Hepatic lymphatics in alcohol-associated liver disease

酒精相关性肝病中的肝淋巴管

• 批准号: 10824029
• 负责人: YASUKO IWAKIRI
• 金额: $ 21.16万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-18 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10824029
• 关键词: Address; Alcohol abuse; Alcohol consumption; Alcoholic Hepatitis; Alcoholic Liver Diseases; Alcohols; Antigen-Presenting Cells; Antigens; California; Cell physiology; Cell surface; Cholestasis; Chronic; Cirrhosis; Clinical; Collaborations; Consumption; Development; Diet; Encapsulated; Endothelial Cells; Ethanol; Exhibits; Extravasation; Foundations; Future; Gene Expression; Goals; Hepatic; Hepatocyte; Hybrids; IL7 gene; Impairment; Inflammation; Inflammation Mediators; Inflammatory Response; Infusion procedures; Liquid substance; Liver; Liver diseases; Lymphangiogenesis; Lymphatic; Lymphatic Endothelial Cells; Lymphatic System; Lymphatic function; Mesothelial Cell; Messenger RNA; Modeling; Molecular; Mus; Pathologic; Patients; Pennsylvania; Phenotype; Population; Prognosis; Protocols documentation; Regulation; Reporter; Role; Structure; Technology; Testing; Tissues; Universities; Vascular Endothelial Growth Factor C; alcohol effect; cholangiocyte; chronic alcohol ingestion; clinically relevant; experimental study; feeding; gain of function; in vivo; lipid nanoparticle; liver inflammation; liver injury; loss of function; lymph nodes; lymphatic drainage; lymphatic dysfunction; lymphatic vessel; novel; novel therapeutic intervention; overexpression; patient subsets; single-cell RNA sequencing; transcriptomics; western diet

SUMMARY A subset of patients with alcohol-associated liver disease (ALD) develop severe alcoholic hepatitis (AH), carrying a very poor prognosis. Control of inflammation is a key to the treatment of AH. Hepatic lymphatics are highly involved in the regulation of the inflammatory response by discharging extravasated fluids, inflammatory mediators, antigens, and antigen-presenting cells to lymph nodes outside the liver. However, how the hepatic lymphatic system is involved in the development of ALD remains largely unknown. The goal of this exploratory study is to advance our understanding of hepatic lymphatics in the progression of AH and explore whether increasing lymphatic vessels (LVs) and lymphatic drainage can be a novel therapeutic strategy for AH. Given that lymphatics generally help to reduce tissue inflammation, we hypothesize that chronic alcohol consumption may impair hepatic lymphatic endothelial cell (EC) function and lymphatic drainage, facilitating the progression to AH. Contrarily, enhancing lymphangiogenesis (new LV formation) via overexpression of vascular endothelial growth factor (VEGF)-C, the most potent lymphangiogenic factor, may ameliorate AH. To test these hypotheses, we propose the following two Aims: Aim 1. Determine the role of the hepatic lymphatic system in AH. Aim 2. Explore the potential of the VEGF-C mRNA LNP (lipid nanoparticle) technology for the treatment of severe AH. This study will explore an important, but poorly understood subject, liver lymphatics in ALD, addressing the effect of alcohol on hepatic lymphatic functions and its implications in the development of AH. Results from the two Aims above will provide the foundation for many future studies to advance our understanding of the lymphatic system in liver disease in general and AH in particular, including a study addressing the molecular mechanism of lymphatic impairment by alcohol as well as a study aiming at clinical use of VEGF-C mRNA-LNP for the treatment of AH.

概括 一部分患有酒精相关性肝病 (ALD) 的患者会发展为严重的酒精性肝炎 (AH)，预后非常差。控制炎症是治疗 AH 的关键。肝的 淋巴管通过排出外渗物高度参与炎症反应的调节 液体、炎症介质、抗原和抗原呈递细胞到达肝外的淋巴结。 然而，肝淋巴系统如何参与 ALD 的发展仍然很大程度上未知。 这项探索性研究的目的是增进我们对肝淋巴管疾病进展的理解。 AH 并探讨增加淋巴管 (LV) 和淋巴引流是否可以成为一种新的治疗方法 AH 的策略。 鉴于淋巴管通常有助于减少组织炎症，我们假设慢性炎症 饮酒可能会损害肝淋巴内皮细胞（EC）功能和淋巴引流， 促进进展至 AH。相反，通过增强淋巴管生成（新的左室形成） 血管内皮生长因子 (VEGF)-C（最有效的淋巴管生成因子）的过度表达可能 改善一下啊。为了检验这些假设，我们提出以下两个目标： 目标 1. 确定肝淋巴系统在 AH 中的作用。 目标2.探索VEGF-C mRNA LNP（脂质纳米颗粒）技术治疗以下疾病的潜力 严重啊。 本研究将探讨一个重要但知之甚少的主题，即 ALD 中的肝淋巴管，解决 酒精对肝淋巴功能的影响及其对 AH 发展的影响。结果来自 上述两个目标将为许多未来的研究奠定基础，以加深我们对 淋巴系统在一般肝病和特别是 AH 中的作用，包括一项针对分子 酒精损害淋巴管的机制及VEGF-C mRNA-LNP的临床应用研究 用于治疗AH。