GQ SIGNALING IN EOSINOPHIL RECRUITMENT/ACTIVATION

嗜酸性粒细胞在呼吸道的募集包括嗜酸性粒细胞表面受体、内皮细胞、间质基质蛋白和呼吸道上皮细胞的协同作用。嗜酸性粒细胞的激活和迁移由黏附分子和趋化因子控制，这些黏附分子和趋化因子通过与异源三聚体G蛋白偶联的共同的跨膜细胞表面受体家族发出信号。GQ蛋白偶联到配体结合的表面受体，激活随后的细胞内信号蛋白，包括磷脂酶和腺苷环化酶。这些细胞内效应分子的激活通过IP3、CA+2和cAMP等分子导致信号放大，进而调节白细胞迁移所需的配体结合亲和力(即焦点黏附接触)和细胞激活(即肌动蛋白动员)。我们建议通过过敏性哮喘的小鼠模型来确定GQ在嗜酸性粒细胞募集和激活中的作用。这项建议的具体目标是：(1)确定GQ偶联受体在嗜酸性粒细胞趋化和黏附中的作用，(2)表征GQ在细胞间相互作用中的作用，以及体内涉及嗜酸性粒细胞运输的其他细胞类型；(3)建立嗜酸性粒细胞系特异性GQ基因敲除，以区分其在嗜酸性粒细胞运输和下游嗜酸性粒细胞效应功能(嗜酸性粒细胞诱导的病理和生理变化)中的作用。

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).