Mechanism elucidation and drug development of early-stage FOP respond to TGF-b signaling using patient-derived iPSCs
| Project/Area Number |
19K16540
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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 49010:Pathological biochemistry-related
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| Research Institution | Kyoto University |
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Principal Investigator |
Zhao Chengzhu 京都大学, iPS細胞研究所, 特定研究員 (50778678)
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| Project Period (FY) |
2019-04-01 – 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: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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| Keywords | 進行性骨化性線維異形成症 / FOP / iPS細胞 / iPS 細胞 / フレア・アップ / 間葉系幹細胞 |
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| Outline of Research at the Start |
本研究は希少疾患であるFOP病態初期の熱感と疼痛を伴う腫脹が生じるフレア・アップ現象に着目し、FOP患者由来iPS細胞 (FOP-iPSC) を用いて、病態メカニズム解明および候補治療薬探索を目指す。具体はフレア・アップ部位の主な細胞成分と考えられる間葉系幹細胞 (MSC) の過剰増殖・動員現象に着目し、FOP-iPSCから分化誘導されたMSCを用いることで、初期病態のin vitro再現系を構築する。一方、MSCの増殖・動員には、TGF-βシグナルが重要であるため、構築した再現系を用いて、FOP細胞が特異的にTGF-βシグナルに反応する分子メカニズムの解明及び治療候補薬の探索を行う。
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| Outline of Final Research Achievements |
Fibrodysplasia ossificans progressiva (FOP) is a genetic disorder characterized by progressive heterotopic bone (HO) formation in soft tissues. Early FOP lesion, also knows as 'flare-up’, initiates by soft tissue injury, followed by endochondral ossification to form HO. FOP patients harbor gain-of-function mutations in ACVR1, conferring overactivation of BMP signaling which induces differentiation of stromal cells in flare-up tissue into HO. However, the cause of flare-up formation has not been reported. In a this study, we established an in vitro flare-up model by using FOP patient-derived induced pluripotent stem cells (FOP-iPSCs). Based on this model, we found a 'ligand A' specifically increased proliferation activity of FOP cells. Besides, ligand A administration induced flare-up and HO in FOP model mice. The findings of this project could add substantially to our understanding and provide a new therapeutic target of FOP.
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| Academic Significance and Societal Importance of the Research Achievements |
近年盛んに行われた FOP の骨化および軟骨化メカニズムの解明とそれを抑制する新規候補となる化合物探索研究と比較して、フレア・アップ期については現状では現象論的な臨床研究にとどまり、病態メカニズムも未解明な点が多い。本研究で構築した in vitro 病態再現系、およびそれを基づいて見出したリガンド A はフレア・アップに関連する分子シグナルの解明、 及びそれを抑える治療法の探索へとつながると期待される。
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Report
(3 results)
Research Products
(6 results)
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[Journal Article] In vivo regeneration of rat laryngeal cartilage with mesenchymal stem cells derived from human induced pluripotent stem cells via neural crest cells2021
Author(s)
Masayoshi Yoshimatsu, Hiroe Ohnishi, Chengzhu Zhao, Yasuyuki Hayashi, Fumihiko Kuwata, Shinji Kaba, Hideaki Okuyama, Yoshitaka Kawai, Nao Hiwatashi, Yo Kishimoto, Tatsunori Sakamoto, Makoto Ikeya, Koichi Omori
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Journal Title
Stem Cell Research
Volume: 52
Pages: 102233-102233
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Pro-angiogenic scaffold-free Bio three-dimensional conduit developed from human induced pluripotent stem cell-derived mesenchymal stem cells promotes peripheral nerve regeneration2020
Author(s)
Mitsuzawa S, Zhao C, Ikeguchi R, Aoyama T, Kamiya D, Ando M, Takeuchi H, Akieda S, Nakayama K, Matsuda S, Ikeya M
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Journal Title
Scientific Reports
Volume: 10(1)
Issue: 1
Pages: 1-15
DOI
Related Report
Peer Reviewed
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