| Project/Area Number |
12670573
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Respiratory organ internal medicine
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| Research Institution | Keio University |
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Principal Investigator |
ASANO Koichiro Keio University School of Medicine, Department of Medicine, Assistant professor, 医学部, 講師 (60192944)
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| Co-Investigator(Kenkyū-buntansha) |
SHIOMI Tetsuya Keio University School of Medicine, Department of Medicine, Instructor, 医学部, 助手 (50286465)
YAMAGUCHI Kazuhiro Keio University School of Medicine, Department of Medicine, Associate professor, 医学部, 助教授 (30129712)
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| Project Period (FY) |
2000 – 2001
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| Project Status |
Completed (Fiscal Year 2001)
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| Budget Amount *help |
¥3,300,000 (Direct Cost: ¥3,300,000)
Fiscal Year 2001: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2000: ¥1,700,000 (Direct Cost: ¥1,700,000)
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| Keywords | plasma PAF acetylhydrolase / PAF receptor / asthma / pharmacogenetics / 遺伝子多型 / 血小板活性化因子 / 血小板活性化因子受容体 / 血漿PAFアセチル水解酵素 |
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| Research Abstract |
Platelet activating factor (PAF) is a lipid mediator which is involved in the pathophysiology of asthma. There is a large inter-subject variation in the responsiveness to PAF, which may explain the inconsistency of anti-asthma effect of PAF antagonists. There are several evidences that suggest PAF responsiveness is partially determined genetically. We examined the genetic variations in a PAF-degrading enzyme, plasma PAF acetylhydrolase, and in the PAF receptor.
Approximately 4% of Japanese subjects lack plasma PAF acetylhydrolase genetically. We examined PAF responsiveness using PAF inhalation test in 8 subjects with plasma PAF acetylhydrolase deficiency and 16 subjects with normal enzyme activity. We found a large inter-subject variation in the responsiveness to PAF, however, there was no significant association between plasma PAF acetylhydrolase genotype or activity and PAF responsiveness.
We then examined the genetic structure of PAF receptor gene, finding a missense mutation that converts alanine at 224 with aspartic acid in the third intracellular loop. When stably transfected in CHO cells, the mutant receptor demonstrated impaired responses to PAF (Ca^<2+> transient, inositol phosphate turnover, inhibition of CAMP synthesis, and chemotaxis). There was no direct association between this A224D mutation and asthma, but ,t may be associated with PAF antagonist responsiveness.
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