Eyes Absent phosphatase inhibitors in eye disease

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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.