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.

本应用中提出的工作确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）及其胚胎配体，可以针对或逆转 肝纤维发生的进展。尽管研究了分子机制方面的研究进展 推动肝纤维发生的进展，FDA批准的治疗仍然受到严重限制，或者在某些方面受到严格限制 限制去除病因的病例。肝纤维化的一个特征是多余的沉积 激活的肝星细胞（HSC）的细胞外基质成分是由炎症驱动的过程 并在损伤部位募集免疫细胞。这些免疫细胞提供 炎症/纤维化微环境对于静态HSC转差至纤维化至关重要 肌纤维细胞。 肝纤维化的分子基础尚不完全理解。连接细胞结合EPH受体与 膜螺旋线晶状体配体启动双向信号传导级联对潜水员生物学的影响 与纤维发生有关的过程，包括细胞重塑，血管生成，迁移/增殖和 上皮到间质转换（EMT）。该项目的长期目标是开发基于治疗的 靶向受体酪氨酸激酶（RTK）EPHB2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脏中， Ephb2/Ephrin-B信号传导对于将静态HSC转分解为纤维纤维的至关重要 纤维发生过程中的肌纤维细胞。在此提案中检验的中心假设是慢性 肝损伤，HSC上调EPHB2，当与在Ephrin-B配体上结合时， 肝微环境，激活EPHB2表达HSC的HSC启动了一个分化过程，导致其 转化为纤维化肌纤维细胞。该假设已从我们的初步数据中提出 表明在小鼠的纤维化生活和人肝肝硬化中，EPHB2都高度更新。 HSC Express EPHB2及其在小鼠中的缺乏会减弱感染和非感染的肝纤维化 型号。在强大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： AIM 1：证明肝脏需要通过EPHB2的细胞质结构域发出信号 纤维发生。 AIM 2：证明TGF-β1调节HSC上的Ephb2/Ephrin-BS表达。 AIM 3：确定靶向EPHB2是否会减轻肝纤维发生。 据我们所知，这项高度创新和新颖的探索性工作是第一个研究 非致病原驱动肝纤维发生中EPH受体的成员。拟议的研究很重要 因为它具有很大的翻译潜力，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。该项目将是我自己独立实验室的最初重点。