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: 10572240
• 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 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10572240
• 关键词: ATP Synthesis Pathway; Affect; 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; Maintenance; Maltose; Measurement; Mediating; Mitochondria; Mitochondrial Myopathies; Modeling; Mus; Natural regeneration; Oxidative Phosphorylation; Oxides; Partial Hepatectomy; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacology; Phase; Phospholipids; Plasma; Population; Prevention; Process; Prognosis; Proliferating; Proliferation Marker; Proteins; Regimen; Research; Research Personnel; Respiratory Chain; Rodent; Role; Safety; Sampling; Solid; 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; pre-clinical; preclinical study; preservation; prevent; problem drinker; regeneration function; 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.

项目摘要/摘要： 酒精相关性肝炎(AH)是酒精相关性肝病(ALD)的临床表现，具有 预后非常差。目前的治疗方法无效，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，这一过程受到影响。 线粒体功能障碍是ALD和AH的一个标志，可能导致肝脏再生受损。 富含心磷脂的线粒体维持肝细胞所需的能量(例如，ATP) 增殖和肝再生。初步数据显示，肝心磷脂的合成是 临床急性胰腺炎和实验性急性胰腺炎的折衷。维持线粒体生物能量学所需的心磷脂 在损害肝脏再生的ALD中经历氧化和耗竭。然而，治疗与 心磷脂或弹力肽(防止心磷脂氧化的药物)可以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会 维持三磷酸腺苷合成促进肝再生，预防肝细胞凋亡缓解 急性期肝功能不全。本研究使用临床前动物模型和人类体外模型来研究 评价心磷脂补充和保存的治疗效果。目标1将确定小鼠是否患有 心磷脂缺乏的肝细胞由于线粒体三磷酸腺苷的丢失而影响肝再生 在AH的模型中进行合成。Aim 2将测试心磷脂和伊拉米肽的治疗是否会增强 肝线粒体功能、肝再生和肝细胞增殖的实验研究 急性呼吸窘迫综合征动物模型。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 肝细胞增殖和免疫细胞的炎症反应。K99阶段(目标1)将提供 分析肝再生和线粒体功能、sc-RNAseq分析和小鼠使用方面的培训 肝细胞心磷脂缺乏。此马赛克K99/R00建议书将提供必要的培训(K99)以 建立坚实的研究基础，为该领域的独立研究人员提供独立的途径 ALD和肝再生(R00)。这项研究的发现将确定一种治疗策略，通过 增强肝脏再生，可以取代唯一的长期治疗选择，肝移植。