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：
10407583
负责人：
Bradley David Gelfand
金额：
$ 49.5万
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/10407583
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/摘要异常的眼部新血管形成在包括年龄在内的众多条件下导致失明相关的黄斑变性（AMD），糖尿病性视网膜病和早产性视网膜病变。 DICER1是处理微RNA和正弦RNA的RNase。 DICER1的不足是与外部视网膜病理相关，包括脉络膜新生血管形成。这个主张是最近发表的研究的支持，发现多种模型DICER1缺乏症在小鼠中发展异常的脉络膜新生血管形成，以及DICER1的新证据人类新生血管AMD的表达显着降低。但是，主要差距知识对主要DICER1底物类的相对贡献持续存在微-RNA和正弦RNA失衡是脉络膜新生血管形成的原因。在此外，DICER1缺乏症是否阻碍了常规的基因沉默策略和 DICER1在年龄相关的新生血管病理中的作用尚不清楚。总体假设该项目是与年龄相关的DICER1缺乏症通过正弦驱动脉络膜神经性神经性化 RNA积累并阻碍常规的基因沉默策略。我们将测试这个三个特定目标的假设。 1）我们将区分微-RNA的贡献 DICER1在发展和 CNV的严重程度。 2）我们将调整独立于dicer1的基因沉默策略并进行比较它们是CNV模型中传统的DICER1依赖性策略。 3）我们将量化dicer1 在衰老的视网膜中，并确定异位dicer1表达是否改善了CNV的CNV结果老年动物。总的来说，这些主题相关，但独立目标将建立新的关于调解者和后果的基础和翻译相关的知识 DICER1病理性脉络膜新生血管形成缺乏。这些研究可能会开放普遍盲目条件的新介入途径。