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: 8323651
• 负责人: Jayakrishna Ambati
• 金额: $ 8.22万
• 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/8323651
• 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; public health relevance; receptor; tool; tumor

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Corneal neovascularization and transplant rejection, which involve abnormal blood and lymphatic vessels, lead to blindness in millions worldwide. We discovered a naturally occurring molecule (sVEGFR-2) that selectively blocks lymphatic but not blood vessels. By molecularly uncoupling these intertwined processes, we introduce a new research tool that can be used to specifically study lymphatic vascular biology and a new target that can lead to novel therapies for corneal blindness.

描述（由申请人提供）：正常角膜中缺乏血液和淋巴管，对于光学清晰度和最佳视力至关重要。许多病理疾病导致角膜新生血管形成，导致全球数亿人的失明。血管内皮生长因子（VEGF）家族及其受体（VEGFR）是内源性血管生成刺激剂和抑制剂严格调节平衡的关键要素，当破坏时会导致新血管形成。角膜中血管生成的主要阳性调节剂（血管生成）和淋巴管（淋巴管生成）分别是VEGF-A和VEGF-C。在驻留在角膜中的许多血管生成的抑制剂中，我们已经表明，可溶性VEGFR-1（SVEGFR-1）通过充当VEGF-A的陷阱对于角膜血管性是必不可少的（Ambati等人，自然界2006）。相反，差异角膜的分子基础尚未解决。实际上，尚未报告任何组织中淋巴管生成的内源性特异性抑制剂。在新的令人兴奋的研究中，我们确定了小鼠和人类中VEGFR-2的新颖，分泌的剪接变体的存在（SVEGFR-2）（Albuquerque等人自然医学，2009年）。令人惊讶的是，SVEGFR-2的丧失导致淋巴自发入侵，而不是出生时血管进入小鼠角膜。 SVEGFR-2还特别抑制了损伤诱导的角膜淋巴管生成，并大大降低了角膜同种异体移植排斥。该提案将检验以下假设：SVEGFR-2的淋巴特异性是由于其作为单体的存在，与VEGF-C相互作用并与VEGF-A相互作用，但不能与VEGF-A相互作用。该提案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，解释了小鼠和人类SVEGFR-2抑制淋巴管生成的分子机制，但不能抑制淋巴管生成，但不能解决淋巴管生成，并解决Svegfr-2在小鼠角膜造成损伤中的空间和时间表达和功能。通过提供对淋巴管生成的关键内源性调节剂的见解，并确定可能是推进角膜新生血管形成和移植抑制新疗法的潜在目标的机制，这些研究直接解决了NEI Corneal疾病计划的5年目标。这些研究的影响还扩展到病理状态，例如肿瘤转移，淋巴水肿和淋巴管瘤，可以通过调节我们发现的淋巴和血管的内源性偶联器来更好地研究并可能治疗我们。 公共卫生相关性：涉及异常血液和淋巴管的角膜新血管形成和移植排斥反应，导致全球数百万的失明。我们发现了一种天然存在的分子（SVEGFR-2），该分子有选择地阻断淋巴但没有血管。通过分子解开这些相互交织的过程，我们引入了一种新的研究工具，该工具可用于专门研究淋巴管血管生物学和一个新靶标，可以导致新颖的角膜失明疗法。