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

粘附、迁移和吞噬等吞噬功能依赖于细胞骨架的主要重排。这些过程由受体介导的钙信号和蛋白磷酸化级联反应控制。然而，协调不同细胞骨架间室和膜受体相互作用的分子联系并没有很好地定义。在之前的工作中，我们已经发现s100家族的两个成员，MRP8（髓系相关蛋白8）和MRP14在吞噬细胞的细胞动力学调节中发挥相关作用。我们已经证明，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连接蛋白，这取决于细胞内钙浓度和MRP14磷酸化程度。我们现在将重点关注这些相互作用与吞噬细胞炎症激活的相关性。基于初步结果，我们将进一步分析单核细胞中GTPase活性、Syk-/ src -信号传导及其对细胞骨架动力学、极化和迁移的影响的mrp依赖机制。我们将结合使用转基因细胞系、生物化学和生物物理方法以及体外和体内生命细胞成像技术来确定先天免疫激活的新途径。

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.