DSCR1对CaN-NFATc信号通路的调节在病理性视网膜新生血管中的作用及机制研究

研究发现CaN-NFATc信号通路异常激活可导致病理性新生血管形成。DSCR1是CaN-NFATc信号通路的抑制因子，过表达DSCR1能抑制CaN-NFATc信号通路异常激活，减少病理性新生血管生成。我们前期的体内外研究发现缺氧状态下视网膜神经节细胞（RGCs）分泌DSCR1增加，可能通过影响CaN-NFATc通路而抑制血管内皮细胞增殖。本研究以RGCs分泌的DSCR1为靶点，以氧诱导视网膜病变动物模型和低氧诱导的细胞模型为研究对象，通过体内外干预DSCR1的表达，研究DSCR1对CaN-NFATc信号通路的激活、相关炎症因子的表达及对视网膜新生血管形成能力的影响，从上述三个层次阐明DSCR1调控CaN-NFATc信号通路抑制视网膜新生血管生成的机制。该研究有望为治疗视网膜血管性疾病提供新的靶点，具有重要理论和临床意义。

Many studies have shown that abnormal activation of CaN-NFATc signaling pathway can leads to pathological neovascularization during angiogenesis and inflammation. DSCR1 is an important inhibitor of CaN-NFATc pathway. Overexpression of DSCR1 prevents the abnormal activation of the CaN-NFATc signaling pathway and further reduces the formation of pathological neovascularization. Our previous in vivo and in vitro studies demonstrated that retinal ganglion cells (RGCs) secreted more DSCR1 under hypoxia, which may inhibits the CaN-NFATc pathway to suppress the proliferation of vascular endothelial cells. In this project,we will target at RGCs- secreted DSCR1 to investigate the effects of DSCR1 on the regulation of CaN-NFATc signaling pathway activation, relevent inflamatory cytokines expression and inhibition of retinal neovascularization by transferring or depleting DSCR1 gene in both oxygen-induced retinopathy model(in vivo) and hypoxia-induced cell model(in vitro). Our in vivo and in vitro results will provide the first insight into the mechanism by which DSCR1 mediated CaN-NFATc signaling to inhibit pathological retinal neovascularization. Therefore, our study will evaluate if DSCR1 represents a novel therapeutic target to control retinal vascular diseases, which has a profound theoretical and clinical significance.