调控蛋白质亚硝基化的关键分子GSNOR在抑郁症中的功能和机制研究

Depressive disorder has become a serious medical and social problem due to its high prevalence, high recurrence rate, high burden, high disability rate and high suicide rate. By 2020 it is expected to be the second most common disease that leads to human death and disability. It is of great significance to study the pathogenesis and treatment of depressive disorder. Our previous work indicates that GSNOR (S-nitrosoglutathione reductase)，a key enzyme regulating protein nitrosation modification， expression level decreased in hippocampus of chronic mild stress induced depressive mice and knock out GSNOR increased the depressive behavior in different depressive mice models. These results indicate that GSNOR may function in the development of depressive disorder. This project will test the GSNOR expression level in different depressive mice models and study the function of GSNOR in development of depressive disorder by conditional GSNOR knockout or transgenic mice and stereotaxic injection of GSNOR adeno-associated virus mice model. At the same time, this project will reveal the underlying cellular mechanisms from neuronal neurogenesis, plasticity and determine the novel specific molecular mechanism by protein S-nitrosation proteomics methods in this process. These results will provide new insight into the potential therapy for the treatment of depressive disorder.

抑郁症由于其高患病率、高复发率、高疾病负担、高致残率和高自杀率，已成为非常严重的社会问题。预计到2020年抑郁症将成为导致人类死亡和致残的第二大常见疾病，针对其发病机制和治疗策略进行研究具有重大意义。本项目前期实验结果发现调控蛋白质巯基亚硝基化修饰关键蛋白GSNOR（S-nitrosoglutathione reductase）表达水平在慢性应激抑郁模型小鼠海马组织中明显下调，而敲除GSNOR的小鼠在刺激条件下表现出更严重的抑郁相关行为，结果提示GSNOR很可能在抑郁症中发挥重要功能。本项目将检测多种抑郁模型小鼠中GSNOR表达水平变化；利用组织特异性敲除和转基因GSNOR以及腺相关病毒立体定位注射GSNOR小鼠等模型研究其在抑郁症中的功能；从神经元递质传递、新生、可塑性等方面揭示相关的细胞机制；利用蛋白质亚硝基化修饰组学等方法确定分子机制，期望可以在抑郁症靶点和分子机制方面做出创新发现。

抑郁症由于其高患病率、高复发率、高疾病负担、高致残率和高自杀率，已成为非常严重的社会问题。预计到2020年抑郁症将成为导致人类死亡和致残的第二大常见疾病，针对其发病机制和治疗策略进行研究具有重大意义。本项目前期实验结果发现调控蛋白质巯基亚硝基化修饰关键蛋白GSNOR（S-nitrosoglutathione reductase）表达水平在慢性应激抑郁模型小鼠海马组织中明显下调，而敲除GSNOR的小鼠在刺激条件下表现出更严重的抑郁相关行为，结果提示GSNOR很可能在抑郁症中发挥重要功能。本项目将检测多种抑郁模型小鼠中GSNOR表达水平变化；利用组织特异性敲除和转基因GSNOR以及腺相关病毒立体定位注射GSNOR小鼠等模型研究其在抑郁症中的功能；从神经元递质传递、新生、可塑性等方面揭示相关的细胞机制；利用蛋白质亚硝基化修饰组学等方法确定分子机制，期望可以在抑郁症靶点和分子机制方面做出创新发现。