DICER1 deficiency in aberrant chorioretinal neovascularization

DICER1 缺陷导致异常脉络膜视网膜新生血管形成

• 批准号: 10624267
• 负责人: Bradley David Gelfand
• 金额: $ 51.04万
• 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/10624267
• 关键词: Address; Affect; Age; Age related macular degeneration; Aging; Animals; Basic Science; Biogenesis; Biological; Blindness; Blood Vessels; Bypass; Choroid; Choroidal Neovascularization; DICER1 gene; Development; Diabetic Retinopathy; Drug Targeting; Effectiveness; Elements; Enzymes; Exhibits; Exudative age-related macular degeneration; Eye; Feasibility Studies; Gene Silencing; Gene Transfer; Genes; Genetic Transcription; Goals; Growth; Human; Immune; Impairment; Individual; Institution; Intervention; Knowledge; Lesion; Mediator; Medical; MicroRNAs; Modeling; Molecular; Mus; Nuclear; Outcome; Pancreatic ribonuclease; Pathogenesis; Pathologic; Pathologic Neovascularization; Pathology; Pathway interactions; Phenocopy; Predisposition; Process; Proteins; Publishing; RNA; RNA Interference; RNA Processing; Regulation; Retina; Retinal Diseases; Retinal Neovascularization; Retinopathy of Prematurity; Ribonuclease III; Risk Factors; Role; Severities; Testing; Translational Research; Tumor Angiogenesis; United States; VEGFA gene; Variant; Vascular Diseases; Vision; age related; aged; bevacizumab; design; improved; innovation; insight; neovascular; neovascularization; next generation; novel; novel therapeutics; ocular angiogenesis; ocular neovascularization; postnatal; prevent; small hairpin RNA; targeted treatment; therapeutic target; tissue degeneration; tool; vector

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.

摘要/摘要 异常的眼部新生血管在许多情况下导致失明，包括年龄- 相关性黄斑变性(AMD)、糖尿病视网膜病变和早产儿视网膜病变。 DICER1是一种处理微RNA和正弦RNA的核糖核酸酶。DICER1缺乏症是 与视网膜外部病变有关，包括脉络膜新生血管。这项索赔是 最近发表的研究表明，多种DICER1缺乏症模型 小鼠发生异常脉络膜新生血管和DICER1的新证据 在人类新生血管性AMD中的表达显著降低。然而，在以下方面存在重大差距 关于主要DICER1底物类别的相对贡献的知识仍然存在 微小RNA和正弦RNA失衡是脉络膜新生血管形成的重要因素。在……里面 此外，DICER1缺乏是否阻碍了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。的总体假设 这个项目是年龄相关的DICER1缺陷通过正弦驱动脉络膜视网膜新生血管 RNA的积累，阻碍了传统的基因沉默策略。我们将对此进行测试 三个具体目标的假设。1)我们将区分Micro-RNA的贡献 和依赖Sine RNA的DICER1对发育和 CNV的严重程度。2)我们将采用非依赖于DICER1的基因沉默策略并比较 在CNV模型中，它们与传统的依赖DICER1的策略有关。3)我们将量化DICER1 在老化的视网膜中，并确定异位DICER1表达是否改善了CNV结果 年迈的动物。总而言之，这些主题相关但独立的目标将建立新的 关于调解人和后果的基础性和翻译相关知识 病理性脉络膜新生血管中DICER1缺陷的研究因此，这些研究可能会打开 针对普遍失明情况的新干预途径。