Mechanisms underlying hepatic immune cell recruitment in nonalcoholic fatty liver disease

非酒精性脂肪肝中肝脏免疫细胞募集的机制

• 批准号: 10210758
• 负责人: Reben Raeman
• 金额: $ 41.69万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10210758
• 关键词: Acetates; Address; Attenuated; Automobile Driving; Biological Availability; Butyrates; CD4 Positive T Lymphocytes; Cells; Chronic; Cirrhosis; Data; Development; Diet; Dietary Supplementation; Disease Progression; Event; FDA approved; Face; Fatty Liver; Fibrosis; Fructose; Genetic; Glucose; Hepatic; Hepatic Stellate Cell; Histologic; Human; Immune; Immune Targeting; Impairment; In Vitro; Incidence; Infiltration; Inflammation; Inflammatory; Integrins; Investigation; Lead; Ligands; Liver; Mediating; Metabolic; Modeling; Molecular; Monoclonal Antibodies; Mus; Pathogenesis; Pathway interactions; Patients; Play; Primary carcinoma of the liver cells; Propionates; Publishing; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; Testing; Therapeutic; Tissues; United States; Volatile Fatty Acids; base; chemokine; clinically relevant; confocal imaging; cytokine; feeding; hepatocyte injury; immunoregulation; improved; indexing; innovation; insight; interest; intestinal epithelium; intrahepatic; liver transplantation; microbial; monocyte; monomer; mouse model; mucosal addressin cell adhesion molecule-1; non-alcoholic fatty liver; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; receptor; recruit; targeted treatment; therapeutic target; therapeutically effective; western diet

PROJECT SUMMARY/ABSTRACT Nonalcoholic fatty liver disease (NAFLD) is a spectrum of progressive conditions ranging from nonalcoholic fatty liver (NAFL) or hepatic steatosis to the more severe nonalcoholic steatohepatitis (NASH) characterized by excessive inflammation and varying degrees of fibrosis. NASH-related cirrhosis is the second leading cause of liver transplantation in the United States and NASH patients face an increased risk of developing hepatocellular carcinoma. The incidence of NASH and NASH-related cirrhosis continues to rise; there, are no FDA-approved therapies as we lack a clear understanding of the cellular and molecular mechanisms driving the progression of NAFL to NASH and the subsequent development of cirrhosis. While there is mounting evidence that inflammation is central to the initiation and progression of NAFLD, the specific immune pathways that drive inflammation in this setting are not well understood. The objective of this proposal is to improve our functional understanding of the mechanisms by which immune cells contribute to NASH-related hepatic inflammation, and to identify the key molecules underlying recruitment of immune cells to the liver. Our published findings and preliminary data have demonstrated that the heterodimeric integrin receptor α4β7 and its ligand, mucosal addressin cell adhesion molecule-1 (MAdCAM-1), play a pivotal role in NASH-related hepatic inflammation and fibrosis by promoting the recruitment of inflammatory monocytes and CD4 T cells to the liver. These data provide the scientific rationale for our central hypothesis that the α4β7/MAdCAM-1 axis drives hepatic inflammation and fibrosis in NASH by promoting recruitment of proinflammatory monocytes and CD4 T cells to the liver. We will test this hypothesis in both a mouse model of progressive NAFLD and in human liver tissue from NASH patients according to the following integrated Specific Aims. Aim 1 will investigate the contribution of α4β7+ monocytes and CD4 T cells in promoting hepatic inflammation in NASH. Aim 2 focuses on the role of hepatic stellate cells in the regulation of immune cell recruitment to the NASH liver. Lastly, Aim 3 investigates the mechanisms regulating the α4β7/MAdCAM-1 axis in NASH. The results of our investigations will provide comprehensive and mechanistic insights into the inflammatory events crucial to the pathogenesis of NASH, and may lead to the identification of viable therapeutic targets for regulating hepatic inflammation. Given the importance of immune cells in governing metabolic inflammation and the therapeutic potential of targeting immune cells, this proposal addresses significant and clinically relevant issues in NASH.

项目摘要/摘要 非酒精性脂肪肝疾病（NAFLD）是一系列进行性疾病，范围从非酒精脂肪 肝（NAFL）或肝脂肪变性，以更严重的非酒精性脂肪性肝炎（NASH）为特征 炎症过多和纤维化程度不同。纳什相关的肝硬化是 美国和NASH患者的肝移植面临发展肝细胞的风险增加 癌。纳什和纳什相关的肝硬化的事件继续增加。那里没有FDA批准 疗法由于我们对驱动驱动进展的细胞和分子机制缺乏清晰的了解 NAFL到NASH以及随后的肝硬化发展。虽然有越来越多的证据表明炎症 是NAFLD的主动性和进展的中心 这种设置不太了解。该建议的目的是提高我们对 免疫细胞有助于NASH相关的肝注射的机制，并识别钥匙 免疫细胞向肝脏募集的分子。我们已发表的发现和初步数据 证明异二聚体整合素受体α4β7及其配体粘膜地址蛋白细胞粘合剂 分子1（MADCAM-1），通过促进NASH相关的肝注射和纤维化起关键作用 将炎症单核细胞和CD4 T细胞募集到肝脏。这些数据提供了科学原理 为了我们的中心假设，即α4β7/madCAM-1轴驱动NASH的肝炎注射和纤维化。 促进促炎单核细胞和CD4 T细胞募集到肝脏。我们将在 根据纳什患者的进行性NAFLD的小鼠模型和人类肝组织的模型 遵循集成的特定目标。 AIM 1将研究α4β7+单核细胞和CD4 T细胞在 促进纳什的肝发炎。 AIM 2侧重于肝星状细胞在调节中的作用 免疫细胞募集到NASH肝脏。最后，AIM 3调查了调节的机制 NASH中的α4β7/MADCAM-1轴。我们的调查结果将提供全面和机械的 对炎症事件的洞察力对NASH的发病机理至关重要，并可能导致鉴定 可行的治疗靶标，用于确定肝脏注射。鉴于免疫细胞在管理中的重要性 代谢炎症和靶向免疫细胞的治疗潜力，该建议解决 纳什（Nash）中的重大且与临床相关的问题。