Btk促进β2整合素激活介导嗜中性粒细胞募集和迁移的力调控机制研究

由Btk激酶(Bruton's tyrosine kinase)所参与的信号转导，对于流体环境下E-选择素(E-selectin)或趋化因子CXCL1诱导的β2整合素(β2-integrin) 激活，在介导嗜中性粒细胞向炎症部位定向募集和迁移中起到至关重要的作用。这一尚不清晰的力-化学耦合诱导过程，是当前细胞分子生物力学中的前沿热点课题。本项目拟采用流动腔实验为技术手段，研究力环境下Btk参与的β2整合素(LFA-1, Mac-1)的激活过程，定量刻画由此介导的慢速滚动，快速捕捉，铺展爬行和跨膜迁移事件，阐明每一事件中β2整合素的类型和激活水平。以揭示Btk促进整合素有效激活的力调控机制，以深化有关炎症反应等生理学和病理学的理解，并为相关创新药物的设计开发提供有效信息和新思路。

Bruton's tyrosine kinase(Btk) plays a key role in β2 integrin activation induced by E-selectin or CXCL1，which is required for neutrophil recruitment and migration into the inflamed tissue. The aim of this grant is to reveal the force-regulation mechanism of β2 integrin activation through Btk, which is not clear so far and has attracted wide interest in cellular and molecular biomechanics research. In this project, the slow rolling, arrest/firm adhesion, crawling and migration of neutrophil activated by E-selectin or CXCL1 will be quantitative studied, and flow chamber experiment technique will be used in this specific aim: Quantify activation rate of β2 integrin mediated by the E-selectin or CXCL1 under force; Clarify the types of β2 integrin in different adhesion events. Elucidate the force-dependent regulation mechanism of β2 intergrin (LFA-1, Mac-1) activaton in participation with Btk. The results would improve our understanding on inflammatory reaction and offer some new therapeutic approaches for the development novel anti-inflammatory treatments.