Molecular Engineering of Novel Therapies to Treat Corneal Neovascularization

项目概要： 角膜是一种独特的结构，通过完全保持其光学清晰度， 无血管的其中角膜的光学清晰度丧失的疾病是角膜炎的第三大常见原因。 全世界失明虽然这些疾病的病因可能是不同的，但大多数都集中在一个共同的 导致该组织中病理性血管生长的途径，这一过程称为角膜 新生血管形成（CoNV）。CoNV最终是促血管生成因子之间失衡的结果 和角膜利姆布斯中的抗血管生成因子。随着血管和淋巴管长入角膜 可能发生基质、水肿、炎症、蛋白质和脂质沉积以及瘢痕形成，导致角膜混浊， 视力受损或失明。据估计，每年有140万人患上CoNV，其中12%的人 遭受随后的严重视力丧失。 我们最近描述了血管生成素样4（ANGPTL 4）的作用，作为一种有效的促血管生成和 血管高通透性因子在后段疾病中的作用，包括糖尿病视网膜病变、增殖性 镰状视网膜病和葡萄膜黑色素瘤有趣的是，我们最近发现了一种附加效应， 血管高通透性通过ANGPTL 4和VEGFA。此外，我们发现ANGPTL 4结合神经纤毛蛋白， （NRP）1和2，两种质膜同种型，作为VEGF的几个成员的共受体， 家人最近，我们已经观察到ANGPTL 4在促进血管生成中的作用， 段，导致CoNV和角膜翼状胬肉的发展。人们日益认识到 淋巴管生成在眼前节病理性血管生成的发展促使我们探讨 ANGPTL 4在这一过程中的作用。最近，我们已经观察到ANGPTL 4有效地诱导细胞迁移， 和淋巴管内皮细胞（IEC）的发芽，这似乎依赖于ANGPTL 4与 NRP2。总的来说，这些观察结果表明ANGPTL 4可能在肿瘤的发展中发挥核心作用。 CoNV.我们提出，靶向VEGF和ANGPTL 4的联合治疗可能是一种更有效的治疗方法。 CoNV患者的治疗。 本提案的目的是研究ANGPTL 4/NRP单独或与ANGPTL 4/NRP组合的作用。 VEGF作为血管生成和淋巴管生成的调节剂，因此作为影响血管生成和淋巴管生成的重要途径， 角膜的无血管性。这些调查的成功完成将使我们走向一个 靶向ANGPTL 4和VEGF信号传导的组合疗法作为治疗ANGPTL 4的新替代方案 CoNV.

PROJECT SUMMARY: The cornea is a unique structure that remarkably maintains its optic clarity by remaining completely avascular. Diseases in which the optical clarity of the cornea is lost are the third most common cause of blindness worldwide. Although the etiology of these diseases may be distinct, most converge on a common pathway leading to the growth of pathological vessels in this tissue, a process known as corneal neovascularization (CoNV). CoNV is ultimately a consequence of an imbalance between proangiogenic factors and antiangiogenic factors in the corneal limbus. As vascular and lymphatic vessels grow into the corneal stroma, edema, inflammation, protein and lipid deposition, and scarring can occur, leading to corneal opacities, visual impairment or blindness. It is estimated that 1.4 million people develop CoNV per year, 12% of whom suffer the subsequent significant loss of vision. We have recently described the role of Angiopoeitin-like 4 (ANGPTL4), as a potent pro-angiogenic and vessel hyperpermeability factor in posterior segment diseases, including diabetic retinopathy, proliferative sickle retinopathy, and uveal melanoma. Interestingly, we recently found an additive effect in the induction of vessel hyperpermeability by ANGPTL4 and VEGFA. Furthermore, we found that ANGPTL4 binds Neuropilin (NRP)1 and 2, two plasma membrane isoforms that act as co-receptors for several members of the VEGF family. More recently, we have observed a role for ANGPTL4 in promoting angiogenesis in the anterior segment, leading to the development of CoNV and corneal pterygia. Growing appreciation of the role of lymphangiogenesis in the development of anterior segment pathological angiogenesis prompted us to explore a role for ANGPTL4 in this process. Recently, we have observed that ANGPTL4 potently induces the migration and sprouting of lymphatic endothelial cells (lECs), and this appears to be dependent on ANGPTL4 binding to NRP2. Collectively, these observations suggest that ANGPTL4 could play a central role in the development of CoNV. We propose that a combinatorial therapy targeting VEGFs and ANGPTL4 may be a more effective treatment for CoNV patients. The objective of this proposal is to investigate the role of ANGPTL4/NRPs alone or in combination with VEGFs as regulators of hemangiogenesis and lymphangionesis and thus as important pathways influencing the avascularity of the cornea. The successful completion of these investigations will move us towards a combinational therapy targeting ANGPTL4 and VEGF signaling as a novel alternative for the treatment of CoNV.