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

白细胞在炎症组织中的募集以级联的方式进行。白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、整合素介导的停滞、爬行和移行。在滚动时，白细胞收集不同的炎症信号，激活几条途径，导致整合素激活，白细胞与内皮细胞黏附，并向炎症组织迁移。在最后一个促进期，我们证明了P-选择素糖蛋白配体-1分子的一个子集与L-选择素存在结构性的相互作用(顺式相互作用)，并且信号输出依赖于这种相互作用和L-选择素的胞质尾巴。L-选择素/PSGL-1-复合体通过不同的分子传递信号，最终导致LFA-1的激活。PSGL-1/L-选择素复合体诱导的中性粒细胞缓慢滚动和体内募集的信号效应证明了这一途径的功能重要性。这一应用的中心课题是L-选择素和L-选择素/PSGL-1-复合体对白细胞募集和功能的影响，以及对L-选择素和L-选择素/PSGL-1-复合体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化方法。进一步了解这些信号通路是必要的，以便在不影响其他细胞的情况下，针对特定的分子进行治疗并抑制白细胞的特定功能。

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.