DICER1 deficiency in aberrant chorioretinal neovascularization

摘要/概要 异常的眼部新生血管导致许多情况下的失明，包括年龄- 相关性黄斑变性（AMD）、糖尿病性视网膜病和早产儿视网膜病。 DICER 1是一种RNA酶，可以处理micro-RNA和SINE RNA。DICER 1的缺陷是 涉及外部视网膜病理，包括脉络膜新生血管形成。这一申诉 最近发表的研究发现，DICER 1缺陷的多种模型 在小鼠中发展异常的脉络膜新生血管，新的证据表明DICER 1 在人新生血管性AMD中表达显著降低。然而， 关于主要DICER 1底物类的相对贡献的知识持续存在 micro-RNA和SINE RNA失衡是脉络膜新生血管形成的贡献者。在 此外，DICER 1缺陷是否会阻碍常规的基因沉默策略， DICER 1在年龄相关的新生血管病变中的作用尚不清楚。总体假设 该项目是年龄相关的DICER 1缺陷通过SINE驱动脉络膜视网膜新生血管 RNA积累并阻碍常规基因沉默策略。我们将测试这个 三个具体目标。1)我们将区分微RNA的贡献 DICER 1的SINE RNA依赖性加工活性， CNV的严重程度。2)我们将采用DICER 1独立的基因沉默策略， 在CNV模型中，它们与传统的DICER 1依赖性策略相似。3)我们将量化DICER 1 并确定异位DICER 1表达是否改善了老年视网膜病变患者的CNV结局。 老年动物总的来说，这些主题相关，但独立的目标将建立新的 关于介质和后果的基础和预防相关知识 病理性脉络膜新生血管中的DICER 1缺陷。这些研究可能因此而开启 针对普遍设盲情况的新干预途径。

Abstract/Summary Aberrant ocular neovascularization contribute to blindness in numerous conditions including age- related macular degeneration (AMD), diabetic retinopathy, and retinopathy of prematurity. DICER1 is a RNase that processes micro-RNAs and SINE RNAs. Deficiency of DICER1 is implicated in outer retinal pathologies, including choroidal neovascularization. This claim is supported by recently published studies finding that multiple models of DICER1 deficiency develop aberrant choroidal neovascularization in mice, and new evidence that DICER1 expression is significantly reduced in human neovascular AMD. However, major gaps in knowledge persist with respect to the relative contributions of major DICER1 substrate classes micro-RNA and SINE RNA imbalances as contributors to choroidal neovascularization. In addition, whether DICER1 deficiency impedes conventional gene silencing strategies, and the role of DICER1 in age-related neovascular pathologies are unknown. The overall hypothesis of this project is that age-related DICER1 deficiency drives chorioretinal neovascularization via SINE RNA accumulation and impedes conventional gene silencing strategies. We will test this hypothesis in three specific aims. 1) We will distinguish between the contributions of micro-RNA and SINE RNA-dependent processing activities of DICER1 with respect to development and severity of CNV. 2) We will adapt DICER1-independent gene silencing strategies and compare them to traditional DICER1-dependent strategies in models of CNV. 3) We will quantify DICER1 in aging retina, and determine whether ectopic DICER1 expression improves CNV outcomes in aged animals. Collectively, these thematically related, but independent aims will establish new foundational and translationally relevant knowledge about the mediators and consequences of DICER1 deficiency in pathological choroidal neovascularization. These studies may thereby open new interventional avenues for prevalent blinding conditions.