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. Ideally, therapies for these conditions would selectively attenuate pathological angiogenesis while permitting retinal revascularization. We are working on the hypothesis that eyes absent (EYA) proteins use distinct mechanisms to promote either developmental angiogenesis or angiogenesis triggered by tissue hypoxia, as in proliferative retinopathies. Hence pharmacologic inhibition of EYA represents a novel and druggable target for the treatment of proliferative retinopathies. This is based on our preliminary evidence that:

  • The dual-function transactivator-phosphatase EYA proteins contribute to developmental angiogenesis through their ability to promote endothelial cell migration and proliferation.
  • EYA3 promotes pathological neovascularization through its role in DNA damage repair.
  • We have identified small molecule inhibitors of the tyrosine phosphatase activity of EYA3 that potently and preferentially inhibit neovascularization, while promoting normal revascularization in the oxygen-induced retinopathy disease model.

In this project we integrate the tools of mouse genetics and chemical biology to test our hypotheses regarding the role of EYA in the development of the retinal vasculature and in the pathogenesis of proliferative retinopathies. We are also performing target validation and testing our lead EYA inhibitors as candidate ROP therapeutics.