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度炎症性疾病， 无并发症的病例中，发生多器官功能障碍综合征（MODS）的患者的比例上升至80%。 MODS没有特异性治疗，这就是为什么确定可药物靶点和生物标志物的原因。 诊断/预后是迫切需要的。在脓毒症的急性期反应中，循环因子如 因为细胞因子和内毒素引起氧化应激和线粒体形态紊乱， 心脏功能受损，最终导致脓毒性心肌病（SepCM），这是MODS的一种表现。 抑肽酶（PHB 1，2）是一种在线粒体内形成异源寡聚复合物的蛋白质， 在细胞膜和质膜脂筏中，研究表明它们是许多重要细胞的连接点。 功能包括代谢、增殖、氧化应激和凋亡。目前的提案源于 我们最近的研究发现，PHB 1是脓毒症中一种动态的急性期反应蛋白， 败血症在缺乏抗炎转录因子Nrf 2的小鼠中消除（即，NFE2L2）。重要的是， 血源性PHB 1具有生物活性，因为重组人PHB 1（rPHB 1）的给药会激活PI 3 K- AKT信号传导并增强心脏中的有氧葡萄糖氧化和戊糖磷酸途径， 在败血症小鼠模型中保留了心脏线粒体氧化磷酸化（OxPHOS）。我们也 有非常令人兴奋的初步证据表明，血清PHB 1水平与MODS和死亡率相关， 败血症患者本提案中概述的实验将检验我们的中心假设，即血源性PHB 1是一种 应激诱导的“肝细胞因子”在脓毒症期间介导肝-心保护性反馈信号， 增强氧化葡萄糖代谢（即抑制乳酸盐产生）和保护线粒体 心肌的结构和功能。循环PHB 1的这种心脏保护作用可以是 在治疗上用于治疗SepCM。 我们建立的跨学科团队将在三个目标中测试这一假设。目标1的工作将决定 Nrf 2介导的控制肝细胞中PHB 1分泌的机制。在目标2中，我们将确定 败血症期间循环PHB 1赋予的心脏保护机制。目标3中的工作将验证 血清PHB 1可作为脓毒症患者发病率和死亡率的预测性生物标志物 （INVACS队列，犹他州大学）。每个目标都是假设驱动的，工作将使用 原代细胞培养中的功能获得/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脓毒症患者的血清样品。我们将利用互补性， 我们的研究团队独特的专业知识，以阐明循环PHB 1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。