EphB2 receptor tyrosine kinase in liver fibrosis

本申请中提出的工作鉴定了一个新的分子家族，Eph受体（促红细胞生成素 产生肝细胞的）及其肝配蛋白配体，其可以被靶向以预防或逆转肝细胞癌。 肝纤维化的进展。尽管在理解分子机制方面取得了研究进展， 虽然FDA批准的治疗方法推动了肝纤维化的进展，但仍然受到严重限制，或者在某些情况下， 仅限于清除病原体的病例。肝纤维化的一个特征是肝纤维化的过度沉积。 细胞外基质成分由激活的肝星状细胞（HSC），炎症驱动的过程 以及在损伤部位募集免疫细胞。这些免疫细胞提供了 炎性/纤维化微环境对于静止HSC转分化为纤维化细胞至关重要 肌成纤维细胞 肝纤维化的分子基础还不完全清楚。将细胞结合的Eph受体连接至 膜栓系肝配蛋白配体启动影响多种生物学特性的双向信号级联 与纤维发生相关的过程，包括细胞重塑、血管生成、迁移/增殖和 上皮-间充质转化（EMT）。该项目的长期目标是开发一种基于 针对受体酪氨酸激酶（RTK）EphB 2治疗肝纤维化/肝硬化。使用 肝纤维化的小鼠模型该探索性项目的目的是证明在肝中， EphB 2/ ephrin-B信号转导对静止HSC转分化为纤维化细胞至关重要 肌成纤维细胞在纤维形成过程中。本提案中检验的中心假设是， 肝损伤后，HSC上调EphB 2，并且当与肝细胞的各种细胞上表达的Ephrin-B配体结合时， 在肝脏微环境中，活化的表达EphB 2的HSC启动分化过程，导致它们的分化。 转化成纤维原性肌成纤维细胞。这一假设是根据我们的初步数据提出的 显示EphB 2在小鼠的纤维化肝脏和人肝硬化中高度上调。HSCs 表达EphB 2及其缺乏在小鼠中减弱感染性和非感染性肝纤维化 模型在强有力的初步数据的指导下，将通过追求3个具体目标来检验中心假设： 目的1：证明通过EphB 2的胞质结构域的信号传导是肝脏所需的。 纤维化 目的2：探讨TGF-β1对HSC EphB 2/Ephrin-Bs表达的调控作用。 目的3：确定靶向EphB 2的治疗是否会减轻肝纤维化。 据我们所知，这一高度创新和新颖的探索性工作是第一次调查的作用， 非病原体驱动的肝纤维化中Eph受体的成员。所提出的研究是有意义的 因为它具有巨大的翻译潜力，为未来的临床提供新的治疗靶点（EphB 2）， 抗肝纤维化/肝硬化的研究。这个项目将是我自己的独立实验室的最初重点。

The work proposed in this application identifies a novel family of molecules, the Eph receptors (Erythropoietin producing hepatocellular) and their Ephrin ligands, that could be targeted to prevent or reverse the progression of liver fibrogenesis. Despite research progress made in understanding the molecular mechanisms driving the progression of hepatic fibrogenesis, FDA-approved treatments are still severely limited or in some cases restricted to the removal of the etiologic agent. A feature of liver fibrosis is the excessive deposition of extracellular matrix components by activated hepatic stellate cells (HSCs) a process driven by inflammation and recruitment of immune cells at the site of injury. These immune cells provide the pro- inflammatory/fibrogenic microenvironment critical for the transdifferentiation of quiescent HSCs into fibrogenic myofibroblasts. The molecular basis of liver fibrosis is incompletely understood. Ligation of cell–bound Eph receptors to membrane-tethered ephrin ligands initiates a bi-directional signaling cascade affecting diverse biological processes relevant to fibrogenesis including cellular remodelling, angiogenesis, migration/proliferation and epithelial-to-mesenchymal-transition (EMT). The long-term goal of this project is to develop a therapy based on targeting the receptor tyrosine kinase (RTK) EphB2 for the treatment of liver fibrosis/cirrhosis. Using mouse models of liver fibrosis the objective of this exploratory project is to demonstrate that in the liver, EphB2/ ephrin-B signaling is critical for the transdifferentiation of quiescent HSCs into fibrogenic myofibroblasts during fibrogenesis. The central hypothesis being tested in this proposal is that upon chronic liver injury, HSCs upregulate EphB2 and when bound to Ephrin-B ligands expressed on various cells of the liver microenvironment, activated EphB2-expressing HSCs initiate a differentiation process leading to their transformation into fibrogenic myofibroblasts. This hypothesis has been formulated from our preliminary data showing that EphB2 is highly upregulated in both the fibrotic livers of mice and in human liver cirrhosis. HSCs express EphB2 and its deficiency in mice attenuates liver fibrosis in both infectious and non-infectious models. Guided by strong preliminary data the central hypothesis will be tested by pursuing 3 specific aims: Aim 1: Demonstrate that signaling via the cytoplasmic domain of EphB2 is required for liver fibrogenesis. Aim 2: Demonstrate that TGF-β1 regulates EphB2/Ephrin-Bs expression on HSCs. Aim 3: Determine whether therapeutic targeting EphB2 will mitigate liver fibrogenesis. To our knowledge this highly innovative and novel exploratory work is the first to investigate the role of a member of the Eph receptors in non-pathogen driven liver fibrogenesis. The proposed research is significant because it has great translational potential to provide a new therapeutic target (EphB2) for future clinical studies against liver fibrosis/cirrhosis. This project will be the initial focus of my own independent laboratory.