FKBP5基因与童年创伤交互作用调节FKBP51-Akt-synapsin通路在抑郁症发病中的机制研究

童年创伤作为一个重要的环境因素会显著增加个体成年后罹患抑郁症的风险。我们前期的研究表明童年创伤与个体成年后脑结构和功能的改变相关，但其中的机制仍不清楚。FKBP5基因参与了应激反应的调节，也与抑郁症的发生相关。基于此，我们推测FKBP5基因与童年创伤交互作用可能通过遗传学修饰影响基因表达及其下游通路，进而改变大脑结构和功能导致抑郁症发生。因此，本项目试图通过在抑郁症和健康对照中探索童年创伤、rs1360780位点等位基因、FKBP5基因甲基化水平、外周血单个核细胞中FKBP5和突触素（SYN）基因的mRNA水平以及前额叶-边缘系统环路脑结构和功能间的关系，尤其是澄清其在伴童年创伤抑郁症中的相关性；同时通过动物实验，研究FKBP51-Akt-SYN通路在母婴分离模型小鼠抑郁样行为发生中的作用，来阐明上述理论假说。本研究期望为伴童年创伤抑郁症的发病机制提供新证据，并为其诊断及治疗提供新的靶点。

Previous studies have demonstrated that childhood trauma, a major environmental factor, is a great risk factor for the development of depression in adulthood. Our prior findings have revealed that childhood trauma is associated with altered brain structure and function in young adults, however, the underlying mechanisms remain unclear. The FKBP5 gene is involved in the regulation of response to stress, which is also related to depression. In this context, we hypothesize that the interactions between FKBP5 gene and childhood trauma may cause brain structural and functional alterations leading to depression through genetic modification and its subsequent influence on gene expression and the corresponding downstream pathway. Hence, the present study intends to clarify this hypothesis through investigating, in depression patients and healthy controls, the relationship among childhood trauma, allelic status of rs1360780, methylation levels of FKBP5 gene, mRNA levels of FKBP5 and synapsin (SYN) gene in peripheral blood mononuclear cell, and structural as well as functional brain measures of the prefrontal-limbic circuit, especially these associations in depression patients with childhood trauma; Simultaneously, combined with animal experiments, elucidating the effects of FKBP51-Akt-SYN pathway in the development of depressive-like behavior in mice with maternal separation. The present study expects to provide new information for revealing the pathogenesis underlying depression with childhood trauma, and finally to provide new target in the clinical diagnosis and treatment of depression with childhood trauma.