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（请参阅说明）：由于异常血管生成以及相关的视网膜水肿，出血和神经胶质病，导致灾难性丧失视力丧失的绝大多数疾病都是如此。诊所中使用的当前抗血管生成策略用于治疗诸如黄斑变性和糖尿病性视网膜病变靶性血管内皮生长因子（VEGF）或其受体等疾病中的新血管化并发症。但是，抗VEGF治疗的潜在问题限制了其效用；需要重复注射，潜在的次要影响对其他，非内皮，细胞类型和非VEGF血管生成机制的参与可能会限制或减弱患者反应。组合疗法针对多种药物靶向多种途径，可以实现可以避免这些问题的协同血管性活性，但是这种方法受到FDA批准的临床药物的限制，这些临床药物的靶向靶向vegf的上游或下游。我们提出通过靶向微RNA（miRS）对病理血管生成至关重要的调节途径。 miR通常通过与特定位点在其3'未翻译区域（UTR）上结合并募集阻塞翻译的沉默复合物，从而使靶基因的表达静音。我们已经将miR-132确定为在正常血管中未表达的microRNA，但在血管生成组织和被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发芽和增殖，而用互补的抗MIR-132抑制miR-132可以阻止这些反应。因此，我们已经将miR-132鉴定为激活内皮天花板，以促进血管生成和中和miR-132的抗MIR，从而抑制视网膜新生血管形成而不会影响正常血管。我们已经表明，miR-132（P120RASGAP）的分子靶标是静止血管中RAS的有效负调节剂。因此，P120RASGAP被促血管生成的miR-132靶向和抑制。在该提案中，我们将探讨使用新型纳米颗粒输送平台传递给眼睛的抗MIR-132和其他抗MLR的潜在效用，这是一种有效且持续的抗血管生成策略，用于治疗新血管疾病。公共卫生相关性：相关性（请参阅说明）：血管异常生长/功能是多种人类眼部疾病的主要因素，包括糖尿病性视网膜病和与年龄相关的黄斑变性。该提案旨在了解小的RNA分子如何称为microRNAS调节这一过程，并将使用几种特征良好的人眼病动物模型来评估这些分子的治疗潜力。