Eyes Absent phosphatase inhibitors in eye disease

描述（由申请人提供）：许多主要的视力损害性眼部疾病都有血管成分。这些包括早产儿视网膜病变（ROP）、年龄相关性黄斑变性（AMD）和糖尿病视网膜病变（DR）。这些疾病已经是一个严重的公共卫生问题，随着美国和欧洲人口的老龄化，预计发病率将增加。在这个探索性的建议中，我们打算研究Eyes Absent磷酸酶的小分子抑制剂是一般抗血管治疗的有用药物，更具体地用于治疗ROP、AMD和DR的可能性。这一研究路径已经被初步数据所提示，（1）Eyes Absent蛋白显著增强细胞迁移，（2）Eyes Absent蛋白的磷酸酶活性对于增强细胞迁移是必不可少的;（3）血管内皮细胞（VEC）表达Eyes Absent蛋白。由于细胞迁移是血管生成的一个重要组成部分，我们可能会期望缺眼磷酸酶抑制剂具有抗血管生成活性。我们提出了两个实验目标：目标1。鉴定和验证特异性的磷酸酶抑制剂，并测试其对细胞迁移的影响。我们已经鉴定了几种先导化合物，它们是眼睛缺失磷酸酶的特异性抑制剂。使用迄今为止获得的最佳候选物的化学结构，我们将进行集中的高通量药物筛选，以鉴定更有效和特异的抑制剂。我们还将彻底表征溶液和细胞中的所有候选抑制剂，以便我们可以确定最适合进一步筛选的抑制剂。目标2.确定Eyes Absent抑制剂是否抑制血管生成并促进血管消退。使用我们新鉴定的Eyes Absent抑制剂和那些将从继续筛选中出现的抑制剂，我们将使用培养和体内测定来确定它们是否具有抑制血管生成的活性。抗血管生成眼缺失抑制剂的鉴定将为未来的研究铺平道路，这些研究将评估它们在AMD、DR、ROP和癌症模型中的治疗活性，其中抗血管生成治疗可能是有利的。

DESCRIPTION (provided by applicant): A number of major, vision-compromising diseases of the eye have a vascular component. These include retinopathy of prematurity (ROP), age-related macular degeneration (AMD) and diabetic retinopathy (DR). These diseases are already a serious public health concern and with the aging population in the US and Europe, are expected to increase in frequency. In this exploratory proposal, we intend investigating the possibility that small molecule inhibitors of the Eyes Absent phosphatases are useful drugs for anti-vascular therapy in general and more specifically for the treatment of ROP, AMD and DR. This investigative path has been prompted by preliminary data indicating, (1) that Eyes Absent proteins dramatically enhance cell migration, (2) that the phosphatase activity of the Eyes Absent proteins is essential for enhancement of cell migration and (3) that vascular endothelial cells (VECs) express Eyes Absent proteins. Since cell migration is an essential component of angiogenesis, we might expect Eyes Absent phosphatase inhibitors to have anti-angiogenic activity. We propose two experimental aims: Aim 1. Identify and validate specific inhibitors of Eyes Absent's phosphatase activity, and test their effect on cell migration. We have already identified several lead compounds that are specific inhibitors of the Eyes Absent phosphatases. Using the chemical structures of the best candidates obtained thus far we will perform focused high-throughput drug screening to identify more potent and specific inhibitors. We will also thoroughly characterize all candidate inhibitors, in solution and in cells, so that we can identify those most suitable for further screening. Aim 2. To determine whether the Eyes Absent inhibitors suppress angiogenesis and enhance vascular regression. Using our newly identified Eyes Absent inhibitors and those that will emerge from continuing screening, we will determine whether they have activity suppressing angiogenesis using both culture and in vivo assays. Identification of anti-angiogenic Eyes absent inhibitors will pave the way for future studies that assess their therapeutic activity in models of AMD, DR, ROP and cancer, where anti-angiogenic therapy may be advantageous.