β-arrestin 2对抑郁症中神经炎症和神经再生的调节及机制研究

β-arrestin 2是一类能与G蛋白偶联受体（GPCRs）激酶联合作用、触发受体脱敏的可溶性蛋白，其主要表达在神经组织，介导细胞表面多种GPCRs的内吞。β-arrestin 2既能负性调控经典的G蛋白信号，还可作为多功能衔接蛋白启动胞内β-arrestin偏爱性信号转导，参与多种病理生理进程。本项目拟在前期发现抑郁症模型小鼠海马β-arrestin 2表达下调而β-arrestin 1无变化的基础上，应用β-arrestin 2敲除小鼠系统研究β-arrestin 2在抑郁症发生发展中的重要作用，在整体和细胞水平阐明β-arrestin 2对抑郁症中胶质细胞介导的神经炎症和海马成年神经再生的调节作用及其机制，揭示β-arrestin 2在抗抑郁治疗中的价值和意义。预期研究成果不仅有助于深化对抑郁症病理机制的认识，也为研发β-arrestin偏爱的选择性激动剂治疗抑郁症提供新的思路。

β-Arrestins are multifunctional signaling scaffold proteins, which were originally thought only to serve as negative regulators of G protein-coupled receptors (GPCR) signaling. Currently, β-arrestin has been recognized to act as a signal transducer of β-arrestin-biased signaling and to be involved in the pathophysiology of many diseases. Our previous study found that the expression of β-arrestin 2 was markedly decreased in the hippocampus of chronic mild stress (CMS)-induced depressed mice. Thus, the present investigation is designed to explore the crucial role of β-arrestin 2 in the pathogenesis of major depression with β-arrestin 2 knockout mice. We further demonstrate the effects of β-arrestin 2 on glia-mediated neuroinflammation and adult hippocampal neurogenesis. Finally, we will illustrate the potential of β-arrestin 2 in depression therapy. Taken together, this study will give us an insight into the etiology of depression and provide a novel strategy for development of β-arrestin-biased ligands.