Gαi3-Gab1复合物介导VEGF信号转导及视网膜血管增生的作用及机制研究

In the progression of Retinopathy of Prematurity (ROP), elevated VEGF activates its receptor VEGFR2 in retinal vascular endothelial cells (RVEC) to promote retinal vascular proliferation. The underlying pathological mechanisms are yet to be explored. Our preliminary studies have indentified two key adaptor proteins for VEGFR2 signaling: namely inhibitory heterotrimeric G proteins α subunit 3 (Gαi3) and Grb2 associated bind 1 (Gab1). We found that VEGF induced VEGFRα-Gαi3-Gab1 association, which was required for downstream signaling transduction. Silencing and genetic depletion of Gαi3 or Gab1 almost completely blocked VEGF-induced activation of multiple signaling pathways (Akt-mTOR and ERK-MAPK cascades), as well as RVEC cell proliferation and migration. In the current proposal, we will first test expressions of VEGF, VEGFR2, Gαi3 and Gab1 in the retinas of ROP mice. Research efforts will be on how VEGFR2-Gαi3-Gab1 signaling complex mediates VEGF-induced downstream signaling cascade activation and affects RVEC cell functions. In vivo experiments will also be performed to test the potential function of Gαi3 and Gab1 in ROP-induced retinal vascular proliferation. The results of this project will confirm that VEGFRα-Gαi3-Gab1 could be a novel therapeutal target of ROP and other retinal neovascularization diseases.

早产儿视网膜病变（ROP）中血管内皮生长因子（VEGF）水平显著升高，后者作用于视网膜血管内皮细胞上的VEGFR2受体，促血管病理性增生。其作用机制有待进一步阐明。预实验结果初步证实了VEGFR2通路中2个关键接头蛋白：G蛋白抑制性α亚单位3（Gαi3）和Grb2结合蛋白1（Gab1）。VEGF诱导VEGFR2-Gαi3-Gab1耦联，而Gαi3、Gab1敲减或基因敲除则阻断VEGF下游Akt-mTOR和ERK通路的传导，并抑制视网膜血管内皮细胞增殖和迁移。本项目拟首先观察ROP模型小鼠视网膜组织内VEGF、VEGFR2、Gαi3和Gab1的表达情况；重点解析VEGFR2-Gαi3-Gab1信号复合物在VEGF诱导的下游信号转导及视网膜血管内皮功能中的作用及机制；最后在体研究ROP模型中Gαi3、Gab1蛋白促视网膜血管增生的作用。旨在为ROP等视网膜新生血管性疾病提供新的诊治靶点。

早产儿视网膜病变（ROP）中血管内皮生长因子（VEGF）水平显著升高，后者作用于视网膜血管内皮细胞上的VEGFR2受体，促血管病理性增生。其作用机制有待进一步阐明。预实验结果初步证实了VEGFR2通路中2个关键接头蛋白：G蛋白抑制性α亚单位3（Gαi3）和Grb2结合蛋白1（Gab1）。VEGF诱导VEGFR2-Gαi3-Gab1耦联，而Gαi3、Gab1敲减或基因敲除则阻断VEGF下游Akt-mTOR和ERK通路的传导，并抑制视网膜血管内皮细胞增殖和迁移。本项目拟首先观察了ROP模型小鼠视网膜组织内VEGF VEGFR2、Gαi3和Gab1的表达情况；重点解析了VEGFR2-Gαi3-Gab1信号复合物在VEGF诱导的下游信号转导及视网膜血管内皮功能中的作用及机制；最后在体研究了ROP模型中Gαi3、Gab1蛋白促视网膜血管增生的作用。旨在为ROP等视网膜新生血管性疾病提供新的诊治靶点。