Mapping the phenotype and functions of antigen-presenting cells (APCs) during CNS autoimmunity

绘制中枢神经系统自身免疫过程中抗原呈递细胞 (APC) 的表型和功能图谱

• 批准号: 20846339
• 负责人: Professor Dr. Marco Prinz
• 金额: --
• 依托单位: Institut für Neuropathologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2006
• 资助国家: 德国
• 起止时间: 2005-12-31 至 2017-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/20846339?language=en
• 关键词: Mapping; phenotype; functions; antigen; presenting

Several myeloid cells can act as antigen-presenting cells (APCs) during CNS autoimmunity. However, the cell type specific APC functions of myeloid cell subsets in vivo are unclear. This project will therefore explore the relative contribution of microglia, monocyte-derived macrophages and dendritic cells for the activation of pathogenic T cells in a mouse model of multiple sclerosis (MS). We want to use A) fluorescence-based fate-mapping approaches to isolate different antigen-presenting cell lineages and perform genome-wide transcriptome analysis to map genes, pathways and upstream regulators that specify their pathogenic functions during disease. Next, B) cell specific gene targeting will be applied to selectively ablate the APC function of myeloid cell subsets to determine their relative contribution for the activation of pathogenic T cells. Finally, C) by using a candidate gene approach, the role of IKKa (IKK1) in different APCs during CNS autoimmunity will be explored. These studies will give us fundamental new information about the role of different APCs in MS models and their relative contributions to disease pathogenesis. In addition, we will potentially identify critical genes, pathways and upstream regulators in APCs that may represent new therapeutic targets in the treatment of MS.

在CNS自身免疫过程中，一些骨髓细胞可以充当抗原呈递细胞（APC）。然而，骨髓细胞亚群的细胞类型特异性APC功能在体内尚不清楚。因此，该项目将探讨小胶质细胞，单核细胞衍生的巨噬细胞和树突状细胞在多发性硬化症（MS）小鼠模型中激活致病性T细胞的相对贡献。我们希望使用A）基于荧光的命运作图方法来分离不同的抗原呈递细胞谱系，并进行全基因组转录组分析，以绘制在疾病期间指定其致病功能的基因、通路和上游调节因子。接下来，将应用B）细胞特异性基因靶向以选择性地消除骨髓细胞亚群的APC功能，以确定它们对病原性T细胞活化的相对贡献。最后，C）通过使用候选基因方法，将探索IKKa（IKK1）在CNS自身免疫中在不同APC中的作用。这些研究将为我们提供关于不同APC在MS模型中的作用及其对疾病发病机制的相对贡献的基本新信息。此外，我们将潜在地鉴定APC中的关键基因、通路和上游调节因子，这些基因、通路和上游调节因子可能代表MS治疗中的新治疗靶点。