Excessive angiogenesis in patients with ocular diseases, including Diabetic retinopathy (DR) and the wet form of Age-Related Macular Degeneration (AMD) causes he majority of severe vision loss in the US. Excessive angiogenesis is currently treated by inhibition of vascular endothelial growth factor (VEGF), with some therapeutic success, but some patients do not respond to anti-VEGF treatment, calling for additional means to block neovascularization. The VEGF co-receptor Neuropilin-1 (Nrp1) promotes retinal angiogenesis through VEGF dependent and independent effects on Semaphorin3A-mediated vessel permeability. Furthermore, we show that Nrp1 promotes angiogenesis through inhibition of angio- suppressive Tgf- signaling. We will test the hypothesis that blocking of Nrp1 signaling may improve efficacy of anti-VEGF treatment by simultaneously targeting vessel barrier function and angiogenic sprouting through effects on Semaphorin3A and Tgf- signaling. We propose to determine the efficacy of blocking Nrp1 signaling in preclinical models of ocular neovascular disease and establish the role of VEGF, Semaphorin3A and Tgf- pathways downstream of Nrp1. We will elucidate the molecular basis for functional antagonism between Nrp1 and Tgf- signaling, with the goal to determine strategies to block Nrp1 inhibition of this pathway in clinical settings and prevent vision loss in DR and AMD patients.
Excessive blood vessel formation in ocular neovascular disease is currently treated with therapeutic success by inhibition of vascular endothelial growth factor (VEGF), however, since a proportion of patients do not achieve vision improvement, developing treatments that improve response to anti-VEGF agents is likely to improve the lives of patients with ocular neovascular disease. Our preliminary data show that the VEGF co- receptor Neuropilin-1 (Nrp1) promotes retinal angiogenesis through both VEGF dependent and independent effects, prompting us to test the efficacy of selective Nrp1 blockade in preventing neovascular disorders in preclinical models of ocular neovascularization. Mechanistically, we will test the hypothesis that Nrp1 blockade inhibits ocular neovascularization by simultaneously inhibiting VEGF-induced angiogenesis, VEGF and Sema3A-induced permeability and by promoting angio-suppressive Tgf--Smad signaling.
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