胃壁细胞负责内因子释放及酸分泌具有重要的生理学意义。胃壁细胞酸分泌失调可导致反流性食道炎、佐林格综合征等消化道疾病。为此，研究胃酸分泌的详尽机制有重要的理论及转化医学价值。组胺刺激的胃酸分泌是通过ezrin介导的质子泵向顶膜移动及顶膜重排机制来实施的。我们的前期研究已揭示ACAP4与ezrin的相互作用及信号转导通路在胃酸分泌中的重要作用。为进一步阐明ACAP4的生理学功能，我们制备了ACAP4条件性基因剔除小鼠。我们拟采用ACAP4特异性敲除的胃壁细胞为模式体系结合超高分辨率的光敏定位显微镜成像详尽评估ACAP4蛋白及其共价修饰在胃酸分泌过程中的动力学特征。同时，我们拟评估幽门螺杆菌VacA毒素对ACAP4剔除小鼠胃壁细胞可塑性的影响。我们期望通过本项目的实施阐明ACAP4-ezrin信号通路在胃壁细胞生理学过程中的作用机制，揭示ACAP4-ezrin信号通路功能变异对消化生理学的影响。

Gastric parietal cells play an important role in digestive physiology as they orchestrate HCl and intrinsic factor secretion. Perturbation of parietal cell secretion has implicated in clinic gastroenterology such as gastroesophageal reflux disease and Zollinger-Ellison syndrome. Therefore, studying of gastric acid secretion is of great importance not only in better understanding of fundamental physiology but also intervention of diseases associated with aberrant acid secretion..Gastric acid secretion elicited by histamine involves in coupling of proton pump mobilization to apical membrane remodeling by ezrin. Our previous study has revealed the interaction between ezrin and ACAP4, ARF6 activating protein, and their interacting network in parietal cell secretion. To delineate physiological function of ACAP4 in gastric acid secretion, we have developed a tissue specific knockout mouse using Cre-LoxP system. Our preliminary characterization demonstrates the inability of ACAP4 KO parietal cell to respond the histamine stimulation. We plan to combine this powerful model system with biophotonic analyses to illustrate the function of ACAP4 and its post-translation modifications in parietal cell dynamics in response to histamine. In addition, we will evaluate how Helicobacter pylori modulate gastric glandular plasticity in the knockout mice. Successful accomplishment of proposed studies will enable us to consolidate the ACAP4-ezrin signaling cascade into molecular physiology of parietal cell acid secretion. Those studies will also better our understanding as to how perturbation of ACAP4-ezrin interaction contributes to parietal cell pathophysiology.