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

基本信息

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
项目类别：
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

项目摘要

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）的一种临床表现，预后极差。目前的治疗无效，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，这一过程会受到损害。线粒体功能障碍是 ALD 和 AH 的一个标志，可能导致肝再生受损。富含心磷脂的线粒体维持肝细胞所需的能量需求（例如 ATP）增殖和肝再生。初步数据表明，肝脏心磷脂合成是临床 AH 和实验性 AH 均受到损害。维持线粒体生物能需要心磷脂并在 ALD 中经历氧化和消耗，损害肝再生。然而，治疗用心磷脂或埃拉米普肽（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补充和保存心磷脂是否会通过维持 ATP 合成和预防肝细胞凋亡来促进肝再生 AH 肝功能不全。本研究利用 AH 的临床前动物模型和人体体外模型来评估补充和保存心磷脂的治疗效果。目标 1 将确定小鼠是否具有心磷脂缺乏的肝细胞由于线粒体 ATP 的损失而损害了肝脏再生 AH 模型中的综合。目标 2 将测试心磷脂和埃拉米普肽治疗是否会增强实验中的肝线粒体功能、肝再生和肝细胞群增殖 AH的动物模型。目标 3 将鉴定人 AH 肝脏和血浆中的心磷脂种类并评估其效果肝细胞增殖和免疫细胞炎症反应的影响。 K99 相（目标 1）将提供肝再生和线粒体功能测定、sc-RNASeq 分析以及小鼠使用方面的培训肝细胞心磷脂缺乏。此 MOSAIC K99/R00 提案将提供必要的培训 (K99) 建立坚实的研究基础，为作为该领域的独立研究人员提供独立的途径 ALD 和肝再生 (R00)。这项研究的结果将确定治疗 AH 的治疗策略：增强肝脏再生，可以取代唯一的长期治疗替代方案——肝移植。