Mechanisms of neutrophil activation in inflammation

白细胞以级联的方式进入炎症组织。中性粒细胞与内皮细胞的第一次接触是由选择素及其对抗受体介导的，随后是滚动和整合素介导的阻滞。在滚动的过程中，中性粒细胞收集不同的炎症信号，这些信号可以激活几种途径。除了通过g蛋白偶联受体（GPCR）激活中性粒细胞外，整合素和选择素配体也能够向细胞发出信号。这些信号通路可以充分激活中性粒细胞。选择素参与和激活GPCR后的信号通路以及趋同点尚不清楚。我建议使用基因缺陷小鼠和生化方法来研究含有Src激酶和免疫受体酪氨酸基激活基序（ITAM）的接头分子参与e-选择素参与后的下游信号传导和整合素激活。此外，我将利用siRNA和慢病毒技术研究GPCR激活后，GPCR的哪些βγ亚基参与中性粒细胞阻滞。进一步了解这两种信号通路是必要的，以便在治疗上靶向特定分子并抑制中性粒细胞的特定功能而不影响其他分子。

Leukocyte recruitment into inflamed tissue proceeds in a cascade-like fashion. The first contact of neutrophils with the endothelium is mediated by selectins and their counter-receptors, followed by rolling and integrin-mediated arrest. While rolling, neutrophils collect different inflammatory signals which can activate several pathways. In addition to activation of neutrophils by G-protein coupled receptors (GPCR) engagement, integrins and selectin ligands are also able to signal into the cell. These signaling pathways may fully activate neutrophils. The signaling pathways following selectin engagement and activation of GPCR and the points of convergence are poorly understood. I propose to investigate which Src kinase and Immunoreceptor Tyrosinbased Activation Motif (ITAM)-containing adaptor molecules are involved in downstream signaling and integrin activation following E-selectin engagement by using gene-deficient mice and biochemical methods. Furthermore, I will investigate which βγ-subunits of GPCRs are involved in neutrophil arrest following GPCR activation by using siRNA and lentivirus technology. The further understanding of these two signaling pathways is necessary in order to therapeutically target specific molecules and inhibit specific functions of neutrophils without affecting others.