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）：正常角膜中没有血管和淋巴管对于光学清晰度和最佳视力至关重要。许多病理性疾病会导致角膜新生血管形成，从而导致全世界数亿人失明。血管内皮生长因子 (VEGF) 家族及其受体 (VEGFR) 是严格调节内源性血管生成刺激剂和抑制剂平衡的关键要素，当其受到破坏时，会导致新血管形成。角膜中血液（血管生成）和淋巴（淋巴管生成）的主要正调节因子分别是 VEGF-A 和 VEGF-C。在存在于角膜中的许多血管生成抑制剂中，我们已经证明可溶性 VEGFR-1 (sVEGFR-1) 通过充当 VEGF-A 的陷阱，对于角膜无血管性至关重要（Ambati 等人 Nature 2006）。相比之下，无淋巴角膜的分子基础尚未得到解决。事实上，尚未报道任何组织中淋巴管生成的内源性特异性抑制剂。在令人兴奋的新研究中，我们在小鼠和人类中发现了 VEGFR-2 的新型分泌性剪接变体 (sVEGFR-2)（Albuquerque 等人，Nature Medicine 2009）。令人惊讶的是，sVEGFR-2 的缺失会导致小鼠出生时淋巴自发侵入角膜，但不会导致血管自发侵入。 sVEGFR-2 还特异性抑制损伤诱导的角膜淋巴管生成，并显着减少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存在，与 VEGF-C 相互作用并拮抗，但不与 VEGF-A 相互作用并拮抗。该提案的具体目的是明确小鼠和人角膜发育过程中sVEGFR-2的表达和功能，破译小鼠和人sVEGFR-2抑制淋巴管生成而不是血管生成的分子机制，并解决sVEGFR-2的时空表达和功能。 sVEGFR-2 在小鼠角膜损伤和同种异体移植排斥后的功能。通过提供对淋巴管生成的关键内源性调节因子的澄清见解，并确定可能作为推进角膜新生血管形成和移植排斥新疗法的潜在目标的机制，这些研究直接实现了 NEI 角膜疾病项目的 5 年目标。这些研究的影响还延伸到肿瘤转移、淋巴水肿和淋巴管瘤等病理状态，通过调节我们发现的淋巴管和血管的内源性解偶联剂，可以更好地研究并可能治疗这些病理状态。 公共卫生相关性：角膜新生血管形成和移植排斥涉及异常的血管和淋巴管，导致全世界数百万人失明。我们发现了一种天然存在的分子（sVEGFR-2），它可以选择性地阻断淋巴管，但不阻断血管。通过从分子上解开这些相互交织的过程，我们引入了一种新的研究工具，可用于专门研究淋巴血管生物学，以及一个可导致角膜失明新疗法的新靶标。