EYA in Retinal Angiogenesis

描述（由申请人提供）：血管生成是正常视网膜发育所必需的，然而病理性视网膜血管生成可导致失明。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情况。血管生成的一个重要步骤是内皮细胞向新形成的毛细血管网络的迁移、增殖和分化。我们有初步的数据显示EYES ABSENT （EYA）蛋白（它是转录和酪氨酸磷酸酶的激活剂）促进血管生成，Eya3的基因消融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，抑制这种催化活性代表了治疗视网膜血管病变的一个新的分子靶点。为了验证这一假设，我们提出了两个目标：(I)通过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中的功能；（II）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来验证EYA作为抗视网膜病变药物开发的分子靶点。这些目标将通过结合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动物模型在内的技术来实现。的相关性。在这个项目完成后，我们将对EYA蛋白在发育和病理性血管生成中的作用有一个全面的了解。异常眼部血管的形成是导致早产儿和患有糖尿病和老年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是很重要的。传统的治疗方法是激光介导的视网膜消融，最近的治疗方法是眼内注射抗vegf抗体；然而，这两种治疗方案都不是没有局限性的。EYAs是治疗增殖性视网膜病变的一种新的可药物靶点，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。

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.