EphB/EphrinB signaling in Systemic Sclerosis

系统性硬化症中的 EphB/EphrinB 信号传导

基本信息

  • 批准号:
    10697360
  • 负责人:
  • 金额:
    $ 34.56万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-09-15 至 2025-07-31
  • 项目状态:
    未结题

项目摘要

Project Summary This proposal identifies the EphB2 receptor tyrosine kinase and its cognate EphrinB ligands as potential therapeutic targets to prevent vascular damage and fibrosis associated with systemic sclerosis (SSc, also known as scleroderma). A hallmark of SSc is the progressive and overwhelming deposition of extracellular matrix components, especially collagen, to cause the skin to become fibrotic and lose its elasticity. This process is thought to be driven by the recruitment of immune cells to sites of tissue damage, providing an inflammatory microenvironment to enhance fibroblast-to-myofibroblast transitions that in SSc patients leads to pathological expansion of pro-fibrotic cells and massive upregulated expression of collagen and other genes involved in fibrosis. As the biochemical pathways that control these events remain incompletely described, we focused our attention on potential membrane-associated molecules that may help interpret extracellular signals and aid the conversion of dermal fibroblasts into fibrogenic myofibroblasts, and identified the EphB2 receptor interacting with its EphrinB ligands as possible important components. Emerging data support the involvement of EphB-EphrinB in fibrosis of multiple organs, including our previous work, however little is known about the potential role of these highly conserved signaling molecules in the pathogenesis of SSc. Using human skin biopsies and mouse models of skin fibrosis, we will test the hypothesis that upon chronic, immune-mediated skin injury, EphB2 expression becomes strongly upregulated and the enhanced signaling pathways activated by this molecule are critical for the transdifferentiation of quiescent dermal fibroblasts into fibrogenic myofibroblasts to help bring about skin fibrosis. Our general idea is that when bound to EphrinB ligands expressed on various cells of the injured skin microenvironment (including endothelial cells), activated EphB2- expressing fibroblasts will initiate a differentiation process leading to their transformation into pro-fibrotic myofibroblasts. In support of this, preliminary data is provided that shows EphB2 expression is highly upregulated in human skin from SSc patients and in normal human dermal fibroblasts exposed to the pro- fibrotic inflammatory cytokine TGF-β1, and that skin fibrosis can be modulated by disrupting EphB2 either through genetic mutation or novel pharmacological approaches. The preliminary data has guided the formulation of three Specific Aims that will further test our ideas. Aim 1 will determine whether activation of EphB2 forward signalling is required for the progression of skin fibrogenesis. Aim 2 will test the hypothesis that EphB2-EphrinB interactions and signaling contributes to vascular damage and defective angiogenesis in SSc. Finally, Aim 3 will determine whether therapeutic targeting of these molecules will mitigate skin fibrosis. The proposed research is highly significant and innovative as it will reveal a key molecular mechanism that drives excessive fibrosis in SSc, and will also provide important early data on how novel small molecules that target EphB2-EphrinB interactions and signaling could be employed as future therapies to treat SSc.
项目摘要 这项建议将EphB2受体酪氨酸激酶及其同源EphinB配体确定为潜在的 预防系统性硬化症(SSC)相关血管损伤和纤维化的治疗目标 称为硬皮病)。SSC的一个特点是进行性和压倒性的细胞外沉积。 基质成分,尤其是胶原蛋白,使皮肤变得纤维化,失去弹性。这 这一过程被认为是由免疫细胞招募到组织损伤部位推动的,提供了一种 炎症微环境促进SSC患者成纤维细胞到肌成纤维细胞的转变 促纤维化细胞病理性扩张和胶原等基因表达大量上调 与纤维化有关。由于控制这些事件的生化途径仍未完全描述,我们 我们将注意力集中在潜在的膜相关分子上,这些分子可能有助于解释细胞外信号 帮助真皮成纤维细胞向成纤维细胞转化,并鉴定了EphB2受体 作为可能的重要成分与其EPhinB配体相互作用。新出现的数据支持这种参与 包括我们以前的工作在内,EphB-EPhinB在多个器官纤维化中的作用,然而,对EphB-EPhinB在多器官纤维化中的作用知之甚少 这些高度保守的信号分子在SSc发病机制中的潜在作用。使用人类皮肤 活检和小鼠皮肤纤维化模型,我们将检验这一假设,即在慢性、免疫介导的情况下 皮肤损伤,EphB2表达强烈上调,增强的信号通路被激活 是静止期真皮成纤维细胞转分化为纤维化的关键分子 肌成纤维细胞有助于导致皮肤纤维化。我们的总体想法是,当与EPhinB配体结合时 在受损皮肤微环境的各种细胞(包括内皮细胞)上表达活化的EphB2- 表达成纤维细胞将启动分化过程,导致其转化为促纤维化 肌成纤维细胞。为了支持这一点,提供了显示EphB2高表达的初步数据 在系统性红斑狼疮患者的皮肤和暴露于前两者的正常人皮肤成纤维细胞中表达上调。 纤维化炎症细胞因子转化生长因子-β-1,而且皮肤纤维化也可以通过干扰EphB2来调节 通过基因突变或新的药理方法。初步数据指引了 制定三个具体目标,这将进一步检验我们的想法。目标1将决定是否激活 EphB2正向信号在皮肤纤维化的进展过程中是必需的。目标2将检验这一假设 EphB2-EwitinB的相互作用和信号转导在SSC的血管损伤和血管生成缺陷中起作用。 最后,Aim 3将确定这些分子的治疗靶点是否会减轻皮肤纤维化。这个 拟议的研究具有非常重要的意义和创新性,因为它将揭示推动 SSC的过度纤维化,也将提供重要的早期数据,说明新的小分子是如何靶向的 EphB2-EPhinB的相互作用和信号转导可作为未来治疗SSC的方法。

项目成果

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Patrice Mimche其他文献

Patrice Mimche的其他文献

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{{ truncateString('Patrice Mimche', 18)}}的其他基金

EphB/EphrinB signaling in Systemic Sclerosis
系统性硬化症中的 EphB/EphrinB 信号传导
  • 批准号:
    10260572
  • 财政年份:
    2020
  • 资助金额:
    $ 34.56万
  • 项目类别:
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
  • 财政年份:
    2018
  • 资助金额:
    $ 34.56万
  • 项目类别:

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