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

基本信息

批准号：
10183845
负责人：
Bradley David Gelfand
金额：
$ 52.57万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
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/10183845
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 Disease Drug Targeting Effectiveness Elements Enzymes Exhibits Exudative age-related macular degeneration Eye Feasibility Studies Foundations Gene Silencing Gene Transfer Genes Goals Growth Human Immune Impairment Individual Intervention Knowledge Lesion Mediator of activation protein Medical MicroRNAs Modeling Molecular Mus Nuclear Outcome Pancreatic ribonuclease Pathogenesis Pathologic Pathologic Neovascularization Pathology Pathway interactions Phenocopy Process Proteins Publishing RNA RNA Interference RNA Processing Regulation Retina Retinal Diseases Retinal Neovascularization Retinopathy of Prematurity Risk Factors Role Severities Testing Translational Research Tumor Angiogenesis United States VEGFA gene Variant Vision age related aged base 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

项目摘要

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/总结异常的眼部新生血管形成在多种情况下会导致失明，包括年龄- 相关黄斑变性（AMD）、糖尿病性视网膜病变和早产儿视网膜病变。 DICER1 是一种处理 micro-RNA 和 SINE RNA 的 RNase。 DICER1 的缺陷是与外视网膜病变有关，包括脉络膜新生血管形成。这个主张是最近发表的研究发现 DICER1 缺陷的多种模型支持小鼠体内出现异常脉络膜新生血管，新证据表明 DICER1 在人新生血管性 AMD 中表达显着降低。然而，主要差距关于主要 DICER1 底物类别的相对贡献的知识仍然存在 micro-RNA 和 SINE RNA 失衡是脉络膜新生血管形成的原因。在此外，DICER1 缺陷是否会阻碍传统的基因沉默策略，以及 DICER1 在与年龄相关的新生血管病理中的作用尚不清楚。总体假设为该项目的主题是与年龄相关的 DICER1 缺陷通过 SINE 驱动脉络膜视网膜新生血管形成 RNA 积累并阻碍传统的基因沉默策略。我们将测试这个三个具体目标的假设。 1）我们将区分micro-RNA的贡献 DICER1 的 SINE RNA 依赖性加工活动与发育和 CNV 的严重程度。 2）我们将采用不依赖于DICER1的基因沉默策略并进行比较将它们与 CNV 模型中传统的 DICER1 依赖策略进行比较。 3）我们将量化DICER1 并确定异位 DICER1 表达是否改善 CNV 结果年老的动物。总的来说，这些主题相关但独立的目标将建立新的目标有关调解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中 DICER1 缺陷。这些研究可能因此开启针对常见致盲情况的新干预途径。