Gastric acidity-associated disorders such as peptic ulcer and reflux diseases are widespread,and the reported resistance and side effects of currently used medicines suggest an urgent requirement for alternative thera...Gastric acidity-associated disorders such as peptic ulcer and reflux diseases are widespread,and the reported resistance and side effects of currently used medicines suggest an urgent requirement for alternative therapeutic approaches.Here we demonstrate a critical role of ASAP3 in regulating the microvilli structure of parietal cells in vivo,and reveal the feasibility of controlling gastric acidity by targeting ASAP3.Conditional knockout of ASAP3 in mice caused elongation and stacking of microvilli in parietal cells,and substantially decreased gastric acid secretion.These were associated with active assembly of F-actin caused by a higher level of GTP-bound Arf6 GTPase.Consistently,a small molecular compound QS11 inhibited ASAP3 function and significantly reduced gastric acidity in vivo.Of note,the expression of ASAP3 was positively correlated with gastric acid secretion in 90 human cases,and high expression of ASAP3 was associated with reflux disease and peptic ulcer.These results reveal for the first time that ASAP3 regulates the microvilli structures in parietal cells.Our data also suggest ASAP3 as a feasible and drugable therapeutic target for gastric acidity-associated diseases.展开更多
基金This project was supported by grants from the Major Program of National Natural Science Foundation of China(81530072),the Projects of International Cooperation and Exchanges NSFC(81320108024),and the Innovative group projects(81421001)to Jing-Yuan FangNational Natural Science Foundation of China(81572326,81322036,81272383,81602518,81502015 and 81572303)+4 种基金Top-Notch Young Talents Program of China(ZTZ2015-48)Shanghai Municipal Education Commission-Gaofeng Clinical Medicine Grant Support(20152514)National Key Research and Development(R&D)Plan(2016YFC0906000 and 2016YFC0906002)National Key Technology Support Program(2015BAI13B07)the Doctoral Innovation Fund Projects from Shanghai Jiao Tong University School of Medicine to JQ(BXJ201419).
文摘Gastric acidity-associated disorders such as peptic ulcer and reflux diseases are widespread,and the reported resistance and side effects of currently used medicines suggest an urgent requirement for alternative therapeutic approaches.Here we demonstrate a critical role of ASAP3 in regulating the microvilli structure of parietal cells in vivo,and reveal the feasibility of controlling gastric acidity by targeting ASAP3.Conditional knockout of ASAP3 in mice caused elongation and stacking of microvilli in parietal cells,and substantially decreased gastric acid secretion.These were associated with active assembly of F-actin caused by a higher level of GTP-bound Arf6 GTPase.Consistently,a small molecular compound QS11 inhibited ASAP3 function and significantly reduced gastric acidity in vivo.Of note,the expression of ASAP3 was positively correlated with gastric acid secretion in 90 human cases,and high expression of ASAP3 was associated with reflux disease and peptic ulcer.These results reveal for the first time that ASAP3 regulates the microvilli structures in parietal cells.Our data also suggest ASAP3 as a feasible and drugable therapeutic target for gastric acidity-associated diseases.
