Determinants of cardioprotection by circulating prohibitin-1 during sepsis

败血症期间循环抑制素 1 的心脏保护作用的决定因素

• 批准号: 10577340
• 负责人: Ethan John Anderson
• 金额: $ 45.41万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-11 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10577340
• 关键词: Acute-Phase Proteins; Acute-Phase Reaction; Adult; Aerobic; Anti-Inflammatory Agents; Apoptosis; Biological; Biological Markers; Biomedical Engineering; Blood; Blood specimen; COVID-19; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cell Line; Cell membrane; Cell physiology; Cessation of life; Characteristics; Clinical; Clinical Research; Complex; Custom; Dangerousness; Diagnosis; Disease; Drug Targeting; Endotoxins; Enzyme-Linked Immunosorbent Assay; Feedback; Functional disorder; Genetic Transcription; Glucose; Heart; Heart failure; Hepatocyte; Heterodimerization; Human; Incubated; Infection; Inflammatory; Injury; Inner mitochondrial membrane; Knockout Mice; Label; Ligands; Liver; Manuscripts; Measures; Mediating; Membrane Microdomains; Metabolic stress; Metabolism; Mitochondria; Molecular; Morbidity - disease rate; Morphology; Multiple Organ Failure; Mus; Myocardial dysfunction; Myocardium; Organ; Oxidative Phosphorylation; Oxidative Stress; PIK3CG gene; Pathway interactions; Patients; Pentosephosphate Pathway; Primary Cell Cultures; Production; Prognosis; Proliferating; Proteins; Proto-Oncogene Proteins c-akt; Publishing; Recombinants; Reporting; Research; SARS-CoV-2 infection; Sampling; Scientist; Sepsis; Serum; Signal Transduction; Stress; Structure; Techniques; Testing; Therapeutic; Time; Tissues; Trauma; Universities; Utah; Work; cardioprotection; clinically relevant; cohort; cytokine; druggable target; experimental study; glucose metabolism; heart metabolism; heart preservation; inflammatory marker; insight; loss of function; mitochondrial dysfunction; mortality; mortality risk; mouse model; novel; overexpression; oxidation; predictive marker; preservation; prohibitin; response; scaffold; septic; septic patients; severe COVID-19; stem; transcription factor; transcriptomics; uptake

ABSTRACT: Sepsis is a dangerous hyper-inflammatory condition that carries a mortality rate of 25% for uncomplicated cases and rises to 80% for patients who develop multiple organ dysfunction syndrome (MODS). No specific therapies for MODS exist, which is why identification of druggable targets and biomarkers for diagnosis/prognosis are urgently needed. During the acute phase response in sepsis, circulating factors such as cytokines and endotoxins cause oxidative stress and derangements in mitochondrial morphology and function in the heart, ultimately leading to septic cardiomyopathy (SepCM), a manifestation of MODS. Prohibitins (PHB1,2) are proteins that assemble in hetero-oligomeric complexes within the mitochondrial inner membrane and in plasma membrane lipid rafts, where studies show they are at the nexus of many vital cellular functions including metabolism, proliferation, oxidative stress and apoptosis. The current proposal stems from our recent findings that PHB1 is a dynamic acute phase reactant protein in sepsis, and its secretion during sepsis is abrogated in mice lacking the anti-inflammatory transcription factor Nrf2 (i.e., NFE2L2). Importantly, bloodborne PHB1 is biologically active, as administration of recombinant human PHB1 (rPHB1) activates PI3K- AKT signaling and enhances aerobic glucose oxidation and pentose phosphate pathway in the heart, and preserves cardiac mitochondrial oxidative phosphorylation (OxPHOS) in mouse models of sepsis. We also have very exciting preliminary evidence that serum PHB1 levels are associated with MODS and mortality in sepsis patients. Experiments outlined in this proposal will test our central hypothesis that bloodborne PHB1 is a stress-induced ‘hepatokine’ that mediates a liver-to-heart protective feedback signal during sepsis by enhancing oxidative glucose metabolism (i.e. suppressing lactate production) and preserving mitochondrial structure and function in the myocardium. This cardioprotective effect of circulating PHB1 can be therapeutically exploited to treat SepCM. Our established interdisciplinary team will test this hypothesis in three Aims. Work in Aim 1 will determine the Nrf2-mediated mechanisms controlling PHB1 secretion in hepatocytes. In Aim 2 we will identify the mechanisms of cardio-protection conferred by circulating PHB1 during sepsis. Work in Aim 3 will validate serum PHB1 as a predictive biomarker of morbidity and mortality in a cohort of patients with established sepsis (INVACS cohort, University of Utah). Each Aim is hypothesis-driven, and the work will be performed using gain/loss-of-function approaches in primary cell culture, clinically relevant mouse models of severe sepsis, and serum samples from a well-characterized cohort of sepsis patients. We will leverage the complementary and uniquely distinct expertise of our research team to elucidate cardioprotective mechanisms of circulating PHB1, and to exploit these mechanisms to treat a very serious and deadly clinical condition.

摘要：脓毒症是一种危险的高炎性疾病，其死亡率为25%。 不复杂的病例，发展为多器官功能障碍综合征(MODS)的患者高达80%。 目前还没有针对MODS的特定疗法，这就是为什么确定可用药靶点和生物标记物治疗MODS的原因 迫切需要诊断和预后。在脓毒症的急性期反应中，循环因子 由于细胞因子和内毒素导致线粒体形态和线粒体的氧化应激和排列紊乱 最终导致感染性心肌病(SepCM)，这是MODS的一种表现。 Prohibitins(PHB1，2)是一种在线粒体内部以异源低聚复合体形式组装的蛋白质 膜和质膜脂筏中，研究表明它们位于许多重要细胞的连接处 功能包括新陈代谢、增殖、氧化应激和细胞凋亡。目前的提议源于 我们最近的研究发现，PHB1在脓毒症中是一种动态的急性时相反应蛋白，它在脓毒症中的分泌 在缺乏抗炎转录因子Nrf2(即NFE2L2)的小鼠中，脓毒症是被废除的。重要的是 血源性PHB1具有生物活性，因为给予重组人PHB1(RPHB1)可激活PI3K- AKT信号转导，增强心脏葡萄糖有氧氧化和磷酸戊糖途径，以及 保护脓毒症小鼠模型的心肌线粒体氧化磷酸化(OXPHOS)。我们也 有非常令人兴奋的初步证据表明，血清PHB1水平与MODS和死亡率有关 败血症患者。这项提案中概述的实验将检验我们的中心假设，即血源性PHB1是一种 应激诱导的肝细胞因子在脓毒症过程中介导肝到心的保护性反馈信号 增强氧化葡萄糖代谢(即抑制乳酸生成)和保护线粒体 心肌的结构和功能。循环PHB1的这种心脏保护作用可以是 治疗上被用来治疗SepCM。 我们建立的跨学科团队将在三个目标上测试这一假设。目标1中的工作将决定 Nrf2介导的肝细胞PHB1分泌调控机制在目标2中，我们将确定 脓毒症时循环PHB1的心脏保护机制。AIM 3中的工作将验证 血清PHB1作为已确诊脓毒症患者发病率和死亡率的预测生物标志物 (犹他大学INVAC队列)。每个目标都是假设驱动的，工作将使用 原代细胞培养中的获得/功能丧失方法，严重脓毒症的临床相关小鼠模型，以及 来自一组特征明确的败血症患者的血清样本。我们将利用互补的和 我们的研究团队拥有独特的专业知识来阐明循环PHB1的心脏保护机制， 并利用这些机制来治疗一种非常严重和致命的临床疾病。