BRAF knock-in mice provide a pathogenetic mechanism of developmental defects in CFC syndrome
| Project/Area Number |
25860839
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Multi-year Fund |
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| Research Field |
Pediatrics
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| Research Institution | Tohoku University |
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Principal Investigator |
INOUE SHINICHI 東北大学, 医学(系)研究科(研究院), 助教 (70622091)
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| Project Period (FY) |
2013-04-01 – 2015-03-31
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| Project Status |
Completed (Fiscal Year 2014)
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| Budget Amount *help |
¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
Fiscal Year 2014: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | CFC症候群 / BRAF / RASopathies / RAS/MAPK / 先天性心疾患 / ヒストン脱メチル化酵素 / ＢＲＡＦ / 骨格異常 / リンパ管形成異常 / 心臓発生 / 先天奇形症候群 |
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| Outline of Final Research Achievements |
Germline mutations in BRAF cause cardio-facio-cutaneous (CFC) syndrome, which is characterized by heart defects, distinctive facial features and ectodermal abnormalities. To define the pathogenesis and to develop a potential therapeutic approach in CFC syndrome, we generated knock-in mice expressing the Braf Q241R mutation. Knock-in mice manifested embryonic/neonatal lethality, showing liver necrosis, edema, craniofacial abnormalities and multiple heart defects. Prenatal treatment with a MEK inhibitor, PD0325901, or a histone 3 demethylase inhibitor, GSK-J4, rescued the embryonic lethality in knock-in embryos. Combination treatment with PD0325901 and GSK-J4 further increased the rescue from embryonic lethality. These results suggest that Braf knock-in mice recapitulate major features of CFC syndrome and that epigenetic modulation as well as the inhibition of the ERK pathway will be a potential therapeutic strategy for the treatment of CFC syndrome.
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Report
(3 results)
Research Products
(8 results)
