Novel approaches to manipulate sprouting angiogenesis

描述（由申请人提供）：眼部疾病患者的过度血管生成，包括糖尿病视网膜病变（DR）和湿型年龄相关性黄斑变性（AMD），在美国导致大多数严重视力丧失。过度血管生成目前通过抑制血管内皮生长因子（VEGF）来治疗，取得了一些治疗成功，但一些患者对抗VEGF治疗没有反应，需要额外的手段来阻断新血管生成。VEGF共受体Neuropilin-1 （Nrp1）通过VEGF对semaphorin3a介导的血管通透性的依赖和独立作用促进视网膜血管生成。此外，我们发现Nrp1通过抑制血管抑制Tgf-ß信号传导促进血管生成。我们将通过对Semaphorin3A和Tgf-ß信号的影响，同时靶向血管屏障功能和血管新生发芽，从而验证阻断Nrp1信号可以提高抗vegf治疗效果的假设。我们拟在眼新生血管疾病的临床前模型中确定阻断Nrp1信号通路的效果，并确定Nrp1下游的VEGF、Semaphorin3A和Tgf-ß通路的作用。我们将阐明Nrp1与Tgf-ß信号通路之间功能拮抗的分子基础，目的是在临床环境中确定阻断Nrp1抑制该通路的策略，防止DR和AMD患者的视力丧失。

DESCRIPTION (provided by applicant): 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-ß 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-ß 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-ß pathways downstream of Nrp1. We will elucidate the molecular basis for functional antagonism between Nrp1 and Tgf-ß 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.