Regulation of ocular angiogenesis by microRNAs

描述(申请人提供)：本项目重点研究眼部血管生成的microRNA机制。血管生成在眼睛发育和许多主要的致盲视网膜疾病中起着核心作用，如年龄相关性黄斑变性(AMD)。microRNAs作为转录后调节基因表达的内源性小RNA的发现，彻底改变了我们对遗传途径网络的理解，并引发了大量研究，以探索microRNA治疗多种疾病的方法。我们广泛的长期目标是：(A)了解特定的microRNAs如何调节眼血管发育的机制，以及(B)破译这些microRNAs在血管视网膜病变中的作用。我们最近的研究表明，一种特异性的microRNA miR-126是一种内皮细胞特异性的microRNA，它调节血管生成途径，以响应血管内皮生长因子(VEGF)和成纤维细胞生长因子(FGF)。我们也有初步数据表明miR-126在视网膜/脉络膜内皮细胞中特异表达，是视网膜血管生成所必需的。我们的组织假说是，miR-126通过调节多条血管生成通路，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。作为一种具有多种调节功能的小分子，miR-126将成为治疗失明视网膜病变的一个有吸引力的靶点。明确miR-126在视网膜/脉络膜中的表达模式和调控机制。具体目的二是确定miR-126调节视网膜血管发育的要求和机制。具体目的三是确定miR-126在激光诱导的脉络膜新生血管模型中调节新生血管的机制。 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。本研究旨在利用小鼠遗传模型和LNA-抗miR技术，揭示microRNA调控视网膜血管发育和新生血管性AMD的机制，为未来的血管视网膜病变的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.