| Project/Area Number |
07557075
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 試験 |
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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 Mitsuhiro KOBE UNIV MED, 医学部, 日本学術振興会特別研
OKIMURA Yasuhiko KOBE UNIV MED,ASSIST PROF., 医学部附属病院, 助手 (30204100)
MATSUI Toshimitsu KOBE UNIV MED,LECTURER, 医学部附属病院, 講師 (10219371)
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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 |
¥7,000,000 (Direct Cost: ¥7,000,000)
Fiscal Year 1996: ¥1,000,000 (Direct Cost: ¥1,000,000)
Fiscal Year 1995: ¥6,000,000 (Direct Cost: ¥6,000,000)
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| Keywords | CHOLECYSTOKININ / GASTRIN / G PROTEIN-COUPLED RECEPTOR / TYROSINE KINASE / KNOCKOUT MOUSE / GASTRIC ATROPHY / CELL GROWTH / RECEPTOR ANTAGONIST / 受容体作動薬 / 向情神薬 |
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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-dependen 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 decarboxylase genes, respectively. Administration of a proton pump inhibitor, omeprazole, which induced hypertrophy of the gastric mucosa with hypergastrinemia in wild-type littermates, did not eliminate the gastric atrophyy of the homozygotes. These results clearl demonstrated
… More
that the G protein-coupled receptor is essential for the physiological as well as pathological proliferation of gastric mucosal cells in vivo.
We evaluated the antiproliferative potency of CCK-B receptor antagonists by using mouse fibroblasts expressing human CCK-B receptors (N-hCCKBR). Among several antagonists, a benzodiazepine derivative, YM022 had the most potent activities in the competition of [^<125>I]-CCK-8 or [^<125>I]-qadtrin I binding, the inhibition of CCK-8-or gastrin I-induced phosphoinositide hydrosis and cytoplasmic free calcium increase. YM022 inhibited the ligand-induces [^3H]-thymidine incorporation of N-hCCKBR cells in a dose-dependent manner. YM022 also inhibited the proliferation of esveral human cancer cell lines expressing both the genes for gastrin and its receptor. These results suggest that YM022 could intervene in the autocrine stimulation of human tumor cell lines through CCK-B/gastrin receptors. N-hCCKBR cells are an excellent tool to screen a novel human CCK-B receptor antagonist. Less
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