EYA in Retinal Angiogenesis

摘要 血管生成对于正常的视网膜发育是必不可少的，尽管是病理性的。 视网膜血管生成可导致失明。这种情况会发生在视网膜病变等情况下 早产儿(ROP)、老年性黄斑变性和糖尿病视网膜病变。一个 血管生成的关键步骤是血管的迁移、增殖和分化 内皮细胞转化为新形成的毛细血管网络。我们有初步数据 表明眼睛没有(EYA)蛋白(作为转录激活剂) 以及酪氨酸磷酸酶)促进血管生成，以及Eya3的基因消融 会导致视网膜血管系统的缺陷。我们假设酪氨酸磷酸酶 EYA蛋白的活性是促血管生成的，而抑制这种催化活性 代表了一种治疗视网膜血管疾病的新分子靶点。 在这一假说中，我们提出了两个目的：(1)研究EYA在体内的作用 血管内皮细胞特异性靶向缺失Eya3基因的正常视网膜血管生成 和Eya1，以及(Ii)验证EyA作为抗视网膜病变药物的分子靶点 通过测试EYA酪氨酸磷酸酶的特定抑制剂在 氧诱导的小鼠视网膜病变模型。 这些目标将使用一系列技术来实现，包括细胞- 以培养为基础的分析、化学生物学、小鼠遗传学和动物模型 视网膜病变。 关联性。在这个项目完成后，我们将有一个全面的 了解EYA蛋白在发育和病理中的作用 血管生成。眼部血管异常的形成是导致眼部疾病的主要原因 早产儿和患有以下疾病的成年人都会出现灾难性的视力丧失 糖尿病和老年性黄斑变性。因此破译了分子 异常血管生成的潜在机制很重要。这些条件是 传统的治疗方法是激光视网膜切除术，最近的治疗方法是 眼内注射抗血管内皮生长因子抗体；然而，这两种治疗都不是 选项是没有限制的。EYAS代表了一种新的、可用药的靶点 治疗增殖性视网膜病变，这个项目的一个基本特征是 确认EYA为抗血管生成药物开发的靶点。

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.