The role of protein tyrosine phosphatases for the regulation of integrin activity and leukocyte 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。在滚动时，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，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。为了限制炎症和免疫功能，必须关闭信号通路。缺乏负调控因子的小鼠通常具有促炎表型。白细胞表达不同的蛋白酪氨酸磷酸酶(PTPs)，参与调节不同信号通路的活性。此外，信号通路也可以被含有免疫受体酪氨酸抑制基序(ITIMs)的细胞表面受体失活。然而，对于白细胞募集的不同步骤，负性调节因子的作用仍不清楚。因此，该提案的目的是通过使用基因缺陷小鼠、逆转录病毒技术和生化方法来确定这些负调控因子如何影响整合素活性以及白细胞募集的不同步骤。进一步了解负性调节因子在白细胞募集和激活中的作用是必要的，以便在不影响其他细胞的情况下靶向特定的分子和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 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 leading to integrin activation, leukocyte adhesion to endothelium, and transmigration into inflamed tissue. In order to limit inflammation and immune function, signaling pathways must be turned off. Mice lacking negative regulators often have a pro-inflammatory phenotype. Leukocytes express different protein tyrosine phosphatases (PTPs), which are involved in regulating the activity of different signaling pathways. Furthermore, signaling pathways can also be deactivated by cell surface receptors that contain immunoreceptor tyrosine-based inhibitory motifs (ITIMs). However the role of negative regulators for the different steps of leukocyte recruitment is still unknown. Therefore, the aim of the proposal is to identify how these negative regulators may affect integrin activity and the different steps of leukocyte recruitment by using gene-deficient mice, retrovirus technology, and biochemical methods. Further understanding of the role of negative regulators in leukocyte recruitment and activation is necessary in order to therapeutically target specific molecules and inhibit specific functions of leukocytes without affecting others.