| Project/Area Number |
25461549
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Pediatrics
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| Research Institution | Kobe University |
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Principal Investigator |
Nishio Hisahide 神戸大学, 医学(系)研究科(研究院), 教授 (80189258)
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| Co-Investigator(Kenkyū-buntansha) |
NISHIMURA Noriyuki 神戸大学, 大学院医学研究科, 教授 (00322719)
MORIKAWA Satoru 神戸大学, 大学院医学研究科, 講師 (50457074)
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| Project Period (FY) |
2013-04-01 – 2016-03-31
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| Project Status |
Completed (Fiscal Year 2015)
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| Budget Amount *help |
¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2013: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
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| Keywords | 脊髄性筋萎縮症 / ＳＭＮ１遺伝子 / ＳＭＮ２遺伝子 / ＳＭＮ蛋白 / サルブタモール / 交感神経作動薬 / ユビキチン化 / SMN1遺伝子 / SMN2遺伝子 / SMN蛋白 / 交感神経β2受容体 / 交感神経β2受容体作動薬 |
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| Outline of Final Research Achievements |
Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder. SMA is caused by the loss of the SMN1 gene. Although the SMN2 gene also produces SMN protein, it is not enough to compensate for the loss of the SMN1 gene. Salbutamol (adrenergic drug) was reported to improve SMA symptoms. To clarify the mechanism, we treated SMA fibroblasts lacking the SMN1 gene with salbutamol, and analyzed SMN2 mRNA and SMN protein levels. Salbutamol increased SMN protein levels in a dose-dependent manner, although SMN2 mRNA levels were not changed. The salbutamol-induced increase in SMN protein level was blocked by PKA inhibitor and deubiquitinase inhibitor. Immunoprecipitation assay using HeLa cells showed that salbutamol decreased ubiquitinated SMN protein levels, suggesting that salbutamol inhibited ubiquitination. These findings suggest that salbutamol increases SMN protein levels in SMA cells by inhibiting ubiquitin-mediated SMN degradation via activating β2-adrenergic receptor-PKA pathways.
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