EYA in Retinal Angiogenesis

描述(申请人提供)：血管生成对于正常的视网膜发育是必不可少的，然而病理性的视网膜血管生成可导致失明。这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视网膜病变等情况下。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(它们是转录激活因子和酪氨酸磷酸酶)促进血管生成，并且EYA 3的遗传消融导致视网膜血管系统的缺陷。我们假设EYA蛋白的酪氨酸磷酸酶活性是促血管生成的，抑制这种催化活性是治疗视网膜血管疾病的一个新的分子靶点。为了验证这一假说，我们提出了两个目标：(I)通过血管内皮细胞特异性靶向缺失Eya3和Eya1来研究EYA在正常视网膜血管生成中的功能；(Ii)通过在氧诱导的小鼠视网膜病变模型中测试EYA酪氨酸磷酸酶的特异性抑制剂，验证EYA作为抗视网膜病变药物开发的分子靶点。这些目标将使用一系列技术来实现，包括基于细胞培养的分析、化学生物学、小鼠遗传学和视网膜病变的动物模型。关联性。在这个项目完成后，我们将全面了解EYA蛋白在发育和病理性血管生成中所起的作用。眼血管异常的形成是早产儿和患有糖尿病和老年性黄斑变性等疾病的成年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。传统上治疗此类疾病的方法是激光引导的视网膜切除术，以及最近的眼球内注射抗血管内皮生长因子抗体；然而，这两种治疗方法都不是没有局限性的。EYA代表了治疗增生性视网膜病变的一个新的可用药靶点，该项目的一个基本特征是确认EYA作为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.