Mechanism elucidation and drug development of early-stage FOP respond to TGF-b signaling using patient-derived iPSCs

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K16540
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 49010:Pathological biochemistry-related
• Research Institution: Kyoto University
• Principal Investigator: Zhao Chengzhu 京都大学, iPS細胞研究所, 特定研究員 (50778678)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: 進行性骨化性線維異形成症 / FOP / iPS細胞

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.

Free Research Field

分子生物学

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。