小胶质细胞介导神经炎症参与帕金森病（PD）发生发展。Sigma-1受体（Sigma-1R）广泛参与神经元和胶质功能调节，并作为许多神经精神性疾病包括PD的重要靶点。我们前期发现，别构调节Sigma-1R可抑制小胶质细胞M1型活化以及有氧糖酵解，并促进Sigma-1R与己糖激酶HKII的相互作用及增加线粒体内HK-II含量。因此，我们推测sigma-1R可能通过调节代谢重编程而调节小胶质细胞活化。项目将系统研究sigma-1R调节小胶质细胞代谢重编程及在小胶质细胞活化中的作用及其分子机制;以具有自我知识产权的首个高选择性sigma-1 受体别构调节剂SOMCL-668为工具，探讨别构调节sigma-1R抗神经炎症作用及潜在抗PD作用。这一研究将不仅阐明sigma-1受体与神经炎症调控的分子机制，而且为探索以sigma-1R别构调节为靶向的抗神经炎症/抗PD药物发现提供新策略。

Microglia-mediated inflammation contributes to development and pathology of neurodegenerative disease including Parkinsons diseases(PD). Sigma-1 receptor is an important target for neuro-psychiatric diseases including PD. We recently discovered that allosteric modulating sigma-1 receptor elicited a dramatic inhibition on the M1 type microglial activation and glycolysis. This treatment also induced the increased association between sigma-1 receptor and hexokinase-II(HK-II) and , further increased the expression of HK-II in mitochondria. We therefore hypothesized that allosteric activation of sigma-1 receptor may regulate microglila activation via modulating metabolic reprogramming. The study is thus designed to systemically study the effects of allosteric activation of sigma-1 receptor on microglial metabolic reprogramming, and to study how the altered metabolic reprogramming regulates microglila activation and polarization. Further, we will take the advantage of novel and selective sigma-1 receptor allosteric modulator discovered by us, to study how allosteric sigma-1 receptor modulation-regulating neuroinflammation contributes to the dopaminergic neuronal survivals in PD animal model. We believed this work will not only reveals the new mechanism of sigma-1 receptor on neuroinflammatory regulation, but also provides a potential new strategy for PD drug development.