MerTK in NASH-related liver fibrosis

MerTK 在 NASH 相关肝纤维化中的作用

• 批准号: 10216245
• 负责人: Bishuang Cai
• 金额: $ 24.9万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-16 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10216245
• 关键词: Advisory Committees; Affect; All-Trans-Retinol; Award; Biochemical; Biological Assay; Cell Proliferation; Cell Survival; Cell surface; Cholesterol; Chronic Disease; Cicatrix; Cirrhosis; Cleaved cell; Clinical; Collagen; Collagen Gene; Data; Deposition; Development; Diet; Disintegrins; Enzymes; FDA approved; Fibrosis; Fructose; Gene Expression; Genetic; Genetic Polymorphism; Genetic Transcription; Goals; Hepatic; Hepatic Stellate Cell; High Prevalence; Human; Impairment; Inflammation; Injury; Insulin Resistance; Ligands; Light; Liver; Liver Failure; Liver Fibrosis; Liver diseases; MAPK3 gene; MERTK gene; Measures; Mediating; Metalloproteases; Modeling; Molecular; Mus; PI3K/AKT; Palmitic Acids; Pathologic; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Primary carcinoma of the liver cells; Process; Program Development; Proteins; Proto-Oncogene Proteins c-akt; Research; Resolution; Retinoids; Risk; Risk Factors; Role; Scientist; Serum; Signal Transduction; Therapeutic; Transcription Factor AP-1; Translational Research; Tretinoin; Universities; Weight Gain; base; career; career development; cell type; chronic liver disease; design; dietary; genome wide association study; in vivo; liver function; liver injury; loss of function; macrophage; migration; mouse model; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel therapeutic intervention; prevent; receptor; repair function; skills; therapeutic target; tissue repair

Project Summary/Abstract Nonalcoholic steatohepatitis (NASH) has emerged as the leading cause of chronic liver disease worldwide, with liver fibrosis being the most important predictor of liver failure in NASH. The lack of definitive mechanisms of NASH progression, particularly fibrosis limits the design of mechanism-based therapeutic targets and treatment options. Several independent human GWASs have identified MERTK as a risk factor for liver fibrosis. However, the mechanisms of MerTK-mediated liver fibrosis are not completely understood. The overall objective of this proposal is to understand mechanisms of MerTK-induced NASH fibrosis and shed new light on novel therapeutic strategies to prevent NASH progression. Using a diet rich in fructose, palmitic acid, and cholesterol (FPC) developed by our group that promotes human-like NASH pathologic features in mice, I found that genetic targeting of MerTK decreases NASH fibrosis and that MerTK-mediated ERK activation increases the expression of TGFβ1 in macrophages (Ms), and that MerTK activation increases AKT activity and collagen gene expression in hepatic stellate cells (HSCs). Moreover, I made an important discovery that MerTK cell-surface cleavage is decreased in fibrotic livers. Indeed, I found that all-trans retinoic acid (ATRA), a major active metabolite of retinol found in healthy liver, induces MerTK cleavage in both Ms and HSCs. Accordingly, I propose that ATRA-induced MerTK cleavage protects against NASH fibrosis but this cleavage is hampered in fibrotic liver due to the loss of retinoids, leading to the progression of NASH. I propose 3 aims to study the mechanisms of MerTK-induced NASH fibrosis. Aim1 will explore the hypothesis that MerTK in Ms contributes to NASH fibrosis. Mertkfl/flLysmCre+/- and the littermate control mice fed the FPC diet will be used to study the role of M MerTK in NASH fibrosis. I will determine whether M MerTK-induced NASH fibrosis is through the ERK1/2-AP1-TGFβ1 pathway. Aim2 will investigate the hypothesis that MerTK in HSCs contributes to NASH fibrosis. Mertkfl/flLratCre+/- mice fed the FPC diet will be used to study the role of HSC MerTK in NASH fibrosis. I will determine whether HSC MerTK-induced NASH fibrosis is through activating PI3K/AKT. Aim 3 will explore the hypothesis that suppressing MerTK cleavage promotes NASH fibrosis. I will determine the association of fibrosis stages with hepatic ATRA and MerTK cleavage and determine whether ATRA-induced MerTK cleavage is through activating P38 and the MerTK cleaving enzyme, ADAM17 in vivo. This research will be accomplished in the setting of a comprehensive career development program designed to provide me with the skills needed to achieve my career goal as an independent scientist in the field of liver diseases. During the K99 phase, I will continue to gain expertise in molecular, cellular and biochemical approaches to study NASH fibrosis at Columbia University. An advisory committee of established scientists in the fields of NAFLD/NASH, liver fibrosis, HSC activation, and translational science will guide me in the steps towards successful transition to scientific independence over the course of the award period.

项目概要/摘要 非酒精性脂肪性肝炎（NASH）已成为全球慢性肝病的主要原因， 肝纤维化是 NASH 肝衰竭的最重要预测因素。缺乏明确的机制 NASH 进展的进展，特别是纤维化限制了基于机制的治疗靶点的设计和 治疗方案。几个独立的人类 GWAS 已将 MERTK 确定为肝纤维化的危险因素。 然而，MerTK介导的肝纤维化的机制尚不完全清楚。整体 该提案的目的是了解 MerTK 诱导的 NASH 纤维化的机制，并为研究提供新的线索 预防 NASH 进展的新治疗策略。使用富含果糖、棕榈酸和 我发现我们小组开发的胆固醇（FPC）可促进小鼠出现类似人类的 NASH 病理特征 MerTK 的基因靶向可减少 NASH 纤维化，并且 MerTK 介导的 ERK 激活会增加 巨噬细胞 (Mfs) 中 TGFβ1 的表达，以及 MerTK 激活会增加 AKT 活性 肝星状细胞（HSC）中胶原蛋白基因的表达。此外，我还有一个重要的发现： 纤维化肝脏中 MerTK 细胞表面裂解减少。事实上，我发现全反式视黄酸（ATRA）是一种 健康肝脏中发现的视黄醇的主要活性代谢物，可诱导 Ms 和 HSC 中的 MerTK 裂解。 因此，我认为 ATRA 诱导的 MerTK 裂解可以预防 NASH 纤维化，但这种裂解是 由于类视黄醇的丢失，肝脏纤维化受到阻碍，导致 NASH 的进展。我提出3个目标 研究MerTK诱导的NASH纤维化的机制。 Aim1 将探讨 Ms 中 MerTK 的假设 导致 NASH 纤维化。 Mertkfl/flLysmCre+/- 和饲喂 FPC 饮食的同窝对照小鼠将用于 研究 M MerTK 在 NASH 纤维化中的作用。我将确定 M MerTK 诱导的 NASH 纤维化是否是 通过 ERK1/2-AP1-TGFβ1 途径。 Aim2 将研究 HSC 中 MerTK 的假设 导致 NASH 纤维化。使用 FPC 饮食喂养的 Mertkfl/flLratCre+/- 小鼠将用于研究 HSC 的作用 MerTK 在 NASH 纤维化中的作用。我将确定 HSC MerTK 诱导的 NASH 纤维化是否是通过激活 PI3K/AKT。目标 3 将探讨抑制 MerTK 裂解促进 NASH 纤维化的假设。我会 确定纤维化阶段与肝 ATRA 和 MerTK 裂解的关联，并确定是否 ATRA 诱导的 MerTK 裂解是通过体内激活 P38 和 MerTK 裂解酶 ADAM17 来实现的。 这项研究将在一个全面的职业发展计划的背景下完成，该计划旨在 为我提供实现肝脏领域独立科学家职业目标所需的技能 疾病。在K99阶段，我将继续获得分子、细胞和生化方面的专业知识 哥伦比亚大学研究 NASH 纤维化的方法。由知名科学家组成的咨询委员会 NAFLD/NASH、肝纤维化、HSC 激活和转化科学领域将指导我的步骤 在颁奖期间成功过渡到科学独立。