Elucidation of the pathological mechanism of Gorlin syndrome using disease-specific iPS cells

• Project/Area Number: 16K20427
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Functional basic dentistry
• Research Institution: Tokyo Dental College
• Principal Investigator: Onodera Shoko 東京歯科大学, 歯学部, 講師 (90637662)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2016: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 疾患iPS細胞 / 骨芽細胞分化 / 遺伝子解析 / Gorlin症候群 / 骨芽細胞 / 疾患特異的iPS / Hedgehog経路 / Golrin 症候群 / 基底細胞母斑症候群 / 疾患特異的iPS細胞

Outline of Final Research Achievements

Golrin syndrome is an autosomal dominant inherited disorder with a mutation in the Hh receptor, PTCH1. The syndrome have various conditions like bone abnomarty and multipul tumor. Although relationship between mutation location and symptoms is unclear. Genetic analysis showed that there were variants in other Hh receptor receptors PTCH2 and BOC in patients with mutations in PTCH1. This additional mutation may affect activation of Hh pathway. GorliniPS cells established from this syndrome have activation of the WNT pathway and BMP pathway in addition to the activity of the Hh pathway at osteoblast differentiation.This interaction may contributes to bone morphological abnormality with Gorlin syndrome.

Research Products

• [Journal Article] Targeted reversion of induced pluripotent stem cells from patients with human cleidocranial dysplasia showed corrected osteoblastic differentiation both in vitro and in vivo. (2018)
  • Author(s): Ooki A, Nakamura T, Onodera S, Hayashi K, Hasegawa D, Kato H, Onda T, Watanabe A, Kosaki K, Nishimura K, Ohtaka M, Nakanishi M, Sakamoto T, Yamaguchi A, Sueishi K, Azuma T
  • Journal Title: Stem Cell Res Ther Volume: 9 Issue: 1 Pages: 12-12
  • DOI: 10.1186/s13287-017-0754-4
  • Peer Reviewed / Open Access
• [Journal Article] Multi-layered mutatin in hedgehog-related genes in Gorlin syndrome may affect the phenotype. (2017)
  • Author(s): Onodera S, Saito A, Hasegawa D, Watanabe K, Morita N, Nomura T, Shibahara T, Ohba S, Yamaguchi A, Azuma T
  • Journal Title: PLOS ONE Volume: 12 Issue: 9 Pages: e0184702-e0184702
  • DOI: 10.1371/journal.pone.0184702
  • Peer Reviewed / Open Access
• [Journal Article] Gorlin syndrome-derived induced pluripotent stem cells are hypersensitive to Hedgehog-mediated osteogenic induction. (2017)
  • Author(s): Hasegawa D, Shino H, Onodera S, Nakamura T, Saito A, Onda T, Watanabe K, Nishimura K, Ohtaka M, Nakanishi M, Kosaki K, Yamaguchi A, Shibahara T, Azuma T
  • Journal Title: PLos One Volume: 12 Issue: 10 Pages: e0186879-e0186879
  • DOI: 10.1371/journal.pone.0186879
  • Peer Reviewed / Open Access
• [Presentation] Gorlin症候群患者由来iPS細胞の骨芽細胞分化能の異常とその分子メカニズム (2018)
  • Author(s): 小野寺 晶子、東 俊文、斎藤 暁子、長谷川 大悟、片倉 朗、野村 崇、小崎 健次郎、鄭 雄一、柴原 孝彦、大庭 伸介
  • Organizer: 第17回日本再生医療学会総会
• [Presentation] Gorlin症候群患者由来iPS細胞の骨芽細胞分化能の異常とその分子メカニズム (2017)
  • Author(s): 小野寺 晶子、東 俊文、斎藤 暁子、長谷川 大悟、片倉 朗、野村 崇、小崎 健次郎、鄭 雄一、柴原 孝彦、大庭 伸介
  • Organizer: 第35回日本骨代謝学会学術集会
• [Presentation] Whole Eexome Sequence 解析を用いた Gorlin症候群における新規関連遺伝子の検討 (2016)
  • Author(s): 小野寺 晶子
  • Organizer: 第 39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-11-30
• [Presentation] Characterization of iPS cells derived from basal cell nevus syndrome primary oral tissue fibroblast (2016)
  • Author(s): Shoko Onodera
  • Organizer: ESA/SRB/ANZBMS joint meeting 2016
  • Place of Presentation: Gold coast convention and exhibition
  • Year and Date: 2016-08-21
  • Int'l Joint Research
• [Presentation] Gorlin症候群患者由来iPS細胞のGLI3による骨芽細胞分化制御 (2016)
  • Author(s): 小野寺 晶子
  • Organizer: 第34回日本骨代謝学会学術集会
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2016-07-20
• [Remarks] 顎骨疾患プロジェクト
  • URL: http://www.tdc.ac.jp/college/activity/tabid/526/Default.aspx