Regulation of ocular angiogenesis by microRNAs

描述（由申请人提供）：该项目的重点是microRNA对眼部血管生成的机制。血管生成在眼睛发育和许多致盲性视网膜疾病（如年龄相关性黄斑变性（age related macular degeneration，AMD）中起着重要作用，microRNA作为转录后调节基因表达的内源性小分子RNA的发现彻底改变了我们对遗传通路网络的认识，并引发了大量的研究来探索microRNA治疗许多疾病的方法。我们广泛的长期目标是：（a）了解特定microRNA如何调节眼血管发育的机制和（B）破译这些microRNA在血管性视网膜病变中的作用。我们最近的研究表明，一个特定的microRNA，miR-126，是一种内皮细胞特异性microRNA，调节血管生成途径，响应血管内皮生长因子（VEGF）和成纤维细胞生长因子（FGF）。我们也有初步的数据表明，miR-126在视网膜/脉络膜的内皮细胞中特异性表达，并且是萌发视网膜血管生成所必需的。我们对这一提议的组织假设是，通过调节多种血管生成途径，miR-126在眼部血管生成和新生血管性AMD的发病机制中起着关键的调节作用。作为具有多种调节功能的小分子，miR-126将是致盲性血管性视网膜病变的有吸引力的治疗靶点。具体目的I是明确miR-126在视网膜/脉络膜中的表达模式和调控机制。具体目标II是确定miR-126调节视网膜血管发育的要求和机制。具体目的III是确定miR-126在激光诱导的脉络膜新血管形成模型中调节新血管形成的机制。 公共卫生相关性：血管生成在视网膜血管发育和许多主要致盲性视网膜疾病中起着核心作用。目前的研究旨在利用遗传小鼠模型和LNA-抗miR技术揭示microRNA调节视网膜血管发育和新生血管性AMD的机制，这可能为未来血管性视网膜病变的microRNA治疗铺平道路。

DESCRIPTION (provided by applicant): This project focuses on microRNA mechanisms on ocular angiogenesis. Angiogenesis plays a central role in eye development and also many major blinding retinal diseases, such as age related macular degeneration (AMD).The discovery of MicroRNAs as small endogenous RNAs regulating gene expression post-transcriptionally has revolutionized our understanding of genetic pathway networks, and ignited tremendous studies to explore microRNA therapeutics for numerous diseases. Our broad long-term goals are: (a) to understand the mechanisms of how specific microRNAs regulate ocular vascular development and (b) to decipher the roles of these microRNAs in vascular retinopathies. Our recent studies show that a specific microRNA, miR-126, is an endothelial cell specific microRNA regulating angiogenic pathways in response to vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF). We also have preliminary data that miR-126 is expressed specifically in the endothelium in the retina/choroid, and is required for sprouting retinal angiogenesis. Our organizing hypothesis for this proposal is that by regulating multiple angiogenic pathways miR-126 plays a critical regulatory role in ocular angiogenesis and in the pathogenesis of neovascular AMD. As a small molecule with multiple regulatory functions, miR-126 would be an attractive therapeutic target for blinding vascular retinopathies. Specific Aim I is to define the expression pattern and regulation mechanism of miR-126 in the retina/choroid. Specific Aim II is to identify the requirement and mechanism whereby miR-126 regulates retinal vascular development. Specific Aim III is to determine the mechanism by which miR-126 regulates neovascularization in a laser induced choroidal neovascularization model. PUBLIC HEALTH RELEVANCE: Angiogenesis plays a central role in retinal vascular development and also many major blinding retinal diseases. The current study is targeted to uncover the mechanism whereby microRNAs regulate retinal vascular development and neovascular AMD using genetic mouse models and LNA-anti-miR technologies, which may paves the road for future microRNA therapeutics in vascular retinopathies.