G蛋白偶联受体91介导的VEGF基因转录调控在糖尿病性视网膜病变中的作用及机制研究

Diabetic retinopathy (DR) is one of the most serious microvascular complications of diabetes. The pathogenesis is still unclear, in which multiple pathways and multiple molecular are involved. Our preliminary findings showed that the secretion of vascular endothelial growth factor (VEGF) from retinal ganglion cells (RGCs) was also involved in the pathogenesis of DR and it was regulated by G protein-coupled receptor 91 (GPR91). To define the role of GPR91 in the regulation of VEGF transcriptional level and to understand the molecular mechanism further, we propose this research hypothesis: GPR91 on the surface of RGCs will be activated by the simulation of high glucose condition in vitro and in vivo. It firstly activates the MAPK signaling pathway, then activates the nuclear transcription factor C/EBP, AP1 and finally results in the release of VEGF. On the one hand, this project will clarify the role of GPR91 in the pathogenesis of DR and provide experimental evidences for targeted drugs in the prevention and treatment of DR. On the other hand, this project will focus on the upstream signaling pathways regulating VEGF secretion which will give the complement of anti-VEGF treatment in the clinic nowadays.

糖尿病性视网膜病变（DR）是糖尿病患者最严重的微血管并发症之一，目前发病机制的研究涉及多条通路多个分子，但至今尚未明确。我们的前期研究结果显示视网膜神经节细胞（RGCs）分泌的血管内皮生长因子（VEGF）也参与了DR的发病过程，且受G蛋白偶联受体91（GPR91）调控。为进一步明确GPR91调控VEGF转录水平的作用及其机制，本项目提出科研假说：体内外模拟糖尿病的高糖环境诱导激活RGCs上的GPR91受体，通过激活MAPK信号通路继而引起核内C/EBP、AP1转录因子的活化，调控VEGF的转录。一方面，本研究将具体阐述GPR91在DR发病中的作用机制，为寻找早期防治DR的靶向药物提供实验依据；另一方面，本研究着眼介导VEGF分泌的上游信号通路，从调控VEGF分泌而非单纯抑制的角度对如今临床抗VEGF治疗起到补充及完善的作用。

糖尿病性视网膜病变（DR）是糖尿病患者最严重的微血管并发症之一，目前发病机制尚未明确。我们的前期研究结果显示视网膜神经节细胞（RGCs）分泌的血管内皮生长因子（VEGF）参与了DR 的发病过程，且受G 蛋白偶联受体91（GPR91）调控。为进一步明确GPR91 调控VEGF 转录水平的作用及其机制，本项目通过原代培养RGCs细胞氯化钴刺激、氧诱导视网膜病变（OIR）大鼠模型体内外模拟糖尿病的缺血缺氧环境，诱导激活RGCs 上的GPR91 受体，继而通过激活MAPK 信号通路引起核内C/EBP、AP1 转录因子的活化，调控VEGF 的转录。一方面，本研究具体阐述GPR91 在DR 发病中的作用机制，为寻找早期防治DR 的靶向药物提供实验依据；另一方面，本研究着眼于介导VEGF 分泌的上游信号通路，从调控VEGF 分泌而非单纯抑制的角度对如今临床抗VEGF 治疗起到补充及完善的作用。