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）：血管生成对于正常的视网膜发育至关重要，但是病理视网膜血管生成会导致失明。这发生在诸如早产性（ROP），与年龄相关的黄斑变性和糖尿病性视网膜病变之类的条件下。血管生成的一个重要步骤是内皮细胞迁移，增殖和分化为新形成的毛细血管网络。我们有初步数据表明，眼睛缺失（EYA）蛋白（是转录的活化剂以及酪氨酸磷酸酶）会促进血管生成，而EYA3的遗传消融会导致视网膜脉管系统中的缺陷。我们假设EYA蛋白的酪氨酸磷酸酶活性是促血管生成的，并且对这种催化活性的抑制代表了治疗视网膜血管病的nove分子靶标。 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.这些目标将使用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变的动物模型的技术组合来实现。关联。该项目完成时，我们将对Eya蛋白在发育和病理血管生成中所起的作用有全面的了解。异常眼脉管系统的形成是早产儿和患有糖尿病和年龄相关的黄斑变性等疾病的灾难性视力丧失的主要原因。因此，解解了异常血管生成的分子机制很重要。传统上，通过激光介导的视网膜消融，最近通过抗VEGF抗体给药来治疗这种疾病。但是，这些治疗方案都没有限制。 EYAS代表了治疗增生性视网膜病的新型且可药的靶标，该项目的一个基本特征是EYA作为Ani-Angiogenogenogengect药物开发的靶标。