Endogenous Specific Inhibitor of Corneal Lymphangiogenesis

角膜淋巴管生成的内源性特异性抑制剂

• 批准号: 8444478
• 负责人: Jayakrishna Ambati
• 金额: $ 33.86万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8444478
• 关键词: Accounting; Address; Adult; Allografting; Angiogenesis Inducing Agents; Angiogenesis Inhibitors; Binding; Biochemical; Biology; Birth; Blindness; Blood; Blood Vessels; Cell surface; Cornea; Corneal Diseases; Corneal Neovascularization; Data; Dendritic Cells; Development; Disease; Elements; Equilibrium; Extracellular Domain; Family; Family member; Goals; Graft Rejection; Growth; Heterodimerization; Human; Immune; Individual; Inflammatory; Injury; Keratoplasty; Lead; Lymphangiogenesis; Lymphangioma; Lymphatic; Lymphatic Endothelial Cells; Lymphatic vessel; Lymphedema; Mediating; Medicine; Membrane; Modeling; Molecular; Mus; Nature; Neoplasm Metastasis; Optics; Organ; Pathology; Pharmaceutical Preparations; Process; RNA Interference; RNA Splicing; Recombinants; Regulation; Relative (related person); Reporting; Research; Risk; Signal Transduction; Source; Specificity; Surgical sutures; Testing; Tissues; Transplantation; Variant; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor C; Vascular Endothelial Growth Factor D; Vascular Endothelial Growth Factor Receptor-2; Vascular Endothelial Growth Factors; Vision; World Health; allograft rejection; angiogenesis; base; cell motility; corneal allograft; high risk; inhibitor/antagonist; insight; lymph nodes; monomer; neovascularization; novel; novel strategies; prevent; programs; receptor; tool; tumor

Absence of blood and lymphatic vessels in the normal cornea is essential for optical clarity and optimal vision. Numerous pathological disorders result in corneal neovascularization that is responsible for blindness in hundreds of millions of individuals worldwide. The vascular endothelial growth factor (VEGF) family and their receptors (VEGFR) are critical elements of the tightly regulated balance of endogenous angiogenesis stimulators and inhibitors, which when disrupted results in neovascularization. The principal positive regulators of blood (hemangiogenesis) and lymphatic (lymphangiogenesis) in the cornea are VEGF-A and VEGF-C, respectively. Among the many inhibitors of hemangiogenesis that reside in the cornea, we have shown that soluble VEGFR-1 (sVEGFR-1), by acting as a trap for VEGF-A, is essential for corneal avascularity (Ambati et al. Nature 2006). In contrast, the molecular basis of the alymphatic cornea has not been resolved; indeed, no endogenous specific inhibitor of lymphangiogenesis in any tissue has yet been reported. In new and exciting studies, we identified the existence of a novel, secreted splice variant of VEGFR-2 in mouse and human, (sVEGFR-2) (Albuquerque et al. Nature Medicine 2009). Surprisingly, loss of sVEGFR-2 resulted in spontaneous invasion of lymphatic but not blood vessels into the mouse cornea at birth. sVEGFR-2 also specifically inhibited injury-induced corneal lymphangiogenesis and dramatically reduced corneal allograft rejection. This proposal will test the hypothesis that the lymphatic specificity of sVEGFR-2 is due to its existence as a monomer that interacts with and antagonizes VEGF-C but not VEGF-A. The Specific Aims of this proposal are to define the expression and function of sVEGFR-2 during mouse and human corneal development, decipher the molecular mechanisms by which mouse and human sVEGFR-2 inhibit lymphangiogenesis but not hemangiogenesis, and resolve the spatial and temporal expression and function of sVEGFR-2 in the mouse cornea following injury and allograft rejection. By providing clarifying insights into a critical endogenous regulator of lymphangiogenesis and identifying mechanisms that might serve as potential targets for advancing novel therapies for corneal neovascularization and transplant rejection, these studies directly address the 5-year goals of the NEI Corneal Diseases program. The impact of these studies also extends to pathological states such as tumor metastasis, lymphedema, and lymphangioma, which can be better studied and possibly treated by modulating the endogenous uncoupler of lymphatic and blood vessels we have discovered.

正常角膜中缺乏血液和淋巴管，对于光学清晰度至关重要 最佳视野。许多病理疾病导致角膜新血管形成，即 负责全球数亿人的失明。血管 内皮生长因子（VEGF）家族及其受体（VEGFR）是关键要素 内源性血管生成刺激剂和抑制剂的严格调节平衡，当 破坏了新血管形成的结果。血液的主要积极调节剂 （血管生成）和角膜中的淋巴管（淋巴管生成）是VEG​​F-A和VEGF-C， 分别。在驻留在角膜中的许多血管生成抑制剂中，我们有 表明可溶性VEGFR-1（SVEGFR-1）通过充当VEGF-A的陷阱，对于 角膜血管性（Ambati等人自然2006）。相反， 副角膜尚未解决；确实，没有内源性抑制剂的 尚未报道任何组织中的淋巴管生成。在新的令人兴奋的研究中，我们 确定了小鼠和人类中VEGFR-2的小说，分泌的剪接变体的存在， （SVEGFR-2）（Albuquerque等人自然医学2009）。令人惊讶的是，损失SVEGFR-2 导致淋巴自发入侵，而不是在 出生。 SVEGFR-2还特别抑制了损伤引起的角膜淋巴管生成和 大幅度减少了角膜同种异体移植排斥。该提议将检验以下假设 SVEGFR-2的淋巴特异性是由于其作为与和相互作用的单体的存在，并且 拮抗VEGF-C，而不是VEGF-A。该提议的具体目的是定义 小鼠和人角膜发育过程中SVEGFR-2的表达和功能，解密 小鼠和人SVEGFR-2抑制淋巴管生成的分子机制 但不是血管生成，并解决了空间和时间表达和功能 损伤后小鼠角膜中的SVEGFR-2和同种异体移植排斥。通过提供澄清 洞察淋巴管生成的关键内源性调节剂和识别机制 这可能是推进角膜新疗法的潜在目标 这些研究直接解决 NEI角膜疾病计划。这些研究的影响也扩展到病理 肿瘤转移，淋巴水肿和淋巴管瘤等状态，可以更好地研究 并可能通过调节淋巴管和血管的内源性解偶联剂来治疗 我们发现了。