EYA in Retinal Angiogenesis

EYA 在视网膜血管生成中的作用

基本信息

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
项目类别：
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

项目摘要

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.

抽象的血管生成对于正常的视网膜发育至关重要，但是病理学视网膜血管生成会导致失明。这发生在视网膜病等条件下早产（ROP），与年龄相关的黄斑变性和糖尿病性视网膜病。一个血管生成的基本步骤是迁移，增殖和分化内皮细胞成新形成的毛细管网络。我们有初步数据表明眼睛不存在（EYA）蛋白（它们是转录的激活因子以及酪氨酸磷酸酶）促进血管生成，以及Eya3的遗传消融导致视网膜脉管系统缺陷。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视网膜血管病治疗的新型分子靶标。我们提出了两个目标：（i）调查Eya期间的功能使用血管内皮特异性靶向缺失的正常视网膜血管生成Eya3 和EYA1，以及（ii）验证EYA作为抗逆转录病毒药物的分子靶标通过测试Eya酪氨酸磷酸酶的特异性抑制剂的开发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。关联。该项目完成时，我们将拥有一个全面的了解EYA蛋白在发育和病理中的作用血管生成。异常眼脉管系统的形成是早产儿和患有疾病的成年人的灾难性视力丧失，例如糖尿病和与年龄相关的黄斑变性。因此解密分子异常血管生成的机制很重要。这样的条件是传统上用激光介导的视网膜融合进行治疗，最近抗VEGF抗体的眼内给药；但是，这两个治疗都没有选项没有限制。 EYAS代表了新颖且可吸毒的目标治疗增生性视网膜病，该项目的重要特征是 EYA作为抗血管生成药物开发的靶标。