EYA in Retinal Angiogenesis

EYA 在视网膜血管生成中的作用

• 批准号: 8575427
• 负责人: RASHMI S. HEGDE
• 金额: $ 38.25万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8575427
• 关键词: Ablation; Adult; Adverse effects; Age related macular degeneration; Angiogenesis Inhibition; Angiogenesis Inhibitors; Angiogenic Factor; Animal Model; Antibodies; Anus; Ataxia-Telangiectasia-Mutated protein kinase; Attenuated; Binding; Biochemical; Biological Assay; Biology; Blindness; Blood Vessels; Blood capillaries; Cell Culture Techniques; Cell Proliferation; Chemicals; DNA Repair; Data; Defect; Development; Diabetes Mellitus; Diabetic Retinopathy; Disease; Disease model; Endothelial Cells; Eye; Future; Genetic; Growth; Histones; Hypoxia; Lasers; Lead; Mediating; Molecular; Molecular Target; Mus; Oxygen; Pathogenesis; Pathologic Neovascularization; Pathway interactions; Phosphoric Monoester Hydrolases; Play; Premature Infant; Protein Dephosphorylation; Protein Tyrosine Phosphatase; Proteins; Publishing; Reactive Oxygen Species; Retina; Retinal; Retinal Diseases; Retinopathy of Prematurity; Role; Stress; Techniques; Testing; Therapeutic; Tissues; Trans-Activators; Transcription Coactivator; Tyrosine; Validation; Vascular Diseases; Vascular Endothelial Cell; Vascular Endothelial Growth Factors; Vision; angiogenesis; base; bevacizumab; capillary; cell motility; chemical genetics; cost; drug development; inhibitor/antagonist; migration; mouse model; neovascularization; novel; pre-clinical; prevent; public health relevance; retinal angiogenesis; small molecule; tool

Abstract Angiogenesis is essential for normal retinal development, however pathological retinal angiogenesis can lead to blindness. This occurs in conditions such as retinopathy of prematurity (ROP), age-related macular degeneration, and diabetic retinopathy. An essential step in angiogenesis is the migration, proliferation and differentiation of endothelial cells into newly formed capillary networks. We have preliminary data showing that the EYES ABSENT (EYA) proteins (which are activators of transcription as well as tyrosine phosphatases) promote angiogenesis, and that genetic ablation of Eya3 leads to defects in the retinal vasculature. We hypothesize that the tyrosine phosphatase activity of the EYA proteins is pro-angiogenic and that inhibition of this catalytic activity represents a novel molecular target for the treatment of retinal vasculopathies.To test this hypothesis we propose two aims: (I) To investigate the function of EYA during normal retinal angiogenesis using vascular endothelial specific targeted deletion of Eya3 and Eya1, and (II) To validate EYA as a molecular target for anti-retinopathy drug development by testing specific inhibitors of the EYA tyrosine phosphatase in the oxygen-induced mouse model of retinopathy. These aims will be accomplished using a combination of techniques including cell- culture based assays, chemical biology, mouse genetics, and animal models of retinopathy. RELEVANCE. At the completion of this project we will have a comprehensive understanding of the role the EYA proteins play in both developmental and pathological angiogenesis. The formation of abnormal ocular vasculature is a major cause of catastrophic vision loss both in premature infants and in adults with diseases such as diabetes and age-related macular degeneration. Hence deciphering the molecular mechanisms underlying abnormal angiogenesis is important. Such conditions are traditionally treated with laser-mediated ablation of the retina, and more recently with intraocular administration of anti-VEGF antibodies; however, neither of these treatment options is without limitations. The EYAs represent a novel and druggable target for treating proliferative retinopathies, and an essential feature of this project is the validation of EYA as a target for anti-angiogenic drug development.

摘要 血管生成对于视网膜的正常发育至关重要，无论病理性如何 视网膜血管生成可导致失明。这种情况发生在视网膜病变等条件 早产儿（ROP），年龄相关性黄斑变性和糖尿病视网膜病变。一个 血管生成的基本步骤是细胞的迁移、增殖和分化。 内皮细胞进入新形成的毛细血管网络。我们有初步数据 这表明EYA蛋白（EYA是转录激活因子， 以及酪氨酸磷酸酶）促进血管生成和Eya 3基因消除 导致视网膜血管系统的缺陷。我们假设酪氨酸磷酸酶 EYA蛋白的活性是促血管生成的，并且抑制这种催化活性 代表了治疗视网膜血管病变的新分子靶点。 本研究提出两个目的：（1）研究EYA在 使用血管内皮特异性靶向Eya 3缺失的正常视网膜血管生成 和Eya 1，以及（II）验证EYA作为抗视网膜病变药物的分子靶点 通过测试EYA酪氨酸磷酸酶的特异性抑制剂， 氧诱导的视网膜病变小鼠模型。 这些目标将使用包括细胞在内的技术组合来实现。 基于培养的测定、化学生物学、小鼠遗传学和动物模型， 视网膜病变 本案无关在这个项目完成后，我们将有一个全面的 了解EYA蛋白在发育和病理中的作用 血管生成异常眼血管系统的形成是导致眼外伤的主要原因之一。 早产儿和患有疾病的成年人， 糖尿病和老年性黄斑变性。因此破译了 异常血管生成的潜在机制是重要的。这些条件是 传统上用激光介导的视网膜消融治疗，最近用 眼内施用抗VEGF抗体;然而，这些治疗都不 选择没有限制。EYAs代表了一种新的可药物靶点， 治疗增生性视网膜病变，该项目的一个基本特征是， 验证EYA作为抗血管生成药物开发的靶点。