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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：
10260572
负责人：
Patrice Mimche
金额：
$ 33.53万
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 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10260572
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 Pharmaceutical Preparations Pharmacologic Substance Pharmacology Phosphotransferases Play Process 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 extracellular fibrogenesis innovation mortality mouse model mutant novel novel therapeutic intervention 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.

项目总结