疾患iPS細胞応用による難治性腸疾患治療法の開発

• Project/Area Number: 16K19907
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: General surgery
• Research Institution: National Center for Child Health and Development
• Principal Investigator: 内田 孟 国立研究開発法人国立成育医療研究センター, 外科系専門診療部, 医師 (30648697)
• Project Period (FY): 2016-04-01 – 2017-03-31
• Project Status: Discontinued (Fiscal Year 2016)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: ヒルシュプルング病類縁 / ｍRNA / iPS細胞 / 移植外科学 / 腸管オルガノイド

Outline of Annual Research Achievements

先天性腸疾患、続発性の短腸症候群や炎症性腸疾患の中には有効な治療法が見いだせない難治性のものが多い。腸管は内胚葉、中胚葉と外胚葉由来の細胞組織より構成され、個々の細胞が密に機能連携し消化・吸収、腸管免疫そして蠕動運動などを行っている。本研究では、三胚葉組織へ分化する能力のあるヒト多能性幹細胞を応用し、複雑な組織と機能を有する腸管様の多細胞構造体（オルガノイド）作製系を構築することで、難治性腸疾患の再生医療を含めた医薬応用を見据えた研究を行う。本研究にかかる臨床研究計画（「腸に異常を有する疾患の疾患特異的iPS細胞による疾患モデルの作成、疾患解析および治療法開発に関する研究」）が国立成育医療研究センター倫理委員会で承認受けた（受付番号927）。
国立成育医療研究センターにおいて適切なインフォームドコンセント手続きの下同意が得られた組織検体を本研究へ用いる。ヒルシュプルング病類縁疾患組織からホストゲノムへ外来因子が入り込まない初期化方法として、mRNAによる方法を選択し、iPS細胞の樹立に成功した。ヒルシュプルング病類縁－iPS細胞は、安定的に維持培養・保存可能であることを確認した。難治性腸疾患の研究として、極めて有用なバイオツールを構築することが出来た。

Research Products

• [Journal Article] Living donor liver transplantation during the first three months of life (2017)
  • Author(s): Kasahara M, Sakamoto S, Sasaki K, Uchida H, Kitajima T, Shigeta T, Narumoto S, Hirata Y, Fukuda A
  • Journal Title: Liver Transpl Volume: Feb 21 Issue: 8 Pages: 1051-1057
  • DOI: 10.1002/lt.24743
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A xenogeneic-free system generating functional human gut organoids from pluripotent stem cells (2017)
  • Author(s): 2.Uchida H, Machida M, Miura T, Kawasaki T, Okazaki T, Sasaki K, Sakamoto S, Ohuchi N, Kasahara M, Umezawa A, Akutsu H.
  • Journal Title: Journal of Clinical Investigation Insight Volume: 2 Issue: 1
  • DOI: 10.1172/jci.insight.86492
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Hyperammonemia in ornithine transcarbamylase-deficient recipients following living donor liver transplantation from heterozygous carrier donors (2017)
  • Author(s): Rahayatri TH, Uchida H, Sasaki K, Shigeta T, Hirata Y, Kanazawa H, Mali V, Fukuda A, Sakamoto S, Kasahara M
  • Journal Title: Pediatr Transplant Volume: 21 Issue: 1
  • DOI: 10.1111/petr.12848
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Sequential analysis of variable markers for predicting outcomes in pediatric patients with acute liver failure. (2016)
  • Author(s): Uchida H, Sakamoto S, Fukuda A, Sasaki K, Shigeta T, Nosaka S, Kubota M, Nakazawa A, Nakagawa S, Kasahara M
  • Journal Title: Hepatol Res Volume: dec 29 Issue: 12 Pages: 1241-1251
  • DOI: 10.1111/hepr.12859
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Total internal biliary diversion during liver transplantation for type 1 progressive familial intrahepatic cholestasis: a novel approach (2016)
  • Author(s): Mali VP, Fukuda A, Shigeta T, Uchida H, Hirata Y, Rahayatri TH, Kanazawa H, Sasaki K, de Ville de Goyet J, Kasahara M
  • Journal Title: Pediatr Transplant Volume: 20 Issue: 7 Pages: 981-986
  • DOI: 10.1111/petr.12782
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Benefit of early inflow exclusion during living donor liver transplantation for unresectable hepatoblastoma. (2016)
  • Author(s): Uchida H, Fukuda A, Sasaki K, Hirata Y, Shigeta T, Kanazawa H, Nakazawa A, Miyazaki O, Nosaka S, Mali VP, Sakamoto S, Kasahara M
  • Journal Title: J Pediatr Surg Volume: 51 Issue: 11 Pages: 1807-1811
  • DOI: 10.1016/j.jpedsurg.2016.04.021
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Postischemic Anhedonia Associated with Neurodegenerative Changes in the Hippocampal Dentate Gyrus of Rats. (2016)
  • Author(s): Kasahara J, Uchida H, Tezuka K, Oka N.
  • Journal Title: Neural Plast Volume: - Pages: 5054275-5054275
  • DOI: 10.1155/2016/5054275
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Chemotherapy-induced B-cell depletion in hepatoblastoma patients undergoing ABO-incompatible living donor liver transplantation (2016)
  • Author(s): Kanazawa H, Fukuda A, Mali VP, Rahayatri TH, Hirata Y, Sasaki K, Uchida H, Shigeta T, Sakamoto S, Matsumoto K, Kasahara M
  • Journal Title: Pediatr Transplant Volume: 20 Issue: 3 Pages: 401-407
  • DOI: 10.1111/petr.12675
  • Peer Reviewed / Open Access / Int'l Joint Research