The role of calcium-binding proteins MRP8 and MRP14 during cellular dynamics in phagocytes.

钙结合蛋白 MRP8 和 MRP14 在吞噬细胞的细胞动力学过程中的作用。

• 批准号: 404608094
• 负责人: Professor Dr. Johannes Roth
• 金额: --
• 依托单位: Institut für Immunologie
• 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 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/404608094?language=en
• 关键词: role; calcium; binding; proteins; MRP8

Phagocytic functions like adherence, migration and phagocytosis depend on major rearrangements of the cytoskeleton. These processes are controlled by receptor-mediated calcium signaling and protein phosphorylation cascades. However, the molecular links coordinating the interplay of different cytoskeletal compartments and membrane receptors are not well defined. In previous work we have shown that two members of the S100-family, MRP8 (myeloid related protein 8) and MRP14 play a relevant role in the regulation of cellular dynamics in phagocytes. We have demonstrated that these major calcium-binding proteins in neutrophils and monocytes can act as linker proteins between different cytoskeletal structures depending on the intracellular calcium concentration and the degree of MRP14 phosphorylation. We will now focus on the relevance of these interactions for the inflammatory activation of phagocytes. Based on preliminary results we will further analyse MRP-dependent mechanisms of cellular dynamics in monocytes regarding GTPase activities, Syk-/ Src-signalling, and their consequences for cytoskeletal dynamics, polarization and migration. We will use a combination of genetically modified cell lines, biochemical and biophysical approaches and life cell imaging techniques in vitro and in vivo to identify new pathways of innate immune activation.

吞噬功能等粘附，迁移和吞噬作用取决于细胞骨架的主要重排。这些过程由受体介导的钙信号传导和蛋白质磷酸化级联反应控制。然而，分子链路协调不同细胞骨架室和膜受体的相互作用的定义不当。在先前的工作中，我们已经表明，S100家庭的两个成员MRP8（髓样蛋白8）和MRP14在吞噬细胞中细胞动力学的调节中起着相关的作用。我们已经证明，嗜中性粒细胞和单核细胞中的这些主要钙结合蛋白可以作为不同细胞骨架结构之间的接头蛋白，这取决于细胞内钙浓度和MRP14磷酸化程度。现在，我们将关注这些相互作用对于吞噬细胞的炎症激活的相关性。基于初步结果，我们将进一步分析单核细胞中细胞动力学的MRP依赖性机制，涉及GTPase活性，SYK-/ SRC-SIGNALLing及其对细胞骨架动力学，极化和迁移的后果。我们将在体外和体内结合使用转基因细胞系，生化和生物物理方法以及生命细胞成像技术来识别先天免疫激活的新途径。