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。

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.