NLRP3炎性小体在应激致抑郁样行为中的作用研究

Depression is a common mental disease because of its high morbidity, disability rate and burden. Its pathogenesis is very complicated and still remains unclear. In recent years, the cytokine hypothesis of depression suggests a key role for cytokines in the mediation of major depression. Our previous studies showed that the IL-1β levels of serum and brain were increased, and the expression of NLRP3 inflammasome of brain was enhanced in both lipopolysaccharide and chronic unpredictable mild stress (CUMS) induced depressive-like behaviour mice. And the specific inhibitors of inflammasome could significantly relieve the depressive-like behaviour of both models. It is suggested that inflammasomes may participate in the pathogenesis of depression and may be a new target of depression therapy. Therefore, to investigate the key targets of stress induced depressive-like behaviour and the signal pathways of stress activation of inflammasome from the whole, organ and tissue, cellular and molecular level, we will take NLRP3 knockout mice and CUMS mice as model, use fluorescent confocal activity positioning and high flux signal transduction molecule screening techniques, and the specific inhibitors of inflammasome. The work may contribute to understanding the effects of inflammasome on stress induced depression and its mechanism, and propose a novel insight into the prevention and treatment of depression.

抑郁症是一种高发病率、高致残性、高疾病负担的精神疾患，其发病机制复杂，仍不明确。近年来，细胞因子学说在抑郁症发病机制中备受关注。我们前期研究发现，脂多糖和慢性不可预见性温和应激(CUMS)分别诱导的抑郁样行为小鼠的血清和脑内IL-1水平均明显升高，脑中NLRP3炎性小体表达增加，而炎性小体特异性拮抗剂可以显著减轻两种模型动物的抑郁样行为，提示炎性小体在抑郁症发病中起重要作用，并可能成为抑郁症潜在的防治靶点。本项目拟利用炎性小体基因敲除小鼠，以CUMS制备抑郁模型，使用激光共聚焦活性荧光定位、高通量信号转导分子筛选等技术，使用针对炎性小体信号上下游通路的各种抑制剂，在整体、组织器官和细胞分子水平，明确炎性小体是应激诱导抑郁样行为的关键靶点，阐述应激激活炎性小体可能的信号转导通路，阐明炎性小体在抑郁症发病中的作用及分子机制，为抑郁症的防治提供新靶点和策略。

抑郁症是一种高发病率、高致残性、高疾病负担的精神疾患，其发病机制复杂，仍不明确。近年来，细胞因子学说在抑郁症发病机制中备受关注。我们前期研究发现，脂多糖和慢性不可预见性温和应激(CUMS)分别诱导的抑郁样行为小鼠的血清和脑内IL-1beta水平均明显升高，脑中NLRP3炎性小体表达增加，而炎性小体特异性拮抗剂可以显著减轻两种模型动物的抑郁样行为，提示炎性小体在抑郁症发病中起重要作用，并可能成为抑郁症潜在的防治靶点。本项目在整体、组织器官和细胞分子等水平，利用炎性小体基因敲除小鼠，以CUMS制备抑郁模型，使用激光共聚焦活性荧光定位、高通量信号转导分子筛选等技术，使用针对炎性小体信号上下游通路的各种抑制剂进行系统研究。研究明确了应激激活炎性小体及其信号转导通路，结果表明炎性小体是应激诱导抑郁样行为的关键靶点之一。本研究为抑郁症的防治提供了新靶点和策略。