MicroRNAs for therapy of visual disorders

描述(由申请人提供)：项目摘要(见说明)：绝大多数导致灾难性视力丧失的疾病都是由于血管生成异常以及相关的视网膜浮肿、出血和胶质细胞增多症所致。目前临床上用于治疗黄斑变性和糖尿病视网膜病变等疾病的新生血管并发症的抗血管生成策略以血管内皮生长因子(VEGF)或其受体为靶点。然而，抗血管内皮生长因子治疗的潜在问题限制了它的应用；需要重复注射，对其他非内皮细胞类型的潜在继发性影响以及 非血管内皮生长因子血管生成机制的参与可能限制或减弱患者的反应。针对多个途径和多种药物的联合治疗可以达到协同的血管抑制活性，可以绕过这些问题，但由于缺乏FDA批准的针对血管生成血管生成的临床药物，这种方法受到限制。我们建议通过靶向microRNAs(MiRs)来调节对病理性血管生成至关重要的通路；miRs通常通过与靶基因3‘非翻译区(UTR)上的特定位点结合并招募阻止翻译的沉默复合体来沉默靶基因的表达。我们已经确定miR-132是一种在正常血管中不表达，但在血管生成组织和生长因子刺激的内皮细胞中上调的microRNA。MiR-132的表达足以驱动血管的萌发和增殖，而用互补的抗miR-132抗体抑制miR-132可以阻断这些反应。因此，我们确认miR-132可以激活内皮细胞促进血管生成，而抗miR-132可以中和miR-132，从而在不影响正常血管的情况下抑制视网膜新生血管。我们已经证明miR-132的分子靶点p120RasGAP是静息血管中RAS的有效负调节因子。因此，p120RasGAP被促血管生成的miR-132靶向和抑制。在这个方案中，我们将探索利用新型纳米颗粒递送平台将抗miR-132和其他抗MLRs传递到眼睛的潜在用途，作为一种有效和持续的抗血管生成策略用于治疗新生血管眼病。 公共卫生相关性：相关性(见说明)：血管的异常生长/功能是几种人类眼病的主要诱因，包括糖尿病视网膜病变和老年性黄斑变性。这项提议试图了解被称为microRNAs的小RNA分子是如何调节这一过程的，并将使用几个具有良好特征的人类眼病动物模型来评估这些分子的治疗潜力。

DESCRIPTION (provided by applicant): PROJECT SUMMARY (See instructions): 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 novel nanoparticle delivery platform, as a potent and sustained anti-angiogenic strategy for therapy of neovascular eye diseases. PUBLIC HEALTH RELEVANCE: RELEVANCE (See instructions): Abnormal growth/function of blood vessels is a major contributing factor for several human ocular diseases including diabetic retinopathy and age related macular degeneration. This proposal seeks to understand how small RNA molecules termed microRNAs regulate this process and will evaluate the therapeutic potential of these molecules using several well-characterized animal models of human eye disease.