Inhibition of VEGF receptor dimerization and signaling in corneal lymphangiogenes

角膜淋巴管生成中 VEGF 受体二聚化和信号传导的抑制

基本信息

批准号：
8309043
负责人：
JIN-HONG CHANG
金额：
$ 19.94万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8309043
关键词：
Affect Alkalies Binding Biosensor Blindness Burn injury Cell Proliferation Cells Cornea Corneal Diseases Corneal Injury Data Development Dimerization Disease Dose Down-Regulation Endostatins Equilibrium Event Fibroblast Growth Factor 2 Fluorescence Resonance Energy Transfer Goals Heterodimerization Homodimerization Human In Vitro Infection Investigation Lung Lymphangiogenesis Lymphatic Lymphatic Endothelial Cells Lymphatic System Lymphatic vessel Measures Methods Molecular Pathologic Pathology Peptides Phosphorylation Phosphotransferases Physiological Play Process Production Regulation Role Signal Transduction Testing Vascular Endothelial Growth Factor C Vascular Endothelial Growth Factor Receptor Vascular Endothelial Growth Factor Receptor-2 Vascular Endothelial Growth Factor Receptor-3 Vascular Endothelial Growth Factors Wound Infection angiogenesis base conjunctiva corneal epithelium design in vivo inhibitor/antagonist novel novel therapeutic intervention ocular surface receptor research study response

项目摘要

ABSTRACT: Corneal lymphangiogenesis follows severe corneal injuries and infections and is one of the major causes of blindness. Under normal physiological conditions, the cornea is alymphatic and surrounded by lymphatic vessels residing in the conjunctiva while corneal lymphangiogenic privilege is maintained. However, wounding and infection induce corneal lymphangiogenesis. The extrinsic factors that regulate corneal lymphangiogenic privilege include: 1) the presence of angiogenic and lymphangiogenic factors (VEGF-A, -C and -D); 2) expression of sVEGFR-2 in the cornea; 3) expression of VEGFR-3 in corneal epithelium and other anti-lymphangiogenic factors in the cornea. The status of corneal lymphangiogenesis is controlled by the balance of pro- and anti- lymphatic factors. The current hypothesis of corneal lymphangiogenic privilege is governed by extrinsic factors unique to the cornea. Besides the well-documented extrinsic factors involved in regulating corneal lymphangiogenic privilege, changes in the VEGFR-2 may regulate VEGFR3-activation in lymphatic cells also regulate corneal lymphangiogenesis. Our preliminary data demonstrated corneal lymphangiogenesis in diseased human corneas, which correlated with enhanced VEGFR-3 expression in alkali-burn-wounded corneas. In addition, endostatin-containing fragments bind to VEGFR-3 in vitro and have better inhibition of bFGF-induced corneal lymphangiogenesis than angiogenesis. VEGF- C-induced VEGFR-3 dimerization and low dose VEGF-C has better potency in promoting lymphatic cell proliferation. Our long-term objective is to identify the mechanisms that regulate corneal lymphangiogenesis. The proposed experiments are designed to determine the role of VEGF-C-induced VEGFR-3 homodimerization regulated by VEGF-2/-3 heterodimerization and to investigate selective inhibitors for the inhibition of VEGFR-3 homodimerization during corneal lymphangiogenesis.

抽象的：角膜淋巴管生成遵循严重的角膜损伤和感染，是一个失明的主要原因。在正常的生理条件下，角膜是毕晶型，周围被淋巴管包围，居住在结膜中维持角膜淋巴管植物特权。但是，伤害和感染诱导角膜淋巴管生成。调节角膜的外部因素淋巴管生成特权包括：1）存在血管生成和淋巴管源性的存在因素（VEGF -A，-C和-D）； 2）SVEGFR-2在角膜中的表达； 3）表达角膜上皮和其他抗淋巴染因子的VEGFR-3。角膜淋巴管生成的状态受促疾病和抗抗衡的平衡控制淋巴因子。角膜淋巴管植物特权的当前假设受外在的控制角膜独有的因素。除了有据可查的外部因素调节角膜淋巴管生成特权，VEGFR-2的变化可能会调节淋巴细胞中VEGFR3激活还调节角膜淋巴管生成。我们的初步数据表明人的角膜淋巴管发生角膜，与碱燃烧中的VEGFR-3表达增强相关角膜。此外，含有内抑素的片段在体外与VEGFR-3结合，具有比血管生成更好地抑制BFGF诱导的角膜淋巴管生成。 vegf- C诱导的VEGFR-3二聚化和低剂量VEGF-C具有更好的效力促进淋巴细胞增殖。我们的长期目标是确定调节角膜的机制淋巴管生成。提出的实验旨在确定 VEGF-C诱导的VEGFR-3同构化由VEGF-2/-3调节异二聚体并研究抑制VEGFR-3的选择性抑制剂角膜淋巴管生成期间的均二聚化。