| Project/Area Number |
21790194
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| Research Category |
Grant-in-Aid for Young Scientists (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
General anatomy (including Histology/Embryology)
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| Research Institution | Nara Medical University |
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Principal Investigator |
SAKABE Masahide Nara Medical University, 医学部, 助教 (00525983)
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| Project Period (FY) |
2009 – 2010
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| Project Status |
Completed (Fiscal Year 2010)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2010: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2009: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
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| Keywords | 先天異常学 / 奇形学 / レチノイン酸 / 心奇形 / 大血管転位 / 心内膜床形成 / 遺伝子解析 |
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| Research Abstract |
A high concentration of maternal retinoic acid (RA), the active derivative of vitamin A, is well known as a teratogenic agent, and induces several developmental abnormalities. Our previous studies have shown that maternal administration of RA to mice within a narrow developmental window induces outflow tract (OFT) septum defect, which closely resembles human transposition of the great arteries (TGA), although the responsible factors and pathogenic mechanisms of TGA induced by RA remained unknown. We herein demonstrate that the expression of Tbx2 in the OFT myocardium is responsive to RA and its down-regulation is the main cause of abnormal OFT septation. We found that RA could directly down-regulate Tbx2 expression through a functional retinoic acid response element (RARE) in the Tbx2 promoter region, which is also required for the initiation of the Tbx2 transcription during OFT development. Tgfβ2 expression was also down-regulated in the RA treated OFT region and up-regulated by Tbx2 in a culture system. Moreover, defective EMT caused by an excess RA was rescued by the addition of Tgfβ2 using an organ culture system. These data suggest that RA signaling participates in the Tbx2 transcriptional mechanism during OFT development, and the Tbx2-Tgfβ2 cascade is a key pathway in the RA-induced TGA phenotype.
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