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

剖析神经胶质细胞特异性 Sigma-1 受体在慢性炎症性中枢神经系统疾病中的作用

基本信息

批准号：
391625006
负责人：
Professor Dr. Frank Kirchhoff
金额：
--
依托单位：
National Natural Science Foundation of China
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2018
资助国家：
德国
起止时间：
2017-12-31 至 2020-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/391625006?language=en
关键词：
Dissecting roles glia specific Sigma

项目摘要

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.

在中枢神经系统（CNS）中，神经胶质细胞的激活以及促炎细胞因子和趋化因子表达的增加是对多种神经病理学（例如多发性硬化症（MS））的炎症反应过程中的指示性标志。我们和中国合作伙伴的结果表明，Sigma-1 受体（Sig-1R）可能介导星形胶质细胞的激活、小胶质细胞的存活和少突胶质细胞谱系细胞的命运决定。然而，由于缺乏选择性Sig-1R失活动物模型，我们仍然无法阐明Sig-1R在不同胶质细胞类型中的精确体内功能。因此，在本项目中，我们将首先通过生成floxed Sig-1R小鼠和体内CRISPR/Cas9基因删除系统，建立体内选择性灭活Sig-1Rs的方法。其次，我们将利用已建立的条件Sig-1R敲除小鼠和CRISPR/Cas9基因删除系统，研究胶质细胞特异性Sig-1R在MS模型中的功能。第三，我们将应用包括下一代测序在内的先进技术来剖析 MS 模型中神经炎症期间神经胶质细胞特异性 Sig-1R 功能所涉及的分子机制。第四，我们将通过体内双光子激光扫描显微镜（2-P LSM）实时成像研究胶质细胞特异性Sig-1R介导的Ca2+信号传导，这将有助于了解调节Sig-1R下游信号传导（例如MAPK和PI3K/Akt）的潜在Ca2+依赖性机制。该项目将整合德国课题组（转基因小鼠模型和2-P LSM实时成像）和中国课题组（分子生物学和神经炎症研究）的专业知识，从机制上研究胶质细胞特异性Sig-1R在MS中的功能，以Sig-1R作为抗炎靶点，为MS的治疗提供新的理念。