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症性疾病，死亡率高达 25%。 对于无并发症的病例，对于患有多器官功能障碍综合征 (MODS) 的患者，这一比例上升至 80%。 尚无针对 MODS 的具体疗法，这就是为什么要鉴定可药物靶点和生物标志物 迫切需要诊断/预后。在脓毒症的急性期反应期间，循环因素如 因为细胞因子和内毒素会导致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。 抑制素 (PHB1,2) 是在线粒体内部组装成异源寡聚复合物的蛋白质。 膜和质膜脂筏中，研究表明它们是许多重要细胞的纽带 功能包括代谢、增殖、氧化应激和细胞凋亡。目前的提案源于 我们最近的研究结果表明，PHB1 是脓毒症中的一种动态急性期反应蛋白，其在脓毒症过程中的分泌 在缺乏抗炎转录因子 Nrf2（即 NFE2L2）的小鼠中，败血症被消除。重要的是， 血源性 PHB1 具有生物活性，因为重组人 PHB1 (rPHB1) 的施用会激活 PI3K- AKT 信号传导并增强心脏中的有氧葡萄糖氧化和磷酸戊糖途径，以及 在脓毒症小鼠模型中保留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 PHB1 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 PHB1 是一种 应激诱导的“肝因子”在脓毒症期间介导肝脏到心脏的保护性反馈信号 增强氧化葡萄糖代谢（即抑制乳酸产生）并保护线粒体 心肌的结构和功能。循环 PHB1 的这种心脏保护作用可以是 治疗上用于治疗 SepCM。 我们建立的跨学科团队将在三个目标上检验这一假设。目标 1 的工作将决定 Nrf2 介导的控制肝细胞中 PHB1 分泌的机制。在目标 2 中，我们将确定 败血症期间循环 PHB1 赋予心脏保护的机制。目标 3 中的工作将得到验证 血清 PHB1 作为脓毒症患者队列发病率和死亡率的预测生物标志物 （INVACS 队列，犹他大学）。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、临床相关的严重脓毒症小鼠模型，以及 来自一组特征明确的脓毒症患者的血清样本。我们将利用互补性和 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非常严重和致命的临床病症。