Molecular Engineering of Novel Therapies to Treat Corneal Neovascularization

项目总结： 角膜是一种独特的结构，通过完全保持 无血管的。角膜光学透明度丧失的疾病是第三种最常见的原因 世界范围内的失明。尽管这些疾病的病因可能不同，但大多数都集中在一个共同的 在这个组织中导致病理性血管生长的路径，这个过程被称为角膜 新生血管(Conv)。COV最终是促血管生成因子之间失衡的结果 以及角膜缘中的抗血管生成因子。随着血管和淋巴管生长到角膜 间质，水肿，炎症，蛋白质和脂肪沉积，以及疤痕形成，导致角膜混浊， 视力受损或失明。据估计，每年有140万人罹患心血管疾病，其中12% 遭受随之而来的严重视力丧失。 我们最近描述了血管生成素样蛋白4(ANGPTL4)的作用，它是一种强大的促血管生成和 血管高通透性因子在包括增殖性糖尿病视网膜病变在内的后节疾病中的作用 镰刀状视网膜病变和葡萄膜黑色素瘤。有趣的是，我们最近发现了一种相加效应 ANGPTL4和VEGFA对血管通透性的影响。此外，我们还发现ANGPTL4与Neuropilin结合 (NRP)1和2，两种质膜异构体，作为血管内皮生长因子的几个成员的共同受体 一家人。最近，我们观察到ANGPTL4在促进前部血管生成中的作用。 节段性角膜病变，导致角膜反流和角膜翼状胬肉的发生。越来越多的人认识到 淋巴管生成在眼前段病理性血管生成的发展中促使我们去探索 ANGPTL4在这一过程中的作用。最近，我们观察到ANGPTL4有效地诱导了细胞的迁移 和淋巴内皮细胞(LECs)的萌发，这似乎依赖于ANGPTL4结合到 NRP2。总之，这些观察结果表明，ANGPTL4可能在血管紧张素转换酶的发育过程中发挥核心作用。 Conv.我们认为以VEGFs和ANGPTL4为靶点的联合治疗可能更有效 对康复期患者的治疗。 这项建议的目的是研究ANGPTL4/NRPS单独或与 血管内皮生长因子作为血管生成和淋巴管生成的调节因子，从而成为影响血管生成的重要途径 角膜的无血管。这些调查的成功完成将推动我们走向 靶向ANGPTL4和血管内皮生长因子信号转导的联合治疗 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.