MicroRNAs for therapy of visual disorders

MicroRNA用于治疗视觉障碍

基本信息

批准号：
8626401
负责人：
MARTIN FRIEDLANDER
金额：
$ 194.76万
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/8626401
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 Formulations Drug Kinetics Drug Targeting 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

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.

项目摘要（请参阅Instaictions）：由于异常而导致灾难性丧失视力丧失的绝大多数疾病确实如此血管生成和相关的视网膜水肿，出血和神经病。当前的抗血管生成策略在诊所中用于治疗黄斑变性和疾病中的新血管化并发症糖尿病性视网膜病目标血管内皮生长因子（VEGF）或其受体。但是，潜力抗VEGF疗法的问题限制了其效用；需要重复注射，潜在的次要对其他，非内皮，细胞类型的影响以及非VEGF血管生成机制的参与可能限制或减弱患者的反应。联合疗法，针对多种药物的多种途径，可能会实现可以避免这些问题的协同血管性活动，但这种方法是有限的由于没有FDA批准的临床药物，这些药物靶向上游或下游的血管生成 VEGF。我们提出通过靶向微RNA的调节途径至关重要的病理血管生成（mirs）; miR通常通过在其3'上与特定位点结合来实现靶基因的沉默表达。未翻译区域（UTR）并招募阻止翻译的沉默复合体。我们已经确定了 miR-132是在正常血管中未表达的microRNA，但在被生长因子刺激的血管生成组织和内皮细胞中。 miR-132的表达是足以驱动血管发芽和增殖，而miR-132的抑制作用抗MIR-132阻止了这些反应。因此，我们已经将miR-132确定为激活内皮天花板促进血管生成和中和miR-132的抗MIR，从而抑制视网膜新血管形成而不会影响正常血管。我们已经表明，miR-132的分子靶标 P120RASGAP是静止血管中RAS的有效负调节剂。因此，P120RASGAP是针对的，并且被促血管生成的miR-132抑制。在此提案中，我们将探讨抗MIR-132和其他使用新型纳米颗粒递送平台传递到眼睛的抗MLR，作为一个用于治疗新血管眼疾病的有效和持续的抗血管生成策略。