The role of the Tec kinase "Bruton´s Tyrosine Kinase" (Btk) in integrin activation and leukocyte recruitment

Tec 激酶“布鲁顿酪氨酸激酶”(Btk) 在整合素激活和白细胞招募中的作用

• 批准号: 235065831
• 负责人: Dr. Helena Block
• 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 2016-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/235065831?language=en
• 关键词: role; Tec; kinase; Bruton; Tyrosine

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 leukocyte adhesion to endothelium and transmigration into inflamed tissue. Protein kinases are key regulators of cytoskeletal dynamics and affect many cellular processes, including cell polarity, migration, vesicle trafficking and cytokinesis. The key integrators of signals emanating from G-protein coupled receptors (GPCRs), selectin receptors, and integrin molecules that coordinate these processes are protein tyrosine kinases. Tec-kinases form the second-largest group of non-receptor tyrosine kinases. However, the role of the Tec kinase Brutons tyrosine kinase (Btk) and its upstream and downstream effectors in regulating integrin conformational change and leukocyte recruitment caused by various stimuli remains elusive. Therefore, the aim of this project is to investigate the role of Btk in inside-out signaling (the chemoattractant fMLP and selectin) mediated integrin activation, leukocyte recruitment, and other leukocyte functions by using gene-deficient mice, retrovirus technology, and biochemical methods. Further understanding of the role of Btk 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。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种途径，导致白细胞粘附到内皮细胞并迁移到炎症组织中。蛋白激酶是细胞骨架动力学的关键调节因子，并影响许多细胞过程，包括细胞极性、迁移、囊泡运输和胞质分裂。从G蛋白偶联受体（GPCR）、选择素受体和协调这些过程的整合素分子发出的信号的关键整合剂是蛋白酪氨酸激酶。TEC激酶形成第二大组的非受体酪氨酸激酶。然而，Tec激酶Brutons酪氨酸激酶（Btk）及其上游和下游效应物在调节整合素构象变化和各种刺激引起的白细胞募集中的作用仍然难以捉摸。因此，本项目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研究Btk在由内而外信号传导（趋化因子fMLP和选择素）介导的整合素活化、白细胞募集和其他白细胞功能中的作用。进一步了解Btk在白细胞募集和活化中的作用是必要的，以便治疗性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。