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.

项目摘要 脓毒症是重症监护病房的主要死亡原因。我的长期目标是 研究的目的是了解脓毒症引起的多器官衰竭的机制， 为这种毁灭性的临床病症确定潜在的新治疗机会。 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 使用临床前模型研究脓毒症诱导的心肌病中的激酶4（PDK 4）。 以前的研究表明，由于代谢能力不足， 与脓毒症的不良结局相关。我实验室正在进行的调查 令人兴奋的初步证据表明，PDK 4的过度刺激是一个关键的致病因素， 脓毒症心肌代谢稳定性的因素，其潜在机制可能 涉及引起与乳腺癌相关的膜（MAMs）的损伤， 之前未知的PDK 4信号我们还发现，心脏特异性消融 PDK 4具有心脏保护作用，这表明PDK 4是一个有前途的治疗靶点， 败血症这个探索性的项目是为了检验假设，在脓毒症期间，PDK 4 通过MAMs的病理损伤触发代谢能力，导致不充分的， 适应不良的自噬和严重的心脏炎症。使用增益- 功能和功能丧失的方法在体外和体内，我们将研究是否 PDK 4诱导MAMs中的功能缺陷和结构损伤，这反过来 在脓毒症心脏中产生功能失调的线粒体并启动代谢能力 (aim 1）。此外，我们将讨论PDK 4在心脏自噬中的作用， 脓毒症中的炎症通过询问其在抑制自噬中的调节， 细胞因子的产生、炎症因子的活化和免疫细胞因子的浸润。 心肌细胞（aim 2）。总之，这项调查预计不仅将推动 对脓毒症病理学的基本理解，同时也评估是否 阻断PDK 4可改善脓毒症患者的心脏结局，为以下方面奠定科学基础 新疗法的未来发展。