2023 Fiscal Year Final Research Report
TGF-beta Signaling in fibrosis of recessive dystrophic epidermolysis bullosa
| Project/Area Number |
20K08646
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 53050:Dermatology-related
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| Research Institution | Hirosaki University |
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Principal Investigator |
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| Project Period (FY) |
2020-04-01 – 2024-03-31
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| Keywords | 表皮水疱症 / 栄養障害型表皮水疱症 / VII型コラーゲン / TGF-beta |
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| Outline of Final Research Achievements |
In recessive dystrophic epidermolysis bullosa (RDEB), elevated TGF-beta signaling has been reported to drive devastating fibrosis. The exact knowledge of the individual contributions of keratinocytes and fibroblasts to dermal fibrotic response is crucial for development of improved disease-modulating therapies. We investigated the keratinocyte-fibroblast interaction on enhanced TGF-beta signaling in RDEB skin using fibroblasts and keratinocytes originating from RDEB donors. RDEB fibroblasts had an enhanced capacity to activate latent TGF-beta. Additionally, inhibition of thrombospondin-1 (TSP-1), matrix metalloproteinases (MMPs), and RGD-binding integrins, which are representative activators of latent TGF-beta, suppressed the TGF-beta signaling in RDEB fibroblasts. These results suggested the involvement of keratinocytes in initiating and progressing dermal fibrosis via TSP-1, MMPs, and RGD-binding integrins mediating keratinocytes-fibroblasts interaction.
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| Free Research Field |
遺伝性水疱症
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| Academic Significance and Societal Importance of the Research Achievements |
本研究ではRDEBにおける線維化の治療ターゲットとしてLatent TGF-βの活性化抑制に着目し，MMP, インテグリン,トロンボスポンディン，ROSがRDEBFにおけるTGF-βシグナルを活性化させること，これらの阻害によりTGF-βシグナルおよび線維化関連蛋白の発現を抑制できると考えられ，RDEB線維化の新規治療法の発展につながる．さらにRDEBFをとりまく細胞外マトリックスは，癌の上皮間葉転換や浸潤・転移とも密接に関連しているため，この新規治療法が確立されれば，線維化のみならず，RDEBの最も重篤な合併症であるcSCCの進展を抑制できると考えられる．
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