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.

项目总结/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，特别是纤维化限制了基于机制的治疗靶点的设计， 治疗方案。几个独立的人类GWAS已将MERTK确定为肝纤维化的风险因素。 然而，MerTK介导的肝纤维化的机制尚未完全了解。整体 该提案的目的是了解MerTK诱导的NASH纤维化的机制， 预防NASH进展的新治疗策略。使用富含果糖、棕榈酸和 我发现，我们小组开发的一种胆固醇（FPC）促进了小鼠的类人NASH病理特征， MerTK的基因靶向作用可降低NASH纤维化，MerTK介导的ERK活化可增加NASH纤维化的发生率， TGFβ1在巨噬细胞（M β 1）中的表达，MerTK激活增加AKT活性， 胶原基因在肝星状细胞（HSC）中的表达。此外，我有一个重要的发现， MerTK细胞表面裂解在纤维化肝脏中减少。事实上，我发现全反式维甲酸（ATRA）， 在健康肝脏中发现的视黄醇的主要活性代谢物，在MLS和HSC中诱导MerTK裂解。 因此，我认为ATRA诱导的MerTK裂解可以保护NASH纤维化，但这种裂解是不可能的。 由于类维生素A的损失，在纤维化肝脏中受到阻碍，导致NASH的进展。我提出三个目标， 研究MerTK诱导NASH纤维化的机制。Aim 1将探讨M细胞中MerTK 导致NASH纤维化。Mertkfl/flLysmCre+/-和同窝对照小鼠饲喂FPC饮食将用于 研究M β MerTK在NASH纤维化中的作用。我将确定是否MDMerTK诱导的NASH纤维化， 通过ERK 1/2-AP 1-TGFβ1通路。Aim 2将研究HSC中MerTK 导致NASH纤维化。用FPC饮食喂养的Mertkfl/flLratCre+/-小鼠将用于研究HSC的作用。 NASH纤维化中的MerTK。我将确定HSC MerTK诱导的NASH纤维化是否是通过激活 PI3K/AKT。目的3将探索抑制MerTK切割促进NASH纤维化的假设。我会 确定纤维化分期与肝ATRA和MerTK裂解的相关性，并确定是否 ATRA诱导的MerTK切割是通过在体内激活P38和MerTK切割酶ADAM 17。 这项研究将在一个全面的职业发展计划的背景下完成， 为我提供实现我作为肝脏领域独立科学家的职业目标所需的技能 疾病在K99阶段，我将继续获得分子，细胞和生物化学方面的专业知识 在哥伦比亚大学研究NASH纤维化。一个由知名科学家组成的咨询委员会， NAFLD/NASH、肝纤维化、HSC活化和转化科学领域将指导我进行以下步骤 在获奖期间成功过渡到科学独立。