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.
. 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.
|Wang, Yuhua; Tadjuidje, Emmanuel; Pandey, Ram Naresh et al. (2016) The Eyes Absent Proteins in Developmental and Pathological Angiogenesis. Am J Pathol 186:568-78|
|Simon, Mariella; Richard, Elodie M; Wang, Xinjian et al. (2015) Mutations of human NARS2, encoding the mitochondrial asparaginyl-tRNA synthetase, cause nonsyndromic deafness and Leigh syndrome. PLoS Genet 11:e1005097|
|Broering, Tyler J; Wang, Yuan-Liang; Pandey, Ram Naresh et al. (2015) BAZ1B is dispensable for H2AX phosphorylation on Tyrosine 142 during spermatogenesis. Biol Open 4:873-84|
|Rao, Sujata; Chun, Christina; Fan, Jieqing et al. (2013) A direct and melanopsin-dependent fetal light response regulates mouse eye development. Nature 494:243-6|
|Pandey, Ram Naresh; Wang, Tim Sen; Tadjuidje, Emmanuel et al. (2013) Structure-activity relationships of benzbromarone metabolites and derivatives as EYA inhibitory anti-angiogenic agents. PLoS One 8:e84582|