Elucidation of cardiomyocyte dedifferentiation and proliferation mechanisms
| Project/Area Number |
20H03683
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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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| Review Section |
Basic Section 53020:Cardiology-related
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| Research Institution | National Cardiovascular Center Research Institute |
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Principal Investigator |
Kikuchi Kazu 国立研究開発法人国立循環器病研究センター, 研究所, 部長 (10638240)
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| Co-Investigator(Kenkyū-buntansha) |
大谷 健太郎 国立研究開発法人国立循環器病研究センター, 研究所, 室長 (50470191)
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| Project Period (FY) |
2020-04-01 – 2023-03-31
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| Project Status |
Completed (Fiscal Year 2022)
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| Budget Amount *help |
¥18,200,000 (Direct Cost: ¥14,000,000、Indirect Cost: ¥4,200,000)
Fiscal Year 2022: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
Fiscal Year 2021: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
Fiscal Year 2020: ¥11,960,000 (Direct Cost: ¥9,200,000、Indirect Cost: ¥2,760,000)
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| Keywords | 心筋再生 / 心筋細胞 / 脱分化 / 増殖 / 転写因子 / ゼブラフィッシュ / マウス / 心不全 / 心臓再生 / 心筋細胞増殖 / 心筋細胞脱分化 |
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| Outline of Research at the Start |
ゼブラフィッシュは成体であっても心筋細胞の増殖能を保持し，損傷により失われた心筋を心筋細胞の脱分化・増殖を介して再生することができる。最近申請者はゼブラフィッシュの成熟心筋細胞において、脱分化・増殖を誘導する転写因子を同定した。予備データから，この転写因子の心筋再生機能は、成体マウスの心臓においても保存されていることが示唆されている。本研究では，この転写因子のエピゲノム機能および標的遺伝子を網羅的に探索・解明し，新規の心筋再生機序を明らかにする。また，マウスモデルを作製し，ゼブラフィッシュにおける機能との比較解析を行い、さらに心不全治療効果を検討する。
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| Outline of Final Research Achievements |
We performed a genome-wide analysis of Klf1 binding sites and found that most Klf1 binding sites are enriched in distal enhancer regions, which induces a global reduction in chromatin accessibility. Motif enrichment analysis revealed that the binding sites for the core cardiac transcription factors (Gata4, Nkx2-5, Mef2) are significantly enriched in the reduced accessibility regions, indicating that Klf1 induces cardiomyocyte dedifferentiation by suppressing cardiac gene regulatory network controlled by the core cardiac transcription factors. Klf1 also upregulates the expression of diverse cell cycle genes with a simultaneous downregulation of the mitochondrial respiration pathway, which enables cardiomyocytes to proliferate with reduced oxidative stress. We generated transgenic mouse lines and observed that Klf1 induction also leads to the increase of cardiomyocyte proliferation and cardiac size, and further analysis of these mouse lines is underway.
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| Academic Significance and Societal Importance of the Research Achievements |
申請者が見出したKlf1経路は既知のHippo-Yap経路やErbb2経路などとは異なる、全く新しい心筋再生誘導機構である。これまで心筋細胞増殖の誘導は主に増殖促進機構の解明を中心に行われてきたが、本研究によりKlf1が心筋細胞の脱分化と代謝リプログラミングにおいても重要な機能を果たすことが明らかとなった。本研究によるKlf1機能の解明は、ヒト心筋細胞を増殖不能から増殖可能状態へと転換する新規医療技術の開発に大きく貢献することが期待される。
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Report
(4 results)
Research Products
(40 results)
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[Journal Article] Endoderm-derived islet1-expressing cells differentiate into endothelial cells to function as the vascular HSPC niche in zebrafish2023
Author(s)
Hiroyuki Nakajima, Hiroyuki Ishikawa, Takuya Yamamoto, Ayano Chiba, Hajime Fukui, Keisuke Sako, Moe Fukumoto, Kenny Mattonet, Hyouk-Bum Kwon, Subhra P Hui, Gergana D Dobreva, Kazu Kikuchi, Christian S M Helker, Didier Y R Stainier, Naoki Mochizuki
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Journal Title
Developmental Cell
Volume: 58
Issue: 3
Pages: 224-238
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] A zebrafish functional genomics model to investigate the role of human A20 variants in vivo2020
Author(s)
Daniele Cultrone, Nathan W. Zammit, Eleanor Self, Benno Postert, Jeremy Z. R. Han, Jacqueline Bailey, Joanna Warren, David R. Croucher, Kazu Kikuchi, Ozren Bogdanovic, Tatyana Chtanova, Daniel Hesselson, Shane T. Grey
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Journal Title
Sci Rep
Volume: 10
Issue: 1
Pages: 19085-19085
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] Deep conservation of the enhancer regulatory code in animals2020
Author(s)
Emily S. Wong*, Dawei Zheng†, Siew Z. Tan†, Neil L. Bower, Victoria Garside, Gilles Vanwalleghem, Federico Gaiti, Ethan Scott, Benjamin M. Hogan, Kazu Kikuchi, Edwina McGlinn, Mathias Francois*‡, Bernard M. Degnan*‡ (*Corresponding author; †, ‡Contributed equally)
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Journal Title
Science
Volume: 370
Issue: 6517
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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[Journal Article] Trp53 and Rb1 regulate autophagy and ligand-dependent Hedgehog signaling2020
Author(s)
Catherine R. Cochrane, Vijesh Vaghjiani, Anette Szczepny, W. Samantha N. Jayasekara, Alvaro Gonzalez-Rajal, Kazu Kikuchi, Geoffrey W. McCaughan, Andrew Burgess, Daniel J. Gough, D. Neil Watkins, Jason E. Cain
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Journal Title
J Clin Invest
Volume: 130
Pages: 4006-4018
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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