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

Subject Area Experimental Models for the Understanding of Nervous System Diseases
Molecular Biology and Physiology of Neurons and Glial Cells
Term from 2018 to 2021
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 391625006
 
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.
DFG Programme Research Grants
International Connection China
Co-Investigator Dr. Wenhui Huang
Cooperation Partner Professor Dr. Honghong Yao
 
 

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