MerTK in NASH-related liver fibrosis

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患者肝功能衰竭最重要的预测因素。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和 治疗方案。几个独立的人类GWASs已经确定MERTK是肝纤维化的危险因素。 然而，MerTK介导的肝纤维化的机制还不完全清楚。整体而言 本方案的目的是了解MerTK诱导的NASH纤维化的机制，并为 防止NASH进展的新治疗策略。使用富含果糖、棕榈酸和 我发现，我们团队开发的胆固醇(FPC)可以促进小鼠的类人Nash病理特征 MerTK基因靶向减少NASH纤维化及MerTK介导的ERK激活增加 转化生长因子β1在巨噬细胞(MS)中的表达 肝星状细胞(HSCs)中胶原基因的表达此外，我有一个重要的发现， 肝纤维化时MerTK细胞表面裂解减少。事实上，我发现全反式维甲酸(ATRA)，一种 在健康肝脏中发现的视黄醇的主要活性代谢物，在MS和HSCs中都能诱导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 在纤维化的肝脏中由于维甲酸的丢失而受阻，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。AIM1将探索MS的MerTK假说 会导致纳什纤维化。Mertkfl/flLysmCre/-和饲喂FPC饲料的产仔对照组小鼠将被用来 探讨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 通过ERK1/2-AP1-转化生长因子β-1途径。AIM2将研究HSCs中MerTK的假说 会导致纳什纤维化。Mertkfl/flLratCre/-饲喂FPC饮食的小鼠将被用来研究HSC的作用 MerTK在Nash纤维化中的作用我将确定HSC MerTK诱导的NASH纤维化是否通过激活 PI3K/AKT。目的3将探讨抑制MerTK裂解促进NASH纤维化的假设。这就做 确定肝纤维化分期与肝脏ATRA和MerTK裂解的关系，并确定 全反式维甲酸在体内通过激活P38和MerTK裂解酶ADAM17来诱导MerTK的切割。 这项研究将在一个综合职业发展计划的背景下完成，该计划旨在 为我提供所需的技能，以实现我作为肝脏领域独立科学家的职业目标 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。一个由资深科学家组成的咨询委员会 NAFLD/NASH、肝纤维化、HSC激活和翻译科学领域将指导我完成这些步骤 在获奖期内向科学独立的成功过渡。

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.