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%