Restoration and preservation of hepatic cardiolipin levels promotes liver regeneration in AH

肝心磷脂水平的恢复和保存促进 AH 中的肝再生

• 批准号: 10708057
• 负责人: Josiah E Hardesty
• 金额: $ 13.43万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-21 至 2023-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10708057
• 关键词: ATP Synthesis Pathway; Affect; Alcoholic Hepatitis; Alcoholic Liver Diseases; Alcoholic liver damage; Alcohols; Animal Model; Animals; Apoptosis; Binding; Bioenergetics; Biogenesis; Biological Assay; Biological Markers; Cardiolipins; Cells; Cessation of life; Clinical; Clinical Trials; Culture Media; Data; Dextrins; Dose; Enzymes; Ethanol; Euthanasia; Evaluation; Experimental Animal Model; Foundations; Galactosamine; Genes; Genus Hippocampus; Hepatic; Hepatic Insufficiency; Hepatitis; Hepatocyte; Human; Immune; Impairment; In Vitro; Inflammation; Inflammatory Response; Injections; Injury; Lead; Lipids; Liver; Liver Mitochondria; Liver Regeneration; Liver diseases; LoxP-flanked allele; Maintenance; Maltose; Measurement; Mediating; Mitochondria; Mitochondrial Myopathies; Modeling; Mus; Natural regeneration; Oxidative Phosphorylation; Partial Hepatectomy; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phase; Phospholipids; Plasma; Population; Prevention; Process; Prognosis; Proliferating; Proliferation Marker; Proteins; Regimen; Research; Research Personnel; Respiratory Chain; Rodent; Role; Safety; Sampling; Solid; Sorting; Structure; Supplementation; TNF gene; Tail; Testing; Therapeutic; Training; Translations; Treatment Efficacy; Veins; Vesicle; Viral; Viral Genome; alternative treatment; chronic liver disease; cytochrome c; cytokine; disorder control; feeding; hepatocyte injury; improved; in vitro Model; ineffective therapies; lipidomics; liver cell proliferation; liver function; liver transplantation; male; mitochondrial dysfunction; mitochondrial membrane; mortality; novel; oxidation; particle; patient prognosis; pharmacologic; pre-clinical; preclinical study; preservation; prevent; problem drinker; response; restoration; single-cell RNA sequencing; therapeutically effective; treatment arm; treatment strategy

Project Summary/Abstract: Alcohol-associated hepatitis (AH) is a clinical manifestation of alcohol-associated liver disease (ALD) that has a very poor prognosis. Current treatments are ineffective and liver transplantation is the only long-term solution. The liver has the unique ability to regenerate post-injury but in ALD/AH this process becomes compromised. Mitochondria dysfunction is a hallmark of ALD and AH that can contribute to compromised liver regeneration. Mitochondria enriched with cardiolipin maintain the energy requirements (e.g., ATP) necessary for hepatocyte proliferation and liver regeneration. Preliminary data demonstrate that hepatic cardiolipin synthesis is compromised in clinical AH and experimental AH. Cardiolipin is required to maintain mitochondrial bioenergetics and undergoes oxidation and depletion in ALD compromising liver regeneration. However, treatment with cardiolipin or elamipretide (drug that prevents cardiolipin oxidation) can restore hepatocyte mitochondrial function and proliferation. The aim of this study is to determine if cardiolipin supplementation and preservation will promote liver regeneration via maintenance of ATP synthesis and prevention of hepatocyte apoptosis alleviating hepatic insufficiency in AH. This study uses pre-clinical animal models and human in vitro models of AH to assess the treatment efficacy of cardiolipin supplementation and preservation. Aim 1 will determine if mice with cardiolipin deficient hepatocytes have compromised liver regeneration due to loss of mitochondrial ATP synthesis in a model of AH. Aim 2 will test whether treatment with cardiolipin and elamipretide will enhance hepatic mitochondrial function, liver regeneration, and proliferating hepatocyte populations in an experimental animal model of AH. Aim 3 will identify cardiolipin species in human AH liver and plasma and assess their effect on hepatocyte proliferation and inflammatory responses in immune cells. The K99-phase (Aim 1) will provide training in assaying liver regeneration and mitochondrial function, sc-RNASeq analysis, and use of a mouse deficient in hepatocyte cardiolipin. This MOSAIC K99/R00 proposal will provide the training necessary (K99) to build a solid research foundation providing a pathway to independence as an independent researcher in the field of ALD and liver regeneration (R00). Findings from this study will identify a therapeutic strategy to treat AH via enhanced liver regeneration which could replace the only long-term treatment alternative, liver transplantation.

项目概要/摘要： 酒精相关性肝炎（AH）是酒精相关性肝病（ALD）的临床表现， 预后很差。目前的治疗是无效的，肝移植是唯一的长期解决方案。 肝脏具有独特的损伤后再生能力，但在ALD/AH中，这一过程受到损害。 线粒体功能障碍是ALD和AH的标志，可导致肝再生受损。 富含心磷脂的线粒体维持能量需求（例如，肝细胞所必需的ATP） 增殖和肝再生。初步数据表明，肝心磷脂合成是 在临床AH和实验AH中受损。心磷脂是维持线粒体生物能量所必需的 并在损害肝再生的ALD中经历氧化和消耗。然而，治疗与 心磷脂或依拉普利肽（防止心磷脂氧化的药物）可恢复肝细胞线粒体功能 和扩散。本研究的目的是确定心磷脂的补充和保存是否 通过维持ATP合成和防止肝细胞凋亡来促进肝再生 AH中的肝功能不全。本研究使用AH的临床前动物模型和人类体外模型， 评估心磷脂补充和保存的治疗效果。目标1将确定是否有 心磷脂缺乏的肝细胞由于线粒体ATP的丧失而损害肝再生 在AH模型中进行合成。目的2将测试心磷脂和依拉普利肽治疗是否会增强 肝线粒体功能、肝再生和肝细胞增殖的实验研究 AH动物模型目的3将鉴定人AH肝脏和血浆中的心磷脂种类并评估其作用 对肝细胞增殖和免疫细胞炎症反应的影响。K99阶段（目标1）将提供 肝脏再生和线粒体功能测定、sc-RNASeq分析和小鼠使用方面的培训 缺乏肝细胞心磷脂。本MOSAIC K99/R 00提案将提供必要的培训（K99）， 建立一个坚实的研究基础，提供一个独立的途径，作为一个独立的研究人员在该领域 ALD和肝再生（R 00）。这项研究的结果将确定一种治疗AH的治疗策略， 增强肝再生，可以取代唯一的长期治疗选择，肝移植。