Eyes Absent phosphatase inhibitors in eye disease

眼睛眼病中缺乏磷酸酶抑制剂

基本信息

批准号：
7657586
负责人：
RASHMI S. HEGDE
金额：
$ 22.5万
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：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7657586
关键词：
Age related macular degeneration Binding Biochemistry Biological Assay Biology Blood Vessels Cancer Model Cells Chemical Structure Data Diabetes Mellitus Diabetic Retinopathy Disease Disease model Drug Delivery Systems Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Europe Eye Eye Part Eye diseases Family Frequencies Funding Future Gambling Growth Homologous Gene In Vitro Intention Investigation Lead Libraries Light Malignant Neoplasms Membrane Modeling Pharmaceutical Preparations Phosphoric Monoester Hydrolases Preclinical Drug Evaluation Protein Tyrosine Phosphatase Proteins Public Health Research Design Research Personnel Retina Retinopathy of Prematurity Role Screening procedure Solid Neoplasm Solutions Specificity Structure Testing Therapeutic Vascular Endothelial Cell Vision Work abstracting aging population angiogenesis base cancer therapy cell motility design high throughput screening in vivo inhibitor/antagonist phosphatase inhibitor prevent response small molecule tumor vessel regression

项目摘要

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.

描述（由申请人提供）：眼睛的许多主要，视觉促进性疾病具有血管成分。其中包括早产性视网膜病变（ROP），与年龄相关的黄斑变性（AMD）和糖尿病性视网膜病变（DR）。这些疾病已经是一个严重的公共卫生问题，随着美国和欧洲的老龄化，预计频率将增加。在这项探索性建议中，我们打算调查眼睛不存在磷酸酶的小分子抑制剂是抗血管疗法的有用药物，更具体地用于治疗ROP，AMD和DR。初步数据提示了这一调查路径，（1）眼睛没有蛋白质显着增强细胞迁移，（2）眼睛缺乏蛋白质的磷酸酶活性对于增强细胞迁移至关重要，并且（3）血管内皮细胞的磷酸蛋白是必不可少的（VEC）表达没有蛋白质的眼睛。由于细胞迁移是血管生成的重要组成部分，因此我们可能期望眼睛没有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的：目标1。识别和验证眼睛没有磷酸酶活性的特定抑制剂，并测试其对细胞迁移的影响。我们已经确定了几种铅化合物，这些化合物是没有磷酸酶的眼睛的特定抑制剂。使用迄今为止获得的最佳候选者的化学结构，我们将进行聚焦的高通量药物筛查，以识别更有效和特定的抑制剂。我们还将在溶液和细胞中彻底表征所有候选抑制剂，以便我们可以识别最适合进一步筛查的抑制剂。目的2。确定眼睛不存在抑制剂是否抑制血管生成并增强血管消退。使用我们新鉴定的眼睛没有抑制剂以及将从继续筛查中出现的抑制剂，我们将确定它们是否具有使用培养和体内测定的活性抑制血管生成的活性。抗血管生成眼的鉴定缺乏抑制剂将为将来的研究铺平道路，以评估其在AMD，DR，ROP和癌症模型中的治疗活性，在AMD，DR，ROP和癌症的模型中，抗血管生成治疗可能是有利的。