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：
Patrice Mimche
金额：
$ 34.56万
依托单位：
UNIVERSITY OF UTAH
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

来源：
https://reporter.nih.gov/project-details/10697360
关键词：
Agonist Animal Disease Models Attention Autoimmune Automobile Driving Binding Biochemical Pathway Biological Process Biology Biopsy Blood Vessels Cell membrane Cells Chronic Collagen Connective Tissue Diseases Cutaneous DNA Sequence Alteration Data Deposition Dermal Development Diffuse Disease Elasticity Embryonic Development Endothelial Cells Endothelium EphB2 Receptor Ephrins Event Exposure to Extracellular Matrix FDA approved Family Fibroblasts Fibrosis Formulation Functional disorder Future Genes Genetic Models Glycosylphosphatidylinositols Goals Human Immune Inflammation Inflammatory Injury Interleukin-1 beta Ligands Link Literature Mediating Medicine Membrane Membrane Potentials Mesenchymal Modeling Molecular Molecular Weight Morbidity - disease rate Mus Mutant Strains Mice Myofibroblast Organ Palliative Care Pathogenesis Pathologic Pathology Pathway interactions Patients Phosphotransferases Play Process Production Proliferating Receptor Protein-Tyrosine Kinases Research Role Scleroderma Signal Pathway Signal Transduction Signaling Molecule Site Skin Skin injury Symptoms Systemic Scleroderma Tail Testing Tissues Toll-like receptors Vascular Diseases Work angiogenesis cell injury cell motility chronic autoimmune disease combat cytokine drug-like compound extracellular fibrogenesis innovation mortality mouse model mutant novel novel therapeutic intervention pharmacologic prevent receptor recruit response skin fibrosis small molecule therapeutic target transdifferentiation wound healing

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.

项目概要该提案将 EphB2 受体酪氨酸激酶及其同源 EphrinB 配体确定为潜在的预防与系统性硬化症相关的血管损伤和纤维化的治疗目标（SSc，也 SSc 的一个标志是细胞外的进行性和压倒性沉积。基质成分，尤其是胶原蛋白，会导致皮肤纤维化并失去弹性。该过程被认为是由免疫细胞募集到组织损伤部位驱动的，从而提供了炎症微环境可增强 SSc 患者中成纤维细胞向肌成纤维细胞的转变促纤维化细胞病理性扩张以及胶原蛋白和其他基因表达大量上调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可能有助于解释细胞外信号的潜在膜相关分子上帮助真皮成纤维细胞转化为纤维化肌成纤维细胞，并鉴定出 EphB2 受体与其 EphrinB 配体相互作用作为可能的重要组成部分，新出现的数据支持这一参与。 EphB-EphrinB 在多个器官纤维化中的作用，包括我们之前的工作，但人们对它知之甚少使用人类皮肤研究这些高度保守的信号分子在 SSc 发病机制中的潜在作用。活组织检查和皮肤纤维化小鼠模型，我们将测试以下假设：慢性、免疫介导的皮肤损伤后，EphB2 表达强烈上调，增强的信号通路被激活该分子的作用对于静止真皮成纤维细胞转分化为纤维形成细胞至关重要我们的总体想法是，当肌成纤维细胞与 EphrinB 配体结合时，有助于引起皮肤纤维化。在受损皮肤微环境的各种细胞（包括内皮细胞）上表达，激活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细胞为了支持这一点，提供的初步数据显示 EphB2 表达高度。在 SSc 患者的人类皮肤和暴露于亲的正常人真皮成纤维细胞中上调纤维化炎症细胞因子 TGF-β1，并且可以通过破坏 EphB2 来调节皮肤纤维化通过基因突变或新的药理学方法。制定三个具体目标将进一步测试我们的想法，目标 1 将确定是否激活。 EphB2 正向信号传导是皮肤纤维发生进展所必需的，目标 2 将检验以下假设： EphB2-EphrinB 相互作用和信号传导导致 SSc 中的血管损伤和血管生成缺陷。最后，目标 3 将确定这些分子的治疗靶向是否会减轻皮肤纤维化。拟议的研究具有非常重要的意义和创新性，因为它将揭示驱动的关键分子机制 SSc 中的过度纤维化，还将提供重要的早期数据，说明新型小分子如何靶向 EphB2-EphrinB 相互作用和信号传导可作为未来治疗 SSc 的疗法。