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

白细胞向发炎组织的募集以级联方式进行。中性粒细胞与内皮的第一次接触是由选择素及其反受体介导的，随后是滚动和整合素介导的停滞。当滚动时，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）接合激活嗜中性粒细胞之外，整合素和选择素配体也能够向细胞中发出信号。这些信号通路可以完全激活中性粒细胞，但它们知之甚少。我建议调查是否Skap 2参与整合素激活，白细胞募集，和其他中性粒细胞功能。Skap 2在由内而外（选择素和GPCR触发）和由外而外的整合素信号传导中的作用将通过使用基因缺陷小鼠、逆转录病毒技术、体外测定和生物化学方法进行研究。此外，我们将探索和研究Skap 2的下游效应子，并随后在体外和体内进行结构-功能分析，以研究其生理相关性。为了治疗靶向特定分子并抑制嗜中性粒细胞的特定功能而不影响其他细胞，对这些信号通路的进一步理解是必要的。

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.