Regulation of Cardiac Metabolic Plasticity in Sepsis

脓毒症心脏代谢可塑性的调节

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要败血症是重症监护病房中死亡的主要原因。我的长期目标研究是了解败血症引起的多器官失败的机制为这种毁灭性的临床状况确定潜在的新治疗机会。该应用中提出的研究旨在阐明新的病理线粒体代谢调节激酶，丙酮酸脱氢酶的功能激酶4（PDK4），使用临床前模型在败血症诱导的心肌病中。先前的研究表明，由于代谢不灵活性引起的能量缺乏症紧密与败血症中的不良结果有关。在我的实验室中正在进行的调查令人兴奋的初步证据表明PDK4过度刺激是关键的原因败血症中心肌代谢不灵活性和潜在机制的因素可能涉及在线粒体相关的膜（MAMS）上引起损伤，A 以前未知的PDK4信号。我们还发现心脏特异性消融 PDK4具有心脏保护性，表明PDK4是有前途的治疗靶标败血症。这个探索性项目是为了检验以下假设：败血症期间，PDK4 触发因MAM的病理损伤而触发代谢的不灵活性，导致不足心脏不良适应性自噬和压倒性的炎症。使用两者在体外和体内的功能和功能丧失方法，我们将检查是否是否 PDK4诱导妈妈的功能缺陷和结构性损害，这又产生功能失调的线粒体并启动化粪池中的代谢僵化（目标1）。此外，我们将解决PDK4在心脏自噬中的作用败血症中的炎症是通过询问其在抑制自噬时的调节，细胞因子的产生，炎症因子的激活和免疫浸润心肌中的细胞（AIM 2）。共同期望这项调查不仅会进步对败血症病理学的基本理解，同时也评估是否是否 PDK4的阻塞改善了败血症的心脏结果，为科学基础奠定了科学基础新疗法的未来发展。