MAP4K4磷酸化p120-catenin调控VE-cadherin内吞在糖尿病黄斑水肿中的作用及机制研究

糖尿病黄斑水肿（DME）是糖尿病患者致盲主要原因。但部分DME患者对一线治疗抗VEGF药物反应不良，表明非VEGF依赖的炎症反应途径可能在DME中起作用。我们前期研究发现，视网膜微血管内皮细胞中非VEGF依赖的蛋白激酶MAP4K4可能在缺血缺氧的视网膜中被激活，破坏血视网膜屏障，在DME进展中发挥关键作用。进一步预实验提示，MAP4K4可能通过磷酸化下游p120蛋白，介导p120/VE-cadherin复合体解离，使VE-cadherin内吞降解，从而减弱血管内皮细胞间粘附，导致DME发展。据此，本项目拟在人视网膜微血管内皮细胞及STZ诱导糖尿病视网膜病变模型中，使用抑制剂及病毒转染等方式建立上调或干扰模型，并与抗VEGF药物进行比较或联合作用，检测MAP4K4对血管内皮细胞间粘附及视网膜血管通透性的作用及作用机制，验证课题假设，为DME寻找新发病机制，为其治疗提供新靶点和协同治疗方案。

Diabetic macular edema (DME) represents the leading cause of vision loss in diabetic patients. However, some patients with DME show refractory to the first-line treatment of anti-VEGF drugs, which indicates that the non-VEGF dependent inflammation pathway plays a crucial role in DME. . Our preliminary work indicated that MAP4K4, a VEGF independent protein kinase in retinal microvascular endothelial cells, might be activated in the hypoxic-ischemic retina, damaging the blood-retinal barrier and playing a key role in the development of DME. Further pre-experiments suggested that MAP4K4 might mediate the dissociation of p120/VE-cadherin complex and the endocytosis of VE-cadherin through phosphorylation of downstream protein p120, which could weaken the adhesion between endothelial cells and lead to the development of DME.. According to this, our project plans to establish the up-regulation or interference model in human retinal microvascular endothelial cells and STZ induced diabetic retinopathy model by using inhibitors and virus transduction, and compare or combine the way of MAP4K4 interference with anti-VEGF drugs, to detect the role of MAP4K4 in adhesion between endothelial cells and in retinal vascular permeability, thereby to verify the hypothesis of the project, find new pathogenesis of DME and provide a new treatment target and synergistic therapy to DME.