MicroRNAs for therapy of visual disorders

MicroRNA用于治疗视觉障碍

基本信息

批准号：
8215376
负责人：
MARTIN FRIEDLANDER
金额：
$ 215.3万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-01 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8215376
关键词：
3&apos Untranslated Regions Affect Age related macular degeneration Angiogenesis Promoter Animal Model Attenuated Binding Biochemical Biomedical Engineering Blindness Blood Vessels Chemistry Clinic Clinical Clinical Trials Collaborations Combined Modality Therapy Complex Critical Pathways Development Diabetic Retinopathy Disease Dose Drug Delivery Systems Drug Formulations Drug Kinetics Endothelial Cells Eye Eye diseases FDA approved Gene Targeting Gliosis Growth Growth Factor Hemorrhage Human Image Immunohistochemistry Individual Injection of therapeutic agent Instruction Lead Macular degeneration MicroRNAs Modeling Molecular Molecular Target Outcome Pathologic Neovascularization Pathway interactions Patients Pharmaceutical Preparations Process Qualifying Reagent Recruitment Activity Regulation Rest Retinal Retinal Edemas Retinal Neovascularization Role Series Signal Pathway Signal Transduction Site Small RNA Specimen Structure System Therapeutic Time Tissues Toxicology Translations Vascular Endothelial Growth Factors Vision Disorders angiogenesis antiangiogenesis therapy base cell type choroidal angiogenesis improved in vitro Model inhibitor/antagonist insight mouse model nanoparticle neovascular neovascularization novel novel strategies ocular angiogenesis ocular neovascularization p120 GTPase Activating Protein receptor research study response retinal angiogenesis

项目摘要

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.

描述（由申请人提供）：项目摘要（参见说明）：绝大多数导致灾难性视力丧失的疾病都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造成的。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）或其受体为目标。然而，抗 VEGF 疗法的潜在问题限制了其实用性；需要重复注射，对其他非内皮细胞类型和细胞的潜在副作用非 VEGF 血管生成机制的参与可能会限制或减弱患者的反应。多种药物针对多种途径的联合治疗可能会实现协同血管抑制活性，从而避免这些问题，但这种方法受到 FDA 批准的针对 VEGF 上游或下游血管生成的临床药物的限制。我们建议通过靶向微小 RNA (miR) 来调节对病理性血管生成至关重要的途径； miR 通常通过结合到其 3' 非翻译区 (UTR) 上的特定位点并招募阻止翻译的沉默复合物来沉默靶基因的表达。我们已经鉴定出 miR-132 是一种 microRNA，它不在正常血管中表达，但在血管生成组织和生长因子刺激的内皮细胞中上调。 miR-132 的表达足以驱动血管出芽和增殖，而用互补的抗 miR-132 抑制 miR-132 可阻断这些反应。因此，我们已经鉴定出miR-132可以激活内皮细胞以促进血管生成，而抗miR可以中和miR-132，从而抑制视网膜新生血管形成而不影响正常血管。我们已经证明 miR-132 的分子靶标 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 miR-132 靶向和抑制。在本提案中，我们将探索使用新型纳米颗粒递送平台将抗miR-132和其他抗mlR递送至眼部的潜在效用，作为治疗新生血管性眼病的有效且持续的抗血管生成策略。公众健康相关性：相关性（参见说明）：血管异常生长/功能是多种人类眼部疾病的主要影响因素，包括糖尿病性视网膜病变和年龄相关性黄斑变性。该提案旨在了解称为 microRNA 的小 RNA 分子如何调节这一过程，并将使用几种特征良好的人眼疾病动物模型来评估这些分子的治疗潜力。