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）：角膜淋巴管生成伴随严重角膜损伤和感染，是失明的主要原因之一。在正常生理条件下，角膜是淋巴管的，并且被位于结膜中的淋巴管包围，同时维持角膜淋巴管生成特权。然而，创伤和感染诱导角膜淋巴管生成。调节角膜淋巴管生成豁免的外在因素包括：1）血管生成和淋巴管生成因子（VEGF-A、VEGF-C和VEGF-D）的存在; 2）sVEGFR-2在角膜中的表达; 3）VEGFR-3在角膜上皮中的表达和角膜中的其它抗淋巴管生成因子。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。 目前角膜淋巴管生成豁免的假说是由角膜特有的外在因素决定的。除了参与调节角膜淋巴管生成豁免的充分记录的外在因素之外，VEGFR-2的变化可以调节淋巴细胞中的VEGFR 3活化，也可以调节角膜淋巴管生成。 我们的初步数据表明，在患病的人角膜中，角膜淋巴管生成与碱烧伤角膜中VEGFR-3表达增强相关。此外，含有内皮抑制素的片段在体外与VEGFR-3结合，并且对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在促进淋巴细胞增殖方面具有更好的效力。 我们的长期目标是确定调节角膜淋巴管生成的机制。所提出的实验旨在确定VEGF-2/-3异源二聚化调节的VEGF-C诱导的VEGFR-3同源二聚化的作用，并研究角膜淋巴管生成过程中抑制VEGFR-3同源二聚化的选择性抑制剂。 公共卫生相关性：淋巴管生成是淋巴管产生增加的过程，并且可以是生理性和病理性的。我们推测VEGFR-2干扰VEGFR-3二聚化可能在角膜淋巴管生成的调节中发挥作用。了解角膜淋巴管生成的分子机制将为淋巴管生成相关疾病的治疗提供新的治疗干预措施。