The role of Angiopoietin-TEK signaling in polypoidal choroidal vasculopathy

Age-related macular degeneration (AMD) is the leading cause of vision loss in the industrialized world, placing an ever-increasing burden on the global health system {Bird, 2010 #412}. While the pathogenesis of AMD remains incompletely understood, defects in choroidal blood flow and the choriocapillaris are linked to disease progression and development of neovascular AMD. In addition to AMD, choroidal vascular dysfunction is linked to the related spectrum of pachychoroid diseases, which includes uncomplicated pachychoroid and central serous chorioretinopathy as well as the AMD-like related diseases pachychoroid neovascularization and polypoidal choroidal vasculopathy (PCV). While choroidal neovascularization secondary to AMD is the most common form of exudative AMD in western patients, PCV is the dominant form in patients of Asian and African descent {Wong, 2015 #612}{Imamura, 2010 #613}. Despite their prevalence, the importance of pachychoroid diseases in these populations have been poorly appreciated until recently and little is known about their pathogenesis or optimal treatment strategies. As groups with high rates of PCV make up a large proportion of the world population, there is an urgent need for increased understanding of pachychoroid diseases and their relationship to AMD. Members of the angiopoietin (Angpt)-Tek (also known as Tie2) signaling pathway, including the growth factors ANGPT1 and ANGPT2 and the phosphatase VE-PTP (encoded by the gene PTPRB) are highly expressed in the adult human and mouse choroid. Rare variants in TEK and ANGPT2 have been associated with PCV, and a variant in PTPRB has been linked to central serous chorioretinopathy, a related disease. We have found that specific deletion of the TEK ligand Angpt1 from uveal tissues in mice using a neural crest specific Wnt1-Cre line results in attenuated choriocapillaris development and formation of the dilated branching vascular network characteristic of pachychoroid neovascularization and PCV. Experiments in this proposal will focus on a new animal model of pachychoroid neovascularization, leveraging this tool to gain new insights into pachychoroid biology and identify novel genes and pathways which can be targeted for future therapies.