| 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)
|
|---|
| 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.
|
