2022 Fiscal Year Final Research Report
Novel small molecule chemical compounds for promoting the differentiation efficiency of iPS-derived cardiomyocytes
| Project/Area Number |
20K17129
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 53020:Cardiology-related
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| Research Institution | Keio University |
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Principal Investigator |
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Keywords | 再生医療 / ヒトiPS細胞由来心筋細胞 / BMPシグナル / 心不全 / 低分子化合物 |
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| Outline of Final Research Achievements |
In cardiac differentiation, activation of BMP signaling in the early stage
is important. We searched for small molecule compound activating BMP signaling. To develop the screening system, we used luciferase assay including BMP-responsive element and RNA interference. Among many candidate regulators, we found that knockdown of target factor significantly enhanced luciferase activity. Next, to identify novel antagonists which have high binding-affinity for the candidate factor, we screened compounds by in silico protein structure analysis and narrowed down to 50 candidates among chemical compound data libraries. Next, to test the efficacy of candidate compounds, we confirmed that compounds promoted cardiac differentiation in human iPS cells.
Finally, calculating the correlation function between the chemical structure and the enhancement of BMP signaling activity, we have planned to perform full-screening to identify high efficient lead compounds among massive compound data libraries.
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| Free Research Field |
循環器、心不全、心筋再生
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| Academic Significance and Societal Importance of the Research Achievements |
BMPシグナルを活性化する実用性のある低分子化合物の同定は報告されておらず、独創性でありかつ有用性の高い研究であった。ヒト多能性幹細胞由来心筋を用いた再生医療では、その作成過程において必要な組み換え蛋白の置換によるコスト削減は再生医療の具現化において必要不可欠となっている。また再生医療以外でもBMPシグナル作動低分子化合物の利用価値は高く、骨折や骨形成不全に対して骨形成効果を持つ治療薬として有用である可能性、肺動脈性肺高血圧症などBMPシグナル低下に起因する難病疾患への治療適用の可能性がある。有効性が期待出来るリード化合物候補の探索に繋がるヒット化合物が同定された点で、当研究の意義は大きい。
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