GQ SIGNALING IN EOSINOPHIL RECRUITMENT/ACTIVATION

嗜酸性粒细胞向气道的募集涉及嗜酸性粒细胞表面受体、内皮细胞、间质基质蛋白和气道上皮细胞的协调作用。嗜酸性粒细胞的活化和迁移由粘附分子和趋化因子控制，这些粘附分子和趋化因子通过与异源三聚体G蛋白偶联的跨膜细胞表面受体的共享家族发出信号。Gq蛋白偶联到配体结合的表面受体，其激活随后的细胞内信号传导蛋白，包括磷脂酶和腺苷酸环化酶。这些细胞内效应物的激活导致通过分子如IP 3、CA+2和cAMP的信号放大，其进而调节配体结合亲和力（即，粘着斑接触）和细胞活化（即，肌动蛋白动员），这是白细胞迁移所必需的。我们建议使用小鼠过敏性哮喘模型来确定Gq在嗜酸性粒细胞募集和激活中的作用。本研究的具体目标是：（1）确定Gq偶联受体在嗜酸性粒细胞趋化和粘附中的作用，（2）表征Gq在细胞-细胞相互作用和参与嗜酸性粒细胞体内运输的其他细胞类型中的作用;（3）开发嗜酸性粒细胞谱系特异性Gq敲除以区分其在嗜酸性粒细胞运输和下游嗜酸性粒细胞效应子功能中的作用（嗜酸性粒细胞诱导的病理和生理变化）。

The recruitment of eosinophils to the airways involves the coordinated action of eosinophil cell surface receptors, endothelial cells, interstitial matrix proteins, and airway epithelial cells. The activation and migration of the eosinophils are controlled by adhesion molecules and chemotactic factors which signal through shared families of transmembrane cell surface receptors that are coupled to heterotrimeric G-proteins. Gq proteins are couple to ligand-bound surface receptors that activate subsequent intracellular signaling proteins including phospholipases and adenylyl cyclase. Activation of these intracellular effectors results in signal amplification through molecules such as IP3, CA+2, and cAMP, which, in turn, regulate ligand binding affinities (i.e., focal adhesion contacts) and cellular activation (i.e., actin mobilization), required for migration of leukocytes. We propose to identify the role of Gq in eosinophil recruitment and activation using a mouse model of allergic asthma. The specific objectives of this proposal are: (1) to determine the role of Gq-coupled receptors in eosinophil chemotaxis and adhesion, (2) to characterize the role of Gq in cell-cell interactions and other cell types involved in eosinophil trafficking in vivo; (3) develop an eosinophil lineage-specific Gq knockout to distinguish its role in eosinophil trafficking and downstream eosinophil effector functions (eosinophil induced pathological and physiological changes).