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.

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