The role of L-selectin in leukocyte recruitment and functions.

L-选择素在白细胞募集和功能中的作用。

• 批准号: 191159840
• 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: 2010
• 资助国家: 德国
• 起止时间: 2009-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/191159840?language=en
• 关键词: role; selectin; leukocyte; recruitment; functions.

Leukocyte recruitment into inflamed tissue proceeds in a cascade-like fashion. The first contact of leukocytes with the endothelium is mediated by selectins and their counter-receptors, followed by rolling, integrin-mediated arrest, crawling, and transmigration. While rolling, leukocytes collect different inflammatory signals which can activate several pathways leading to integrin activation, leukocyte adhesion to endothelium, and transmigration into inflamed tissue. In the last promotion period, we demonstrated that a subset of P-selectin glycoprotein ligand-1 (PSGL-1) molecules are constitutively associated with L-selectin (cis-interaction) and that the signaling output is dependent on this interaction and the cytoplasmic tail of L-selectin. The L-selectin/PSGL-1-complex signals through different molecules to ultimately result in LFA-1 activation. The PSGL-1/L-selectin complex-induced signaling effects on neutrophil slow rolling and recruitment in vivo demonstrate the functional importance of this pathway. The central topics of this application are the impact of L-selectin and the L-selectin/PSGL-1-complex on leukocyte recruitment and functions as well as the exploration of the signaling pathway downstream of L-selectin and the L-selectin/PSGL-1-complex. To address these topics, we will use gene-deficient mice, retrovirus technology, and biochemical methods. Further understanding of these signaling pathways is necessary in order to therapeutically target specific molecules and inhibit specific functions of leukocytes without affecting others.

白细胞向发炎组织的募集以级联方式进行。白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、整合素介导的停滞、爬行和迁移。当滚动时，白细胞收集不同的炎症信号，其可以激活导致整合素激活、白细胞粘附到内皮和迁移到发炎组织中的几种途径。在最后一个促进期，我们证明了一个子集的P-选择素糖蛋白配体-1（PSGL-1）分子组成型与L-选择素（顺式相互作用），信号输出依赖于这种相互作用和L-选择素的胞质尾区。的 L-选择素/PSGL-1复合物通过不同的分子发出信号，最终导致LFA-1活化。PSGL-1/L-选择素复合物诱导的信号传导对体内中性粒细胞缓慢滚动和募集的作用证明了该途径的功能重要性。本申请的中心主题是L-选择素和L-选择素/PSGL-1复合物对白细胞募集和功能的影响，以及L-选择素和L-选择素/PSGL-1复合物下游信号通路的探索。为了解决这些问题，我们将使用基因缺陷小鼠，逆转录病毒技术和生物化学方法。为了治疗靶向特定分子并抑制白细胞的特定功能而不影响其他细胞，进一步了解这些信号通路是必要的。