The role of protein tyrosine phosphatases for the regulation of integrin activity and leukocyte recruitment.

蛋白酪氨酸磷酸酶在调节整合素活性和白细胞招募中的作用。

• 批准号: 245856170
• 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: 2013
• 资助国家: 德国
• 起止时间: 2012-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/245856170?language=en
• 关键词: role; protein; tyrosine; phosphatases; regulation

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.

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，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。为了限制炎症和免疫功能，必须关闭信号通路。缺乏负调节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（PTP），参与调节不同信号通路的活性。此外，信号传导途径也可以通过含有基于免疫受体酪氨酸的抑制基序（ITIM）的细胞表面受体失活。然而，负调节因子在白细胞募集的不同步骤中的作用仍然是未知的。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物化学方法来确定这些负调节剂如何影响整合素活性和白细胞募集的不同步骤。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，有必要进一步了解负调节因子在白细胞募集和活化中的作用。

项目成果

The ITIM Domain–Containing NK Receptor Ly49Q Impacts Pulmonary Infection by Mediating Neutrophil Functions

• DOI: 10.4049/jimmunol.1701084
• 发表时间: 2018-06
• 期刊: The Journal of Immunology
• 作者: A. Margraf;Stephanie Volmering;Jennifer Skupski;V. van Marck;A. Makrigiannis;H. Block;A. Zarbock

Mutation in the CD45 Inhibitory Wedge Modulates Integrin Activation and Leukocyte Recruitment during Inflammation

• DOI: 10.4049/jimmunol.1401646
• 发表时间: 2015-01-15
• 期刊: JOURNAL OF IMMUNOLOGY
• 影响因子: 4.4
• 作者: Germena, Giulia;Volmering, Stephanie;Zarbock, Alexander
• 通讯作者: Zarbock, Alexander

Cross-Talk between Shp1 and PIPKIγ Controls Leukocyte Recruitment.

• DOI: 10.4049/jimmunol.1500606
• 发表时间: 2015-08-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Stadtmann A;Block H;Volmering S;Abram C;Sohlbach C;Boras M;Lowell CA;Zarbock A
• 通讯作者: Zarbock A