| Project/Area Number |
17K11936
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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 |
Orthodontics/Pediatric dentistry
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| Research Institution | Osaka University |
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Principal Investigator |
Itoh Shinsuke 大阪大学, 歯学研究科, 助教 (40633706)
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| Co-Investigator(Kenkyū-buntansha) |
黒坂 寛 大阪大学, 歯学部附属病院, 講師 (20509369)
山城 隆 大阪大学, 歯学研究科, 教授 (70294428)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
Fiscal Year 2019: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000)
Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2017: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000)
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| Keywords | 口唇口蓋裂 / 頭頚部先天異常 / DLC1 / ノックアウトマウス / 先天奇形 / 発生生物学 / 歯学 / 発生・分化 / 遺伝子 / シグナル伝達 / ゲノム |
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| Outline of Final Research Achievements |
To elucidate the pathogenic mechanism of cleft lip and palate (CLP), we carried out exome sequencing of genomic DNA from multiple CLP families with the cooperation of patient families. We focused on the DLC1 gene, which has a common mutation among different families.
We created a conditional knockout mouse with the same nucleotide sequence as the above-mentioned familial CLP. A cleft palate was observed in some of these mutant mice, and a part of the palatal bone was defected. DLC1 was expressed in the frontal nasal process and neural tube epithelium at embryonic day 11.5, and the transcriptional factor TFAP2A which is essential for maxillofacial development was co-expressed in neural crest-derived cells of the neural tube and maxillary process. We found a new DLC1 point mutation that causes embryogenesis abnormalities associated with facial cleft development.
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| Academic Significance and Societal Importance of the Research Achievements |
口唇口蓋裂は種々の遺伝子異常が関与する発生頻度の高い先天異常である。哺乳障害、鼻咽腔閉鎖不全、歯牙の欠如をきたし、発音障害、顎顔面発育異常をまねく。口蓋裂の原因は多岐に及ぶが、近年遺伝子改変動物を利用した研究の発展から、飛躍的に口蓋裂発症に関わる遺伝子が報告されている。今回、複数の家族性口蓋裂から新規のDLC1遺伝子の変異を同定した。その変異を再現したコンディショナルノックアウトマウスを作成したところ、一部のマウスに口蓋裂がみられた。顎顔面形成におけるDLC1の関与が示唆され、口蓋裂発症機序の解明に寄与した。今後さらに解析を進めることで、口蓋裂の分子診断および分子治療開発の緒としたい。
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