建立了 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器官功能障碍的技能 目标是确定可以改善患者预后的关键机制和治疗干预措施。 该研究项目特别侧重于阐明 PPARα 如何影响心脏能量产生和 败血症时的心脏功能。 PPARα 是一种核激素受体转录因子，可调节许多 炎症和代谢过程。先前的研究表明，患有感染性休克的儿童 外周血白细胞中 PPARα 显着下调。申请人的初步研究 证明缺乏 PPARα (Ppara-/-) 的小鼠在实验性脓毒症中的死亡率要高得多，但是 用野生型小鼠的骨髓重建并不能挽救死亡表型，表明关键 组织 PPARα 在调节脓毒症器官损伤和死亡率中的作用。脓毒症 Ppara-/- 小鼠的 与野生型相比，严重心脏损伤的血浆和组织标志物显示心脏功能下降 小鼠中，发现与 Ppara-/- 组中的较低脂肪酸氧化有关。总的来说，这些数据 支持以下总体假设：PPARα 通过激活脂肪酸来保护脓毒症患者的心脏功能 氧化作用和增强心脏 PPARα 信号传导将提高生存率。该计划的具体目标 拟议的研究目的是： 1) 确定 PPARα 表达在脓毒症患者心脏功能和生存中的作用 使用新型转基因、心脏特异性 PPARα 敲除小鼠和过度表达的小鼠品系 PPARα 位于心脏； 2) 确定影响 PPARα 依赖性心脏功能的代谢途径 通过测量心脏 ATP 产生和底物利用率、组织基因表达和代谢物来检测心脏 水平，并通过评估线粒体结构和功能； 3) 确定是否具有药理作用 PPARα 激活可改善脓毒症性心脏功能障碍并提高生存率。 这项工作意义重大，并且具有很高的转化潜力，因为 PPARα 信号传导是一种可靶向的 机制与 FDA 批准的激动剂已经上市。这里评估的假设挑战了 普遍认为脓毒症发病率和死亡率是由免疫失调引起的，研究结果将有 重新制定治疗这一重大公共卫生问题的方法的潜力。

项目成果

NMR-based serum and urine metabolomic profile reveals suppression of mitochondrial pathways in experimental sepsis-associated acute kidney injury.

基于 NMR 的血清和尿液代谢组学谱揭示了实验性脓毒症相关急性肾损伤中线粒体途径的抑制。

• DOI: 10.1152/ajprenal.00582.2020
• 发表时间: 2021
• 期刊: American journal of physiology. Renal physiology
• 作者: Standage,StephenW;Xu,Shenyuan;Brown,Lauren;Ma,Qing;Koterba,Adeleine;Lahni,Patrick;Devarajan,Prasad;Kennedy,MichaelA
• 通讯作者: Kennedy,MichaelA

Candidate Biomarkers for Sepsis-Associated Acute Kidney Injury Mechanistic Studies.

• DOI: 10.1097/shk.0000000000001916
• 发表时间: 2022-05-01
• 期刊: Shock (Augusta, Ga.)

Choline Supplementation Attenuates Experimental Sepsis-Associated Acute Kidney Injury.

• DOI: 10.1152/ajprenal.00033.2022
• 发表时间: 2022-07
• 期刊: American journal of physiology. Renal physiology
• 作者: Denise C. Hasson;Miki Watanabe-Chailland;L. Romick-Rosendale;Adeleine Koterba;Dashiell S Miner;P. Lahni;Q. Ma;S. Goldstein;P. Devarajan;Stephen W. Standage