Regulation of the Immune response by CREM

CREM 对免疫反应的调节

• 批准号: 214843902
• 负责人: Professor Dr. Klaus Tenbrock
• 金额: --
• 依托单位: Klinik für Kinder- und Jugendmedizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2014-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/214843902?language=en
• 关键词: Regulation; Immune; response; CREM

Defects in phagocytosis are of hallmark importance in the pathogenesis of systemic lupus erythematosus (SLE). We found that the transcriptional repressor CREMα is heavily expressed in B cells and monocytic cells from patients with SLE. CREMα binds to promoters of genes that contain cAMP response elements (CRE) and negatively regulates their transcription in a chromatin-dependent mechanism. By ChIP on Chip promoter analysis we identified CREM binding to 1807 genes in LPS treated human monocytic cells including regulators of phagocytosis. Moreover CREM-/- and CREMα transgenic mice show altered levels of phagocytosis in vitro. We thus propose that CREMα alters phagocytic functions in monocytic cells and that this is of relevance for SLE. To test this we will expand our studies on in vitro and in vivo phagocytosis in CREM-/- and CREMα transgenic mice. Second, we will use these mice to analyze gene expression of phagocytosis relevant genes, which were identified by ChIP on Chip analysis. Third we will extend our findings towards patients with SLE and knock down CREMα by si-RNA to restore phagocytotic functions. The proposed studies will reveal new insights in the molecular regulation of phagocytosis and of the immune response by CREMα in monocytes and into approaches for new therapies.

吞噬功能缺陷在系统性红斑狼疮（SLE）的发病机制中具有重要意义。我们发现转录抑制因子CREMα在SLE患者的B细胞和单核细胞中大量表达。CREMα结合含有cAMP反应元件（CRE）的基因启动子，并在染色质依赖机制中负调控其转录。通过ChIP on ChIP启动子分析，我们在LPS处理的人单核细胞中发现CREM与1807基因结合，包括吞噬调节因子。此外，CREM-/-和CREMα转基因小鼠的体外吞噬水平发生改变。因此，我们提出CREMα改变单核细胞的吞噬功能，这与SLE有关。为了验证这一点，我们将扩大对CREM-/-和CREMα转基因小鼠体内和体外吞噬的研究。其次，我们将利用这些小鼠分析吞噬相关基因的基因表达，这些基因是通过ChIP on ChIP分析鉴定的。第三，我们将把我们的发现扩展到SLE患者，并通过si-RNA敲低CREMα以恢复吞噬功能。这些研究将为单核细胞吞噬和免疫反应的分子调控提供新的见解，并为新的治疗方法提供新的途径。