| Project/Area Number |
17H04228
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pediatrics
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| Research Institution | Kyoto Prefectural University of Medicine (2019)
Osaka University (2017-2018) |
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Principal Investigator |
Yashiro Kenta 京都府立医科大学, 医学(系)研究科(研究院), 教授 (60432506)
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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 |
¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000)
Fiscal Year 2019: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2018: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2017: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000)
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| Keywords | 心筋緻密化 / GFRA2 / 心臓前駆細胞 / シグナル経路 / リガンド / 分化 / 細胞間相互作用 / 新規シグナル経路 / 心筋緻密化障害 / 心臓発生 / 心筋分化 / 臨床遺伝学 / ゲノム編集 / ヒトゲノム研究 / 発生・分化 / 再生医学 / 遺伝学 / 解剖学 / 循環器 / GFRA1/2新規シグナル経路 |
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| Outline of Final Research Achievements |
An unknown non-canonical signal via GFRA2, a glial-cell derived neurotrophic factor receptor family member, is vital for compaction of ventricular myocardium in the mouse embryos. Defect of this is a potent cause of left ventricular noncompaction (LVNC) in humans. In this study, aiming to validate this signal pathway, we have performed the followings: (1) To identify a factor directly interacting GFRA2, genetic modification (GM) on mouse embryonic stem (ES) cells has been completed. Screening with this cell is planned next. (2) GM of mouse ES cells to generate the mice for conditional targeting of Gfra2 as well as for lineage tracing of GFRA2+ cells has been completed. Elucidating the phenotype of GM mice and the fate-map are planned next. (3) Transcription factor Sox17 is found to be specific for endocardium lineage and be essential for compaction. (4) Some mutation of GFRA2 has been found among LVNC patients, although whether sits responsibility for the disease is still unclear.
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| Academic Significance and Societal Importance of the Research Achievements |
心筋緻密化障害は難治で予後不良であり、分子病態も多くが不明である。この疾患に関する基礎研究による知見も限定的かつ断片的で、かつヒト症例の遺伝学とは未だ有機的に関連づけられていない。本研究は、心筋緻密化に関与する分子機構をGFRA2という新たな視点から解析し、断片的な知見のギャップを埋めようとするものである。さらに、心筋緻密化過程に関与する新たな糸口として転写因子Sox17を見い出し、新たな解析の起点を提示できた。また、病的意義はまだ不明あるが、ヒト心筋緻密化障害症例においてGFRA2の変異も見出している。今後も研究を継続し、心筋緻密化機構の解明とヒト心筋緻密化障害の分子病態の理解を深めたい。
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