DICER1 deficiency in aberrant chorioretinal neovascularization - Administrative Supplement OKT Request

异常脉络膜视网膜新生血管形成中的 DICER1 缺陷 - 行政补充 OKT 请求

• 批准号: 10647413
• 负责人: Bradley David Gelfand
• 金额: $ 6.02万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10647413
• 关键词: Administrative Supplement; Age related macular degeneration; Aging; Animals; Blindness; Bypass; Choroidal Neovascularization; DICER1 gene; Development; Diabetic Retinopathy; Exudative age-related macular degeneration; Foundations; Gene Silencing; Goals; Human; Intervention; Knowledge; Mediator of activation protein; Medical; MicroRNAs; Modeling; Mus; Outcome; Pancreatic ribonuclease; Pathogenesis; Pathologic; Pathology; Pathway interactions; Process; Publishing; RNA; Retina; Retinal Diseases; Retinopathy of Prematurity; Role; Severities; Short Interspersed Nucleotide Elements; Testing; age related; aged; improved; neovascular; neovascularization; novel; ocular neovascularization

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.

总结/摘要 异常的眼部新生血管导致许多疾病的失明，包括年龄相关性黄斑变性， 视网膜变性（AMD）、糖尿病性视网膜病和早产儿视网膜病。DICER 1是一种RNA酶， micro-RNA和SINE RNA。DICER 1的缺乏涉及外部视网膜病理，包括脉络膜 新生血管形成这一说法得到了最近发表的研究的支持，研究发现DICER 1的多种模型 缺乏DICER 1会在小鼠中形成异常的脉络膜新生血管，新的证据表明DICER 1的表达是 在人类新生血管性AMD中显著降低。然而，在知识方面仍然存在重大差距， 主要DICER 1底物类别micro-RNA和SINE RNA失衡作为贡献者的相对贡献 脉络膜新生血管此外，DICER 1缺陷是否会阻碍常规基因沉默， 然而，DICER 1在年龄相关的新生血管病理学中的作用尚不清楚。总体假设 年龄相关的DICER 1缺陷通过SINE RNA驱动脉络膜视网膜新生血管 积累并阻碍常规基因沉默策略。我们将在三个具体的实验中验证这一假设。 目标。1)我们将区分micro-RNA和SINE RNA依赖性加工的贡献 DICER 1的活性与CNV的发展和严重程度有关。2)我们将适应DICER 1-独立 基因沉默策略，并将其与CNV模型中的传统DICER 1依赖性策略进行比较。第三条 我们将定量衰老视网膜中的DICER 1，并确定异位DICER 1表达是否改善CNV 老年动物的结局总的来说，这些主题相关，但独立的目标将建立新的 关于DICER的介质和后果的基础和预防相关知识1 病理性脉络膜新生血管形成缺陷。这些研究可能因此开启新的干预性研究。 普遍设盲条件的途径。