| Project/Area Number |
18K15120
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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 49030:Experimental pathology-related
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| Research Institution | Kyoto University |
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Principal Investigator |
Miki Kenji 京都大学, iPS細胞研究所, 研究員 (10772759)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2018: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000)
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| Keywords | HCM / isogenic hiPSC / ゲノム編集 / isogenic / iPS / MYH7-R719Q / RNA-seq / hiPS細胞 / isogenic iPS細胞 / CRISPR |
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| Outline of Final Research Achievements |
In this study, I established several hiPSC lines with isogenic HCM mutations using CRISPR/Cas9 technology, and differentiated them into cardiomyocytes (CMs). I found that CMs with MYH7-R719Q mutation showed significant cardiac hypertrophy at the cellular level. Next, I performed the screening of compounds that inhibit hypertrophy in this hiPSC-CMs and identified the target gene by chemical proteomics using the compound (Gene name is unpublished as of this moment). In addition, the hiPSCs in which the gene was knocked out showed cardiac hypertrophy at the cellular level similar to that of human iPS cells with the MYH7-R719Q mutation. Although further analysis is needed, I have found a possible new mechanism of cardiac hypertrophy that has not been reported before.
Furthermore, I was able to publish two papers related to this research within a period of time.
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| Academic Significance and Societal Importance of the Research Achievements |
HCMの原因遺伝子としてこれまで10種以上の遺伝子及び900以上の突然変異が報告されており、様々なHCM患者由来のiPS細胞を用いて研究されているが、そのメカニズムの解明及び有効な治療薬の開発には至っていない。私はisogenic変異株を用いる戦略で同一の遺伝的背景を持つ複数のHCM変異iPS細胞株を作製し、これらを詳細に解析することで、これまで報告されていない新規のHCMメカニズムの可能性を見出した。このメカニズムをさらに解析することで、多くのHCM患者に適応できる治療薬の開発に繋がる可能性があるとともに、今回採用した戦略は様々な疾患領域へ応用可能な方法であり、その意義は大きいと考えている。
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