Elucidation of novel anti-angiogenic therapies for the prevention and treatment of neovascular glaucoma

摘要：新生血管性青光眼(NVG)是一种潜在的继发性致盲青光眼，其特征是 虹膜新生血管(NVI)和房角新生血管(NVA)的形成，导致眼压升高 (眼压)和视力预后不良。大多数病例的基本发病机制是后段缺血。 继发于视网膜疾病，包括增殖性糖尿病视网膜病变、视网膜中央静脉阻塞(CRVO) 和眼部缺血综合征，通常与血管生成的表达上调有关 后段的影响因素。当这些因素扩散到前段时，它们促进了生长 虹膜表面的异常血管导致NVI，并超过虹膜角度，引起NVA。 这些血管的成熟可导致小梁上形成纤维血管膜。 可阻碍房水流出，导致眼压升高和NVG发生的网状结构。 这种纤维血管膜的收缩可导致继发性闭角型青光眼。 眼压急剧上升。有趣的是，NVG的风险与视网膜缺血的面积成正比， 支持低氧调节基因产物在其发育过程中的作用。诊断及时有效 在疾病的早期阶段进行疾病治疗对于减少NVG和视力障碍的机会至关重要 减损。不幸的是，全视网膜缺血视网膜组织的大规模破坏 光凝(PRP)仍然是大多数NVG眼的首选标准。最近，血管内皮生长因子 用于治疗缺血性视网膜疾病的抑制剂已被纳入NVG临床 管理层，通常作为PRP的佐剂。然而，这些抗血管内皮生长因子药物只能导致暂时的 NVI/NVA前房角新生血管消退。尽管取得了巨大的进步 在过去几十年对NVG的治疗中，对积极的NVG没有有效的治疗方法。 成长期的或已确定的疾病。这突显了确定分子机制的紧迫性 规范NVI和NVA，为NVG的预防和管理设计更有效的方法。我们的 血管生成素样蛋白4(ANGPTL4)对促血管生成和血管高通透性的初步支持作用 因子及其新型受体Neuropilin 1在NVI/NVA和NVG的发生发展中的作用。我们的建议意在 研究：目的1)ANGPTL4在促进虹膜形成中的作用及其与VEGFs的协同作用 体外和体内新生血管的形成；目的2)神经粘连蛋白抑制剂作为虹膜抗血管生成因子的作用 目的3)VEGF、ANGPTL4和sNRP1的表达对血管生成的影响 CRVO患者NVG的发生发展。

Summary: Neovascular glaucoma (NVG) is a potentially blinding secondary glaucoma, characterized by the development of neovascularization of the iris (NVI) and angle (NVA), leading to elevated intraocular pressure (IOP) and poor visual prognosis. The underlying pathogenesis in most cases is posterior segment ischemia secondary to retinal diseases including proliferative diabetic retinopathy, central retinal vein occlusion (CRVO) and ocular ischemic syndrome, which are usually associated with an upregulated expression of angiogenic factors in the posterior segment. When these factors diffuse to the anterior segment, they promote the growth of abnormal blood vessels on the surface of the iris, causing NVI, and over the iris angle, causing NVA. Maturation of these vessels can result in the formation of a fibrovascular membrane over the trabecular meshwork that can obstruct aqueous outflow, resulting in an increase in IOP and the development of NVG. Contraction of this fibrovascular membrane can lead to secondary angle closure glaucoma (ACG) with a dramatic rise in IOP. Interestingly, the risk for NVG is directly proportional to the area of retinal ischemia, supporting a role for hypoxia-regulated gene products in its development. Prompt diagnosis and effective disease treatments in the early stages of the disease are crucial to reduce the chances of NVG and visual impairment. Unfortunately, the large-scale destruction of ischemic retinal tissue with panretinal photocoagulation (PRP) remains the preferred standard in the majority of eyes with NVG. Recently, VEGF inhibitors used for the management of ischemic retinal diseases have been incorporated for NVG clinical management, usually as adjuvants to PRP. However, these anti-VEGF agents result in only a temporary regression of new vessels in the anterior chamber angle involved in NVI/NVA. In spite of tremendous progress in the therapeutic management of NVG over the past decades, there are no effective therapies for the actively growing or established disease. This underscores the urgency to identify the molecular mechanisms that regulate NVI and NVA, to design more effective approaches for the prevention and management of NVG. Our preliminary support a role for Angiopoietin-like 4 (ANGPTL4), a pro-angiogenic and vessel hyperpermeability factor, and its novel receptor, Neuropilin 1, in the development of NVI/NVA and NVG. Our proposal intends to investigate: Aim 1) the role of ANGPTL4 and its synergism with VEGFs in the promotion of iris neovascularization in vitro and in vivo; Aim 2) the role of Neuropilin inhibitors as antiangiogenic factors in iris neovascularization in vitro and in vivo; Aim 3) how the expression of VEGF, ANGPTL4, and sNRP1 influences the development of NVG in CRVO patients.