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.
Lay Abstract A number of common diseases are partly a result of blood vessels that grow in places they should not. For example, when a tumor gets larger its growth must be supported by a network of blood vessels. People with diabetes often have trouble with their vision and this is the result of abnormal blood vessel growth in their retina, the part of the eye that detects light. Older people who have age-related macular degeneration also have vision problems because blood vessels have grown abnormally in the retina. These diseases and others like them have prompted researchers to try and find ways to prevent the formation of the new blood vessels that are disease-associated. In this funding application, we will determine whether a family of newly discovered enzymes (called the Eyes Absent proteins) have an important role in the formation of new blood vessels. We will identify drugs that bind to and inactivate the Eyes Absent enzymes and determine whether this inactivation prevents new blood vessels from forming. If successful, this work will suggest therapies to treat the vision problem associated with diseases like diabetes and age-related macular degeneration and may also be useful in the treatment of cancer.
| Tadjuidje, Emmanuel; Hegde, Rashmi S (2013) The Eyes Absent proteins in development and disease. Cell Mol Life Sci 70:1897-913 |
| Tadjuidje, Emmanuel; Wang, Tim Sen; Pandey, Ram Naresh et al. (2012) The EYA tyrosine phosphatase activity is pro-angiogenic and is inhibited by benzbromarone. PLoS One 7:e34806 |
| Al-Shabrawey, Mohamed; Mussell, Rene; Kahook, Khalid et al. (2011) Increased expression and activity of 12-lipoxygenase in oxygen-induced ischemic retinopathy and proliferative diabetic retinopathy: implications in retinal neovascularization. Diabetes 60:614-24 |
| Miller, S J; Lan, Z D; Hardiman, A et al. (2010) Inhibition of Eyes Absent Homolog 4 expression induces malignant peripheral nerve sheath tumor necrosis. Oncogene 29:368-79 |
| Pandey, R N; Rani, R; Yeo, E-J et al. (2010) The Eyes Absent phosphatase-transactivator proteins promote proliferation, transformation, migration, and invasion of tumor cells. Oncogene 29:3715-22 |
