MicroRNAs for therapy of visual disorders

项目总结（见说明）： 绝大多数导致灾难性视力丧失的疾病是由于异常的 血管生成和相关的视网膜水肿、出血和神经胶质增生。目前的抗血管生成策略 在临床上用于治疗黄斑变性等疾病中的新血管形成并发症， 糖尿病视网膜病变靶向血管内皮生长因子（VEGF）或其受体。然而，潜力 抗VEGF治疗的问题限制了其效用;需要重复注射，潜在的继发性 对其他非内皮细胞类型的影响和非VEGF血管生成机制的参与可能 限制或减弱患者的反应。联合治疗，用多种药物靶向多个途径， 可以实现协同的血管抑制活性， 由于缺乏FDA批准的靶向血管生成上游或下游的临床药物， VEGF。我们建议通过靶向微小RNA来调节病理性血管生成的关键途径 miR通常通过结合靶基因3'端的特定位点来沉默靶基因的表达。 非翻译区（UTR）和募集沉默复合物阻断翻译。我们已经确定 miR-132是一种微小RNA，在正常血管中不表达，但在正常血管中上调。 血管生成组织和用生长因子刺激的内皮细胞。miR-132的表达是 足以驱动血管发芽和增殖，而用互补的 anti-miR-132阻断这些反应。因此，我们已经鉴定了miR-132激活内皮细胞， 促进血管生成和中和miR-132的抗miR，从而抑制视网膜病变。 新生血管形成而不影响正常血管。我们已经证明miR-132的分子靶点， p120 RasGAP是静息血管中Ras的有效负调节因子。因此，p120 RasGAP被靶向， 被促血管生成的miR-132抑制。在本建议书中，我们将探讨 使用新的纳米颗粒递送平台，将抗miR-132和其他抗miR递送至眼睛， 有效和持续的抗血管生成策略，用于治疗新生血管性眼病。

PROJECT SUMMARY (See instaictions): The vast majority of diseases that cause catastrophic loss of vision do so as a result of abnormal angiogenesis and associated retinal edema, hemorrhage and gliosis. Current anti-angiogenic strategies used in the clinics to treat complications of neovascularization in diseases like macular degeneration and diabetic retinopathy target vascular endothelial growth factor (VEGF) or its receptors. However, potential problems with anti-VEGF therapy limits its utility; the need for repeated injections, potential secondary effects on other, non-endothelial, cell types and the involvement of non-VEGF angiogenic mechanisms may limit or attenuate patient responses. Combination therapy, targeting multiple pathways with multiple drugs, may achieve synergistic angiostatic activity that can circumvent these problems but this approach is limited by the absence of FDA-approved clinical drugs that target angiogenesis either upstream or downstream of VEGF. We propose modulating pathways critical to pathological angiogenesis by targeting micro RNAs (miRs); miRs generally function to silence expression of target genes by binding to specific sites on their 3' untranslated region (UTR) and recruiting a silencing complex that blocks translation. We have identified miR-132 as a microRNA which is not expressed in normal blood vessels, but which is up-regulated in angiogenic tissues and in endothelial cells stimulated with growth factors. Expression of miR-132 is sufficient to drive vascular sprouting and proliferation, whereas inhibition of miR-132 with a complementary anti-miR-132 blocks these responses. Thus, we have identified miR-132 as activating endothelial ceils to promote angiogenesis and an anti-miR that neutralizes miR-132, thereby suppressing retinal neovascularization without affecting normal vessels. We have shown that the molecular target of miR-132, p120RasGAP, is a potent negative regulator of Ras in resting vessels. Thus, p120RasGAP is targeted and suppressed by the pro-angiogenic miR-132. In this proposal, we will explore the potential utility of anti-miR-132 and other anti-mlRs delivered to the eye using a novel nanoparticle delivery platform, as a potent and sustained anti-angiogenic strategy for therapy of neovascular eye diseases.