胱硫醚-β-合成酶介导小胶质细胞极化致糖皮质激素CNS毒性作用及机制研究

糖皮质激素（GC）临床使用引起中枢神经系统（CNS）毒性已成为用药安全不容忽视的重要问题，但机制尚不清楚。GC能调控小胶质细胞（MG）M1/M2型极化，诱发或抑制神经炎症。胶质细胞中胱硫醚-β-合成酶（CBS）可催化生成硫化氢（H2S），调节MG相关神经炎症。预实验发现GC暴露致MG中CBS表达下降及H2S生成减少，且miR-671-5p能负向调控CBS mRNA。申请人推测GC可提高miR-671-5p表达，下调CBS/H2S，介导MG向M1型极化致CNS毒性。本项目将通过体内体外模型，探讨：①GC暴露引起的信号变化、小胶质细胞极化与CNS毒性改变；②GC通过miR-671-5p/CBS/H2S对MG极化调控的分子机制；③在体干预miR-671-5p、CBS验证毒性机制并提出潜在治疗策略。本项目将从MG极化这个新视角揭示毒性作用机制，为GC致CNS毒性的防治提供新的靶点和新的思路。

Glucocorticoids-induced central nervous system (CNS) toxicity has become a serious concern in the clinical practice, but the mechanism remains unclear. Glucocorticoids modulate either pro-inflammatory M1 or anti-inflammatory M2 polarization of microglia, which induces or inhibits neuroinflammation, respectively. In microglia, cystathionine β-synthase (CBS) catalyze the generation of H2S, which can modulate microglia related neuro-inflammation. Our previous study demonstrated that exposure of glucocorticoid led to down-regulation of the expression of CBS and decrease level of H2S, and miR-671-5p could down-regulate CBS mRNA. Therefore, we propose that glucocorticoid-induced CNS toxicity might be caused by up-regulated miR-671-5p, and down-regulated CBS/H2S, followed by M1 polarization of microglia. The present project would investigate alteration in miR-671-5p/CBS/H2S signal and microglia polarization state as well as neuroimmune priming effect by in vivo and in vitro models. Then, the role of miR-671-5p/CBS/H2S on the regulation of microglia polarization will be studied to elucidate the molecular mechanism of toxicity. Finally, the underlying mechanism will be further explored through drug intervention using in vivo model. Thereafter, drug intervention strategy will be proposed. From the understanding of microglia polarization, it would explore the mechanism and eventually provide new ideas for the prevention and treatment of glucocorticoids-induced CNS toxicity.