| Project/Area Number |
07457224
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
内分泌・代謝学
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| Research Institution | KOBE UNIVERSITY |
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Principal Investigator |
CHIHARA Kazuo KOBE UNIV MED,PROFESSOR, 医学部, 教授 (00107955)
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| Co-Investigator(Kenkyū-buntansha) |
ITO Matsuhiro KOBE UNIV MED, 医学部, 日本学術振興会特別研
MATSUI Toshimitsu KOBE UNIV MED,LECTURER, 医学部附属病院, 講師 (10219371)
KAJI Hidesuke KOBE UNIV MED,LECTURER, 医学部附属病院, 講師 (90224401)
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| Project Period (FY) |
1995 – 1996
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| Project Status |
Completed (Fiscal Year 1996)
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| Budget Amount *help |
¥6,700,000 (Direct Cost: ¥6,700,000)
Fiscal Year 1996: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 1995: ¥5,500,000 (Direct Cost: ¥5,500,000)
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| Keywords | CHOLECYSTOKININ / GASTRIN / G PROTEIN-COUPLED RECEPTOR / TYROSINE KINASE / KNOCKOUT MOUSE / GASTRIC ATROPHY / CELL GROWTH / RECEPTOR ANTAGONIST / 神経内分泌細胞 / 細胞骨格 / FAK |
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| Research Abstract |
Many peptide hormone and neurotransmitter receptors belonging to the seven membrane-spanning G protein-coupled receptor family have been demonstrated to transmit ligand-dependent mitogenic signals in vitro. However, the physiological roles of the mitogenic activity through G protein-coupled receptors in vivo remain to be elucidated. Here, we have generated G protein-coupled cholecystokinin (CCK)-B/gastrin receptor deficient-mice by gene targeting. The homozygous mice showed a remarkable atrophy of the gastric mucosa macroscopically, even in the presence of severe hypergastrinemia. The atrophy was due to a decrease in parietal cells and chromogranin A-positive ECL cells expressing the H^+, K^+-ATPase and histidine decarboxylse genes, respectively. Oral administration of a Proton pump inhibitor, which induced hypertrophy of the gastric mucosa with hypergastrinemia in wild-type littermates, did not eliminate the gastric atrophy of the homozygotes. These results clearly demonstrated that the G protein-coupled CCK-B/gastrin receptor is essential for the physiological as well as pathological proliferation of gastric mucosal cells in vivo.
CCK and gastrin promote the growth of NIH 3T3 cells into which the CCK-B/gastrin receptor had been introduced via a eukaryotic expression vector. In addition, treatment with very low concentrations of CCK-8 (10^<-10>M) induced the formation of actin stress fibers within one minute. Stress fiber formation increased for 30 minutes. microinjection of rho GDP dissociation inhibitor or Clostridium botulinum ADP-ribosyltransferase C3 which is known to impair the function of a small GTP-binding protein, rho p21, inhibited the stress fiber formation by CCK-8. These results indicate that CCK-B/gastrin receptor could regulate stress fiber formation in a rho p21-dependent manner. The signals from CCK-B/gastrin receptor might affect cell growth as well as cell motility of adhesion by regulating the actin cytoskeleton.
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