| Project/Area Number |
18590246
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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 |
General pharmacology
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| Research Institution | Hoshi University |
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Principal Investigator |
MISAWA Miwa Hoshi University, Sch. of Pharm., Dept. of Pharmacol, Professor (20061294)
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| Co-Investigator(Kenkyū-buntansha) |
CHIBA Yoshihiko Hoshi University, Sch. of Pharm., Dept. of Pharmacol, Assistant professor (00287848)
SAKAI Hiroyasu Hoshi University, Sch. of Pharm., Dept. of Pharmacol, Research Associate (00328923)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥3,830,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥330,000)
Fiscal Year 2007: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2006: ¥2,400,000 (Direct Cost: ¥2,400,000)
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| Keywords | bronchial asthma / airway hyperesponsiveness / Ca^<2+> sensitization / RhoA / transcription factor / statins / geranylgeranylation / 気道過敏性 / lovastatin / glucocorticoid / CPI-17 / Il-13 / STAT6 |
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| Research Abstract |
The mechanisms of pathogenesis of airway hyperresponsiveness(AHR) in allergic bronchial asthma were investigated pharmacologically and molecular biologically. The following results were obtained.
1. The contractile responsiveness to endothelin-1(ET-1) was increased in the bronchi isolated from rats subjected with repeated antigen challenges. In the augmented ET-1-induced contractility an increase in Ca^<2+> sensitization phenomenon was involved ; phosphorylations(activations) of CTI-17 and myosin light chain kinase were enhanced. 2. The expressions and activations of matrix metalloproteinase(MMP)-12 mRNA and protein of bronchial muscle were increased by repeated antigen challenges, suggesting that MMP-12 is responsible for ABR. 3. The probable transcription factors in bronchial smooth muscle which are activated by antigen exposure were examined covering it using nuclear extraction of the muscle by the method of protein/DNA array method. Among the transcription factors activated by exposuring antigen, it was found that USF-1, Sp1, NF-El, STAT5 and STAT6 are the transcription factors that have potency to bind to the elements of RhoA promoter area 4. Interleukin-13 was demonstrated to induce AHR through the transcription factor STAT6. 5. Lovastatin, one of the statins, when administered in vivo, inhibited the AHR in rats generated by repeated antigen challenges ex they It was shown that at that time, lovastatin also inhibited the translocation of RhoA to cell membrane. These findings suggest that statins may be effective for improvement of AHR in patients with bronchial asthma. 6. It was also suggested that glucocorticoids exert effectiveness for bronchial asthma by inhibiting the RhoA upregulation seen in the bronchial smooth muscle at antigen-exposure.
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