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.

摘要/摘要 异常的眼部新生血管形成会导致多种疾病导致失明，包括年龄相关性黄斑病变 变性（AMD）、糖尿病性视网膜病变和早产儿视网膜病变。 DICER1 是一种 RNase，可处理 micro-RNA 和 SINE RNA。 DICER1 缺乏与外视网膜病变有关，包括脉络膜病变 新血管形成。最近发表的研究支持了这一说法，研究发现 DICER1 的多种模型 缺乏导致小鼠异常脉络膜新生血管形成，新证据表明 DICER1 表达与 人类新生血管AMD显着减少。然而，在知识方面仍然存在重大差距 主要 DICER1 底物类 micro-RNA 和 SINE RNA 失衡的相对贡献 至脉络膜新生血管。此外，DICER1缺陷是否会阻碍常规基因沉默 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 该项目的重点是年龄相关的 DICER1 缺陷通过 SINE RNA 驱动脉络膜视网膜新生血管形成 积累并阻碍传统的基因沉默策略。我们将在三个具体方面检验这一假设 目标。 1) 我们将区分 micro-RNA 和 SINE RNA 依赖性加工的贡献 DICER1 的活动与 CNV 的发展和严重程度有关。 2）我们将独立于 DICER1 进行调整 基因沉默策略，并将其与 CNV 模型中传统的 DICER1 依赖策略进行比较。 3） 我们将量化衰老视网膜中的 DICER1，并确定异位 DICER1 表达是否会改善 CNV 老年动物的结果。总的来说，这些主题相关但独立的目标将建立新的目标 关于 DICER1 的中介因素和后果的基础知识和转化相关知识 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介入治疗 常见致盲情况的途径。