EphB2 receptor tyrosine kinase in liver fibrosis

EphB2受体酪氨酸激酶在肝纤维化中的作用

• 批准号: 9766288
• 负责人: Patrice Mimche
• 金额: $ 19.06万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-17 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9766288
• 关键词: Affect; Attenuated; Autoimmune Diseases; Automobile Driving; Biological Process; Cells; Cholestasis; Cicatrix; Cirrhosis; Clinical Research; Cytoplasmic Tail; Data; Deposition; Docking; Eph Family Receptors; EphB2 Receptor; Ephrin B Receptor; Ephrins; Erythropoietin; Etiology; Event; Excision; Extracellular Matrix; FDA approved; Family; Fibrosis; Future; Goals; Hepatic Fibrogenesis; Hepatic Stellate Cell; Hepatocyte; Hepatology; Human; Immune; Inflammation; Inflammatory; Injury; Knowledge; Laboratories; LacZ Genes; Ligands; Ligation; Liver; Liver Cirrhosis; Liver Fibrosis; Malaria; Mediating; Membrane; Metabolic Diseases; Mission; Modeling; Molecular; Morbidity - disease rate; Mus; Myofibroblast; Organ; Organ failure; Parasitic Diseases; Pathology; Pathway interactions; Peptides; Pharmacology; Phosphotransferases; Process; Receptor Protein-Tyrosine Kinases; Recombinants; Research; Role; Signal Transduction; Signaling Molecule; Site; System; Testing; Therapeutic Uses; Tissues; Transforming Growth Factor beta; United States National Institutes of Health; Virus Diseases; Work; Wound Healing; angiogenesis; base; chronic liver injury; cytokine; disability; epithelial to mesenchymal transition; fibrogenesis; hepatocellular carcinoma cell line; human disease; inflammatory milieu; innovation; macrophage; malaria infection; member; migration; mortality; mouse model; new therapeutic target; novel; prevent; receptor; recruit; therapeutic target; trafficking; transdifferentiation

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.

本申请中提出的工作鉴定了一个新的分子家族，即 Eph 受体（促红细胞生成素 产生肝细胞）及其 Ephrin 配体，可以有针对性地预防或逆转 尽管在了解其分子机制方面取得了进展。 尽管导致肝纤维化进展，但 FDA 批准的治疗方法仍然受到严重限制，或者在某些情况下 仅限于去除病因的病例，肝纤维化的一个特征是肝纤维化的过度沉积。 激活的肝星状细胞 (HSC) 产生的细胞外基质成分是炎症驱动的过程 以及在损伤部位募集免疫细胞。这些免疫细胞提供了亲和力。 炎症/纤维化微环境对于静止 HSC 转分化为纤维化至关重要 肌成纤维细胞。 细胞结合 Eph 受体与肝纤维化的分子基础尚不完全清楚。 膜束缚的肝配蛋白配体启动影响多种生物的双向信号级联 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 该项目的长期目标是开发一种基于上皮间质转化（EMT）的疗法。 靶向受体酪氨酸激酶 (RTK) EphB2 治疗肝纤维化/肝硬化。 肝纤维化小鼠模型这个探索性项目的目的是证明在肝脏中， EphB2/ ephrin-B 信号传导对于静止 HSC 转分化为纤维化细胞至关重要 该提案中测试的中心假设是慢性肌纤维母细胞。 肝损伤后，HSC 上调 EphB2，并且当与肝配蛋白 B 配体结合时，该配体表达于肝损伤的各种细胞上。 在肝脏微环境中，激活的表达 EphB2 的 HSC 启动分化过程，导致其 这一假设是根据我们的初步数据提出的。 显示 EphB2 在小鼠纤维化肝脏和人类肝硬化中均高度上调。 表达 EphB2 及其在小鼠体内的缺乏可减轻感染性和非感染性肝纤维化 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： 目标 1：证明肝脏需要通过 EphB2 细胞质结构域进行信号传导 纤维发生。 目标 2：证明 TGF-β1 调节 HSC 上的 EphB2/Ephrin-Bs 表达。 目标 3：确定针对 EphB2 的治疗是否会减轻肝纤维化。 据我们所知，这项高度创新和新颖的探索性工作是第一个调查 Eph受体在非病原体驱动的肝纤维化中的成员所提出的研究具有重要意义。 因为它具有巨大的转化潜力，可以为未来的临床提供新的治疗靶点（EphB2） 针对肝纤维化/肝硬化的研究将是我自己的独立实验室的最初重点。