Dissecting the roles of glia-specific Sigma-1 receptors in chronic inflammatory CNS disease

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In the central nervous system (CNS), activation of glia cells with increased expression of proinflammatory cytokines and chemokines are indicative hallmarks during the inflammatory response to a variety of neuropathologies such as multiply sclerosis (MS). Results of our Chinese partners and us suggest that Sigma-1 receptors (Sig-1R) may mediate activation of astrocyte, survival of microglia and fate commitment of oligodendrocyte lineage cells. However, due to the lack of selective Sig-1R inactivation animal models, we are still not able to elucidate the precise in vivo functions of Sig-1Rs in different glial cell types. Therefore, in this project, we will firstly establish the methods to selectively inactivate Sig-1Rs in vivo by generating floxed Sig-1R mice and in vivo CRISPR/Cas9 gene-deleting system. Secondly, we will study the functions of glia-specific Sig-1Rs in the MS models with the established conditional Sig-1R knockout mice and CRISPR/Cas9 gene-deleting system. Thirdly, we will apply advanced techniques including next-generation sequencing to dissect the molecular mechanisms involved in glia-specific Sig-1R functions during neuroinflammation in the MS models. Fourthly, we will study the glia-specific Sig-1R mediated Ca2+ signaling by in vivo two-photon laser-scanning microscopy (2-P LSM) live imaging, which will help to understand the potential Ca2+-dependent mechanisms modulating the downstream signaling of Sig-1Rs such as MAPK and PI3K/Akt. The proposed project will integrate the expertise of the German group (transgenic mouse models and 2-P LSM live imaging) and the Chinese group (molecular biology and neuroinflammation study) to mechanistically study the functions of glia-specific Sig-1Rs in MS, which will provide novel concept to the treatment of MS by focusing on the Sig-1R as an anti-inflammatory target.