EYA in Retinal Angiogenesis

EYA 在视网膜血管生成中的作用

基本信息

批准号：
8706152
负责人：
RASHMI S. HEGDE
金额：
$ 37.49万
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/8706152
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

DESCRIPTION (provided by applicant): 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 nove 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 intraocula 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 ani-angiogenic drug development.

描述（由申请人提供）：血管生成对于正常视网膜发育至关重要，但是病理性视网膜血管生成可能导致失明。这种情况发生在早产儿视网膜病变 (ROP)、年龄相关性黄斑变性和糖尿病性视网膜病变等疾病中。血管生成的一个重要步骤是内皮细胞迁移、增殖和分化成新形成的毛细血管网络。我们的初步数据表明，EYES ABSENT (EYA) 蛋白（转录激活剂和酪氨酸磷酸酶）可促进血管生成，而 Eya3 的基因消除会导致视网膜血管系统缺陷。我们假设 EYA 蛋白的酪氨酸磷酸酶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的新分子靶标。为了检验这一假设，我们提出了两个目标：(I) 使用血管内皮特异性靶向删除 Eya3 和 Eya1 来研究 EYA 在正常视网膜血管生成过程中的功能，以及 (II) 验证 EYA 作为抗视网膜病变药物开发的分子靶点通过在氧诱导的视网膜病变小鼠模型中测试 EYA 酪氨酸磷酸酶的特异性抑制剂。这些目标将通过结合多种技术来实现，包括基于细胞培养的测定、化学生物学、小鼠遗传学和视网膜病动物模型。关联。该项目完成后，我们将对 EYA 蛋白在发育和病理性血管生成中发挥的作用有一个全面的了解。异常眼部血管系统的形成是早产儿和患有糖尿病和年龄相关性黄斑变性等疾病的成人灾难性视力丧失的主要原因。因此，破译异常血管生成的分子机制非常重要。传统上，此类病症的治疗方法是激光介导的视网膜消融，最近则采用眼内注射抗 VEGF 抗体进行治疗。然而，这些治疗选择都不是没有限制的。 EYA 代表了治疗增殖性视网膜病的新颖且可药物化的靶点，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。