DICER1 deficiency in aberrant chorioretinal neovascularization - Administrative Supplement OKT Request

摘要/摘要 包括老年性黄斑在内的多种情况下，异常的眼部新生血管会导致失明 变性(AMD)、糖尿病视网膜病变和早产儿视网膜病变。DICER1是一种核糖核酸酶 微RNA和正弦RNA。DICER1缺乏与包括脉络膜在内的视网膜外部病变有关 新生血管。这一说法得到了最近发表的研究的支持，研究发现DICER1的多种模型 缺陷导致小鼠异常的脉络膜新生血管，新的证据表明DICER1表达是 人类新生血管性AMD显著减少。然而，在以下方面，知识上的主要差距依然存在 作为贡献者的主要DICER1底物类微RNA和正弦RNA失衡的相对贡献 脉络膜新生血管。此外，DICER1缺乏是否会阻碍传统的基因沉默 策略，以及DICER1在年龄相关的新生血管病理中的作用尚不清楚。总体假设 该项目的核心是与年龄相关的DICER1缺陷通过正弦RNA驱动脉络膜视网膜新生血管 积累，并阻碍传统的基因沉默策略。我们将从三个具体的方面来检验这一假设 目标。1)我们将区分Micro-RNA和Sine RNA依赖的加工的贡献 DICER1的活性与CNV的发展和严重程度有关。2)我们将采用独立于DICER1的 基因沉默策略，并在CNV模型中将它们与传统的依赖DICER1的策略进行比较。3) 我们将对老化视网膜中的DICER1进行量化，并确定异位表达DICER1是否可以改善CNV 老年动物的结局。总而言之，这些主题相关但独立的目标将建立新的 关于DICER1调解人和后果的基础性和翻译性相关知识 病理性脉络膜新生血管缺乏。这些研究可能因此开启新的干预性治疗 治疗普遍失明的途径。

SUMMARY/ABSTRACT 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.