Molecular characterization of Skap2 for integrin activation and leukocyte activation and recruitment

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，但人们对它们知之甚少。我建议研究Skap2是否参与整合素激活、白细胞募集和其他中性粒细胞功能。通过基因缺陷小鼠、逆转录病毒技术、体外实验和生化方法研究Skap2在由内向外(选择素和GPCR触发)和外向整合素信号转导中的作用。此外，我们还将探索和研究Skap2的下游效应，并随后在体外和体内进行结构-功能分析，以探讨其生理相关性。进一步了解这些信号通路是必要的，以便在不影响其他人的情况下，针对特定的分子进行治疗，抑制中性粒细胞的特定功能。

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 receptor (GPCR) engagement, integrins and selectin ligands are also able to signal into the cell. These signaling pathways may fully activate neutrophils, but they are poorly understood. I propose to investigate whether Skap2 is involved in integrin activation, leukocyte recruitment, and other neutrophil functions. The role of Skap2 in inside-out- (selectin- and GPCR-triggered) and outside-in integrin signaling will be investigated by using gene-deficient mice, retrovirus technology, in vitro assays, and biochemical methods. Additionally, we will explore and investigate downstream effectors of Skap2 and subsequently do structure-function analysis in vitro and in vivo to investigate the physiological relevance. The further understanding of these signaling pathways is necessary in order to therapeutically target specific molecules and inhibit specific functions of neutrophils without affecting others.