YB-1调控帕金森病小胶质细胞功能稳态的机制研究

免疫炎症反应的负反馈调控是机体得以维持内环境平衡的重要环节。然而PD等疾病进展中，小胶质细胞异常活化介导的炎症反应无法得到有效限制，最终引起慢性神经毒性效应。因此阐明小胶质细胞炎症反应的“刹车”机制将有助于更好发挥其神经保护性效应。前期我们发现小胶质细胞活化后RBP YB-1反馈性升高，下调YB-1后RNA-seq显示YB-1广泛参与小胶质细胞代谢、炎症反应等基因表达调控。因此结合文献我们提出：Nurr1-YB-1正反馈环路在转录后水平介导代谢重编程调控小胶质细胞炎症反应，抑制其过度活化，保护多巴胺神经元。本项目拟利用YB-1+/-基因小鼠、代谢组学、RIP-seq多组学联合分析等在体内外水平探讨：1、YB-1对PD炎症反应的反馈性抑制效应；2、Nurr1与YB-1彼此形成正反馈环路，促进YB-1表达；3、YB-1在转录后水平介导代谢重编程调控小胶质细胞炎症反应，保护多巴胺神经元的机制。

Negative feedback regulation of immune inflammatory response is an important step for the body to maintain homoiostasis. However, in the progress of diseases such as PD, the inflammatory response mediated by abnormal activation of microglia cannot be effectively restricted, which eventually causes chronic neurotoxic effects. Therefore, elucidating the "brake" mechanism of inflammatory response of microglia will help to better exert its neuroprotective effect. In previous studies, we found that RBP (RNA binding protein) YB-1 increased after activation of microglia. After down-regulating YB-1, RNA-seq showed that YB-1 was widely involved in gene expression regulation of microglia metabolism, inflammatory response and so on. Therefore, combined with the literature, we propose that the Nurr1-YB-1 positive feedback loop mediates metabolic reprogramming at the post-transcriptional level, regulates the inflammatory response of microglia, inhibits its excessive activation, and protects dopamine neurons. This project intends to use YB-1+/- gene mice, metabolomics, and RIP-seq multi-omics joint analysis to explore in vivo and in vitro: 1. The feedback inhibitory effect of YB-1 on PD inflammation; 2. Nurr1 and YB-1 form a positive feedback loop with each other to promote the expression of YB-1; 3. YB-1 mediates metabolic reprogramming at the post-transcriptional level to regulate microglia inflammation and protect dopamine neurons.