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: 8177528
• 负责人: JIN-HONG CHANG
• 金额: $ 23.86万
• 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 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8177528
• 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

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Lymphangiogenesis is the process of increased production of lymphatic vessels and can be both physiological and pathological. We hypothesize that VEGFR-2 interferes with VEGFR-3 dimerization may play a role in the regulation of corneal lymphangiogenesis. Understanding the molecular mechanisms of corneal lymphangiogenesis will provide novel therapeutic interventions in the treatment of lymphangiogenesis-related disorders.

描述（由申请人提供）：角膜淋巴管生成是严重角膜损伤和感染后发生的，是导致失明的主要原因之一。在正常的生理条件下，角膜是淋巴性的，被居住在结膜的淋巴管包围，而角膜的淋巴管生成特权保持不变。然而，损伤和感染可诱导角膜淋巴管生成。调节角膜淋巴管生成特权的外在因素包括：1)血管生成因子和淋巴管生成因子（VEGF-A、-C和-D）的存在；2) sVEGFR-2在角膜中的表达；3) vegf -3在角膜上皮中的表达及角膜内其他抗淋巴管生成因子的表达。角膜淋巴管生成的状态是由促淋巴因子和抗淋巴因子的平衡控制的。目前角膜淋巴管生成特权的假设是由角膜特有的外在因素决定的。除了有充分证据表明参与调节角膜淋巴管生成特权的外在因素外，VEGFR-2的变化可能调节淋巴细胞中vegfr3的激活，也调节角膜淋巴管生成。我们的初步数据表明，患病的人角膜中存在角膜淋巴管生成，这与碱烧伤损伤角膜中VEGFR-3表达的增强有关。此外，含有内皮抑素的片段在体外与VEGFR-3结合，对bfgf诱导的角膜淋巴管生成的抑制作用优于血管生成。VEGF- c诱导的VEGFR-3二聚化和低剂量VEGF- c对淋巴细胞增殖有较好的促进作用。我们的长期目标是确定调节角膜淋巴管生成的机制。本实验旨在确定vegf - c诱导的由VEGF-2/ 3异源二聚化调节的VEGFR-3同二聚化的作用，并研究在角膜淋巴管生成过程中抑制VEGFR-3同二聚化的选择性抑制剂。