Regulation of Cardiac Metabolic Plasticity in Sepsis

脓毒症心脏代谢可塑性的调节

• 批准号: 10629401
• 负责人: Qun Sophia Zang
• 金额: $ 23.1万
• 依托单位: LOYOLA UNIVERSITY CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-26 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10629401
• 关键词: Ablation; American; Animal Model; Animals; Attenuated; Autophagocytosis; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cause of Death; Cells; Clinical; Critical Care; Data; Development; Disease; Endoplasmic Reticulum; Endotoxemia; FRAP1 gene; Family; Foundations; Functional disorder; Future; Glucose; Goals; Health; Heart; Heart Mitochondria; Homeostasis; Immune; Immune response; Impairment; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Investigation; Knock-out; Laboratories; Life; Lipids; Mediating; Medical; Membrane; Metabolic; Metabolism; Mitochondria; Molecular; Multiple Organ Failure; Myocardial; Myocardium; Organ; Outcome; PDH kinase; Pathologic; Pathology; Patients; Pattern; Performance; Phosphotransferases; Physiological; Pneumonia; Pre-Clinical Model; Process; Production; Protein Isoforms; Proteomics; Pyruvate Dehydrogenase Complex; Regulation; Research; Role; Sampling; Sepsis; Signal Transduction; Stress; Structure; Subcellular Spaces; Testing; adverse outcome; attenuation; cytokine; design; effective therapy; experimental study; gain of function; heart metabolism; immune cell infiltrate; improved; in vivo; inhibition of autophagy; loss of function; mTOR inhibition; mitochondrial metabolism; novel; novel therapeutics; oxidation; programs; pyruvate dehydrogenase kinase 4; response; septic; therapeutic target

Project Summary Sepsis is a leading cause of death in critical care units. The long-term goal of my research is to understand the mechanisms of sepsis-induced multi-organ failure and to identify potential new therapeutic opportunities for this devastating clinical condition. Studies proposed in this application are designed to elucidate novel pathological functions of a mitochondrial metabolism regulatory kinase, pyruvate dehydrogenase kinase 4 (PDK4), in sepsis-induced cardiomyopathy using preclinical models. Previous studies showed that energy deficiency due to metabolic inflexibility is tightly associated with adverse outcomes in sepsis. Ongoing investigation in my lab obtained exciting preliminary evidence suggesting that overstimulation of PDK4 is a key causative factor for myocardial metabolic inflexibility in sepsis, and the underlying mechanism may involve causing impairments at mitochondria-associated membranes (MAMs), a previously unknown signal of PDK4. We also found that cardiac specific ablation of PDK4 is cardiac protective, suggesting that PDK4 is a promising therapeutic target for sepsis. This exploratory project is to test the hypothesis that, during sepsis, PDK4 triggers metabolic inflexibility via pathological injuries at MAMs, leading to an insufficient, maladaptive autophagy and overwhelming inflammation in the heart. Using both gain-of- function and loss-of-function approaches in vitro and in vivo, we will examine whether PDK4 induces functional deficiency and structural damage in MAMs, which in turn produce dysfunctional mitochondria and initiate metabolic inflexibility in septic hearts (aim 1). Further, we will address the roles of PDK4 in cardiac autophagy and inflammation in sepsis by interrogating its regulation in the inhibition of autophagy, production of cytokines, activation of inflammatory factors, and infiltration of immune cells in myocardium (aim 2). Together, this investigation is expected not only to advance the fundamental understanding of sepsis pathology but also to evaluate whether blockage of PDK4 improves cardiac outcomes in sepsis, laying a scientific foundation for future development of novel therapies.

项目概要 脓毒症是重症监护病房死亡的主要原因。我的长期目标 研究目的是了解脓毒症引起的多器官衰竭的机制并 为这种破坏性的临床病症找出潜在的新治疗机会。 本申请中提出的研究旨在阐明新的病理学 线粒体代谢调节激酶丙酮酸脱氢酶的功能 激酶 4 (PDK4)，在脓毒症诱发的心肌病中使用临床前模型。 先前的研究表明，由于代谢不灵活而导致的能量缺乏与 与败血症的不良后果相关。我的实验室正在进行的调查获得了 令人兴奋的初步证据表明 PDK4 的过度刺激是一个关键的致病因素 脓毒症心肌代谢不灵活的影响因素及其潜在机制 涉及造成线粒体相关膜（MAM）损伤， PDK4 以前未知的信号。我们还发现心脏特异性消融 PDK4 具有心脏保护作用，表明 PDK4 是一个有前途的治疗靶点 败血症。这个探索性项目旨在检验以下假设：在脓毒症期间，PDK4 通过 MAM 的病理损伤引发代谢不灵活，导致代谢不充分、 适应不良的自噬和心脏中严重的炎症。使用两种增益 体外和体内的功能和功能丧失方法，我们将检查是否 PDK4 诱导 MAM 功能缺陷和结构损伤，进而 产生功能失调的线粒体并引发脓毒症心脏的代谢僵化 （目标1）。此外，我们将讨论 PDK4 在心脏自噬和 通过探究脓毒症炎症对自噬抑制的调节， 细胞因子的产生、炎症因子的激活以及免疫细胞的浸润 心肌细胞（目标 2）。总之，这项调查预计不仅会推进 对脓毒症病理学的基本了解，还可以评估是否 PDK4 阻断可改善脓毒症患者的心脏结局，为 新疗法的未来发展。