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

• 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
• 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

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.

摘要： 角膜淋巴管生成伴随严重的角膜损伤和感染， 失明的主要原因。在正常生理条件下，角膜 淋巴管和周围的淋巴管驻留在结膜， 维持角膜淋巴管生成豁免。然而，伤口和感染 诱导角膜淋巴管生成。调节角膜的外在因素 淋巴管生成豁免包括：1）存在血管生成和淋巴管生成 因子（VEGF-A、-C和-D）; 2）sVEGFR-2在角膜中的表达; 3） 角膜上皮中的VEGFR-3和角膜中的其他抗淋巴管生成因子。 角膜淋巴管生成的状态受促淋巴管生成因子和抗淋巴管生成因子的平衡控制。 淋巴因子 目前角膜淋巴管生成豁免的假设是由外在的 角膜特有的因素。除了有据可查的外在因素外， 调节角膜淋巴管生成豁免，VEGFR-2的变化可能调节 淋巴细胞中的VEGFR 3活化也调节角膜淋巴管生成。 我们的初步数据表明，在患病的人角膜淋巴管生成 角膜，这与碱烧伤后VEGFR-3表达增强相关。 角膜此外，含有内皮抑制素的片段在体外与VEGFR-3结合，并具有 bFGF诱导的角膜淋巴管生成的抑制作用优于血管生成。血管内皮生长因子- 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内皮细胞的机制， 淋巴管生成所提出的实验旨在确定 VEGF-2/-3调控VEGF-C诱导的VEGFR-3同源二聚化 本发明的目的是为了抑制VEGFR-3的异二聚化，并研究用于抑制VEGFR-3的选择性抑制剂。 角膜淋巴管生成过程中的同源二聚化。