Hedgehog signaling in human diseases
| Project/Area Number |
16K09960
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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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| Research Field |
Pediatrics
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| Research Institution | Chiba University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
宮下 俊之 北里大学, 医学部, 教授 (60174182)
梅澤 明弘 国立研究開発法人国立成育医療研究センター, 再生医療センター, 副所長/再生医療センター長 (70213486)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | ヘッジホッグ / Gorlin症候群 / 基底細胞母斑症候群 / 基底細胞癌 / 髄芽腫 / 皮膚線維芽細胞 / iPS細胞 / ヘッジホッグシグナル / ゴーリン症候群 / PTCH1 / 高発癌性疾患 / シグナル伝達 / 脳神経疾患 / 再生医学 / 遺伝学 / ゲノム |
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| Outline of Final Research Achievements |
The hedgehog signaling pathway is a vital factor for embryonic development and stem cell maintenance. Dysregulation of its function results in tumor initiation and progression. The aim of this research was to establish a disease model of hedgehog-related tumorigenesis with Gorlin syndrome-derived induced pluripotent stem cells (GS-iPSCs). Induced neural progenitor cells from GS-iPSCs (GS-NPCs) shows constitutive high GLI1 expression and higher sensitivity to smoothened (SMO) inhibition compared to wild-type induced neural progenitor cells (WT-NPCs). The differentiation process from iPSCs to NPCs may have similarity in gene expression to Hedgehog signal related-carcinogenesis. Therefore, GS-NPCs may be useful for screening compounds to find effective drugs to control Hedgehog signaling activity.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究では、世界初のGorlin症候群iPS細胞を作製し、ヘッジホッグシグナルの発生段階での特性を解明したことは大きな学術的成果といえる。特にGorlin iPS細胞を分化誘導させることで、未分化な状態から神経分化に移行した時点でヘッジホッグシグナルが最も亢進し阻害剤が効果的に働くこと、また遺伝子変異がある場合には亢進が持続して癌化に至ることが解明したことは、個体が発生から組織分化する過程でヘッジホッグ経路を始めとした多様なシグナル系が選択的に活性化されることを示した点で興味深い。本研究でGorlin症候群由来のiPS細胞はヘッジホッグシグナル異常症の疾患モデルとして有用であることが示された。
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Report
(4 results)
Research Products
(15 results)
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[Journal Article] A novel PTCH1 mutation in basal cell nevus syndrome with rare craniofacial features2019
Author(s)
Murata Y, Kurosaka H, Ohata Y, Aikawa T, Takahata S, Fujii K, Miyashita T, Morita C, Inubushi T, Kubota T, Sakai N, Ozono K, Kogo M, Yamashiro T.
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Journal Title
Human Genome Variation
Volume: 6
Issue: 1
Pages: 16-16
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Nevoid basal cell carcinoma syndrome caused by splicing mutations in the PTCH1 gene.2017
Author(s)
Kato, C., Fujii, K., Arai, Y., Hatsuse, H., Nagao, K., Takayama, Y., Kameyama, K., Fujii, K., and Miyashita, T.
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Journal Title
Familial Cancer
Volume: 16
Issue: 1
Pages: 131-138
DOI
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
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[Journal Article] Brain morphology in children with nevoid basal cell carcinoma syndrome.2017
Author(s)
Shiohama, T., Fuji, K., Miyashita, T., Mizuochi, H., Uchikawa, H., Shimojo, N.
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Journal Title
American Journal of Medical Genetics A
Volume: 173
Issue: 4
Pages: 946-952
DOI
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
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[Journal Article] Somatic mosaicism containing double mutations in PTCH1 revealed by generation of induced pluripotent stem cells from nevoid basal cell carcinoma syndrome.2017
Author(s)
Ikemoto, Y., Takayama, Y., Fujii, K., Masuda, M., Kato, C., Hatsuse, H., Fujitani, K., Nagao, K., Kameyama, K., Ikehara, H., Toyoda, M., Umezawa, A. and Miyashita, T.
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Journal Title
Journal of Medical Genetics
Volume: －
Issue: 8
Pages: 579-584
DOI
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
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