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

Skap2 整合素激活和白细胞激活和招募的分子表征

基本信息

批准号：
287891957
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：
Research Grants
财政年份：
2016
资助国家：
德国
起止时间：
2015-12-31 至 2021-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/287891957?language=en
关键词：
Molecular characterization Skap2 integrin activation

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 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.

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。这些信号通路可能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。Skap2在由内向外（选择素和gpcr触发）和由外向内整合素信号传导中的作用将通过基因缺陷小鼠、逆转录病毒技术、体外实验和生化方法进行研究。此外，我们将探索和研究Skap2的下游效应物，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。进一步了解这些信号通路是必要的，以便治疗靶向特定分子和抑制中性粒细胞的特定功能而不影响其他。