Novel approaches to manipulate sprouting angiogenesis

描述（由申请人提供）：在美国，患有眼部疾病（包括糖尿病视网膜病变（DR）和湿性黄斑变性（AMD））的患者中过度血管生成导致大多数严重视力丧失。目前通过抑制血管内皮生长因子（VEGF）来治疗过度的血管生成，具有一些治疗成功，但是一些患者对抗VEGF治疗没有反应，需要另外的手段来阻断新血管形成。VEGF共受体Neuropilin-1（Nrp 1）通过对脑信号蛋白3A介导的血管通透性的VEGF依赖性和非依赖性作用促进视网膜血管生成。此外，我们发现Nrp 1通过抑制血管抑制性TGF-β信号传导促进血管生成。我们将检验以下假设：阻断Nrp 1信号传导可通过影响脑信号蛋白3A和TGF-β信号传导同时靶向血管屏障功能和血管生成出芽来提高抗VEGF治疗的功效。我们建议在眼部新生血管疾病的临床前模型中确定阻断Nrp 1信号传导的功效，并建立Nrp 1下游的VEGF、Semaphorin 3A和TGF-β通路的作用。我们将阐明Nrp 1和TGF-β信号传导之间功能性拮抗作用的分子基础，目的是确定在临床环境中阻断Nrp 1抑制该通路并预防DR和AMD患者视力丧失的策略。

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.