Regulation of Cardiac Metabolic Plasticity in Sepsis

项目摘要 败血症是重症监护病房的主要死亡原因。我的长期目标是 研究目的是了解脓毒症引起多器官衰竭的机制，并 为这一毁灭性的临床疾病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 线粒体代谢调节蛋白--丙酮酸脱氢酶的功能 使用临床前模型研究败血症诱导的心肌病中的蛋白激酶4(PDK4)。 以往的研究表明，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有关。我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原因 脓毒症时心肌代谢不灵活的因素，其潜在机制可能 涉及到引起线粒体相关膜(MAM)的损伤， 此前未知的PDK4信号。我们还发现，心脏特异性消融 PDK4具有心脏保护作用，提示PDK4是一种很有前途的治疗靶点。 败血症。这一探索性项目是为了验证一种假设，即在脓毒症期间，PDK4 通过MAM的病理损伤触发代谢不灵活，导致代谢不足， 适应不良的自噬和心脏的强烈炎症。使用这两种增益 功能和功能丧失的方法在体外和体内，我们将检查 PDK4诱导MAM功能缺陷和结构损伤，进而 败血症心脏产生功能障碍的线粒体并启动代谢不灵活 (目标1)。此外，我们将讨论PDK4在心脏自噬和 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、炎症因子的激活和免疫的渗透 心肌细胞(目标2)。总而言之，这项调查预计不仅会推进 对脓毒症病理的基本认识也要评价是否 阻断PDK4可改善脓毒症患者的心脏结局，为 新疗法的未来发展。

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.