Novel approaches to manipulate sprouting angiogenesis

描述(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)和湿性老年性黄斑变性(AMD)，是美国大部分严重视力丧失的原因。目前治疗过度血管生成的方法是抑制血管内皮生长因子(VEGF)，取得了一定的治疗效果，但一些患者对抗VEGF治疗没有反应，呼吁采取额外的手段来阻断新生血管。血管内皮生长因子共同受体Neuropilin-1(Nrp1)通过对Semaphorin3A介导的血管通透性的依赖和非依赖作用促进视网膜血管生成。此外，我们还发现Nrp1通过抑制血管生成抑制的转化生长因子-β信号来促进血管生成。我们将验证这一假设，即阻断Nrp1信号可能通过同时靶向血管屏障功能和通过影响Semaphorin3A和转化生长因子-B信号来促进血管生成，从而提高抗血管内皮生长因子的治疗效果。我们建议在眼部新生血管疾病的临床前模型中确定阻断Nrp1信号通路的有效性，并确定Nrp1下游的血管内皮生长因子、Semaphorin3A和转化生长因子-β通路的作用。我们将阐明Nrp1和转化生长因子-B信号之间功能拮抗的分子基础，目的是确定在临床环境下阻断Nrp1抑制这一途径的策略，并防止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.