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Mechanisms of neutrophil activation in inflammation

炎症中中性粒细胞激活的机制

基本信息

批准号：
70673720
负责人：
Professor Dr. Alexander Zarbock
金额：
--
依托单位：
Klinik für Anästhesiologie, operative Intensivmedizin und Schmerztherapie
依托单位国家：
德国
项目类别：
Independent Junior Research Groups
财政年份：
2008
资助国家：
德国
起止时间：
2007-12-31 至 2013-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/70673720?language=en
关键词：
Mechanisms neutrophil activation inflammation

项目摘要

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.

白细胞在炎症组织中的募集以级联的方式进行。中性粒细胞与内皮细胞的第一次接触是由选择素及其受体介导的，随后是滚动和整合素介导的停滞。在滚动过程中，中性粒细胞收集不同的炎症信号，这些信号可以激活几条途径。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内传递信号。这些信号通路可能会完全激活中性粒细胞。选择素参与和激活GPCR后的信号通路以及汇聚点还知之甚少。我打算利用基因缺陷小鼠和生化方法，研究哪些Src激酶和免疫受体酪氨酸激活基序(ITAM)适配器分子参与了E-选择素参与的下游信号和整合素激活。此外，我将利用小干扰RNA和慢病毒技术，研究GPCRs的哪些βγ亚基参与了GPCRs激活后中性粒细胞的停滞。为了在不影响其他细胞的情况下靶向特定分子并抑制中性粒细胞的特定功能，进一步了解这两个信号通路是必要的。