MerTK in NASH-related liver fibrosis

MerTK 在 NASH 相关肝纤维化中的作用

• 批准号: 10201897
• 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/10201897
• 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; 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 therapeutics; prevent; receptor; 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.

项目摘要/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肝衰竭最重要的预测指标。缺乏确定的机制 NASH进展，尤其是纤维化限制了基于机制的治疗靶标的设计和 治疗选择。几个独立的人类GWASS已将MERTK确定为肝纤维化的危险因素。 但是，尚不完全了解MERTK介导的肝纤维化的机制。总体 该建议的目的是了解MERTK诱导的NASH纤维化的机制，并为 防止NASH进展的新型热策略。使用富含果糖，棕榈酸和 我的小组开发的胆固醇（FPC）在小鼠中促进类似人类的nash病理特征，我发现 MERTK的遗传靶向降低了NASH纤维化，MERTK介导的ERK激活增加了 TGFβ1在巨噬细胞（MS）中的表达，并且MERTK激活增加了Akt活性和 肝星状细胞（HSC）中的胶原蛋白基因表达。而且，我做出了一个重要发现， Mertk细胞表面裂解在纤维化寿命中降低。确实，我发现全反式视黄酸（ATRA），a 在健康肝脏中发现的视黄醇的主要活性代谢产物，诱导了MS和HSC的MERTK裂解。 根据我的建议，ATRA诱导的MERTK裂解可防止NASH纤维化，但这种乳沟是 由于类维生素的损失，在纤维化肝脏中受到阻碍，导致NASH的进展。我建议3的目的 研究MERTK诱导的NASH纤维化的机制。 AIM1将探讨METK中MERTK的假设 有助于NASH纤维化。 mertkfl/fllysmcre +/-和喂食FPC饮食的同窝控制小鼠将用于 研究MMERTK在NASH纤维化中的作用。我将确定MMERTK诱导的NASH纤维化是否为 通过ERK1/2-AP1-TGFβ1途径。 AIM2将研究HSC中MERTK的假设 有助于NASH纤维化。 Mertkfl/fllratcre +/-喂食FPC饮食将用于研究HSC的作用 NASH纤维化中的MERTK。我将确定HSC MERTK诱导的NASH纤维化是否通过激活 pi3k/akt。 AIM 3将探讨抑制MERTK裂解的假设可促进NASH纤维化。我会 确定纤维化阶段与肝脏ATRA和MERTK裂解的关联，并确定是否是否 ATRA诱导的MERTK裂解是通过激活P38和MERTK裂解酶，体内ADAM17。 这项研究将在旨在的全面职业发展计划的环境中完成 为我提供实现我作为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，细胞和生化的专业知识 研究哥伦比亚大学NASH纤维化的方法。成立科学家的咨询委员会 NAFLD/NASH，肝纤维化，HSC激活和转化科学的领域将指导我 在整个奖项期间成功过渡到科学独立性。