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; 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 异常的眼部新血管化在许多情况下导致失明，包括与年龄相关的黄斑 退化（AMD），糖尿病性视网膜病和早产性视网膜病变。 DICER1是一种处理的RNase 微RNA和正弦RNA。 DICER1的缺乏与外部视网膜病理有关，包括脉络膜 新血管形成。最近发表的研究表明，这一主张是DICER1的多个模型 缺乏在小鼠中发展出异常的脉络膜新生血管化，并且新的证据表明DICER1是 人类新生血管AMD的显着降低。但是，知识的主要差距仍然存在 主要DICER1底物类的相对贡献微-RNA和正弦RNA不平衡作为贡献者 脉络膜新生血管形成。此外，dicer1缺乏是否阻碍了常规的基因沉默 策略以及DICER1在与年龄相关的新生血管病理中的作用尚不清楚。总体假设 这个项目的是与年龄相关的DICER1缺乏症通过正弦RNA驱动脉络膜新神经血管化 积累并阻碍常规的基因沉默策略。我们将以三个特定的特定方式检验该假设 目标。 1）我们将区分微RNA和正弦RNA依赖性处理的贡献 DICER1在CNV的发展和严重程度方面的活动。 2）我们将与dicer1无关 基因沉默策略，并将其与CNV模型中的传统dicer1依赖性策略进行比较。 3） 我们将在衰老视网膜中量化DICER1，并确定异位dicer1表达是否改善CNV 老年动物的结果。总的来说，这些主题相关，但独立目标将建立新的 关于DICER1的基础和翻译相关的知识和后果 病理脉络膜新生血管形成缺乏。这些研究可能会开放新的介入 普遍盲目条件的途径。