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）是一种潜在的致盲性继发性青光眼，其特征在于： 虹膜（NVI）和房角（NVA）新生血管形成，导致眼内压升高 (IOP)视力预后差。在大多数情况下，潜在的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） 和眼缺血综合征，这通常与血管生成素表达上调有关。 后段的因素。当这些因子扩散到眼前节时，它们促进生长 虹膜表面的异常血管，引起NVI，以及超过虹膜角，引起NVA。 这些血管的成熟可导致在小梁上形成纤维血管膜。 可阻塞房水流出的网状结构，导致IOP升高和NVG的发展。 这种纤维血管膜的收缩可导致继发性闭角型青光眼（ACG）， IOP急剧升高。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中的作用。及时诊断和有效 在疾病的早期阶段的疾病治疗是至关重要的，以减少NVG和视觉的机会， 损伤不幸的是，缺血性视网膜组织的大规模破坏与全视网膜 光凝（PRP）仍然是大多数NVG眼睛的首选标准。最近，VEGF 用于治疗缺血性视网膜疾病的抑制剂已被纳入NVG临床治疗中。 管理，通常作为PRP的佐剂。然而，这些抗VEGF剂仅导致暂时的 NVI/NVA中涉及的前房角中的新血管的消退。尽管取得了巨大的进步 在过去的几十年中，在NVG的治疗管理中，没有有效的治疗方法来治疗活动性 正在生长或已形成的疾病。这强调了确定分子机制的紧迫性， 规范NVI和NVA，设计更有效的方法来预防和管理NVG。我们 初步支持血管生成素样4（ANGPTL 4）的作用，ANGPTL 4是一种促血管生成和血管通透性过高的蛋白， 因子及其新型受体Neuropilin 1在NVI/NVA和NVG的发展中的作用。我们的建议旨在 目的：1）ANGPTL 4在虹膜促分化中的作用及其与VEGF的协同作用 目的2）Neuropilin抑制剂作为抗血管生成因子在虹膜中的作用 目的3）VEGF、ANGPTL 4和sNRP 1的表达如何影响血管新生， CRVO患者NVG的发生。

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.