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Study of cystic fibrosis using pancreatic ductal and biliary epithelia from human pluripotent stem cells

Research Project

Project/Area Number 20K08285
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 53010:Gastroenterology-related
Research InstitutionNagoya University

Principal Investigator

Ishiguro Hiroshi  名古屋大学, 総合保健体育科学センター, 教授 (90303651)

Co-Investigator(Kenkyū-buntansha) 小川 真一郎  信州大学, 医学部, 特任教授 (30419353)
相馬 義郎  国際医療福祉大学, 薬学部, 教授 (60268183)
山本 明子  名古屋大学, 総合保健体育科学センター, 教授 (60402385)
Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywords嚢胞性線維症 / CFTRバリアント / 胆管 / 膵導管細胞 / 胆管上皮細胞 / iPS細胞 / 膵管 / 気管支
Outline of Research at the Start

嚢胞性線維症はCFTRを原因分子とする遺伝性の難病である。国内患者の平均寿命は約23年と予後が悪く、CFTR分子を標的とする根本的治療が必要である。そのためには、生体内の環境を再現して、それぞれの患者が保有するCFTRバリアントの性質を評価し、治療薬候補の効果を分析しなければならない。本研究では、嚢胞性線維症患者由来iPS細胞を樹立し、膵管や胆管へ三次元構築誘導して研究を実施する。

Outline of Final Research Achievements

While cystic fibrosis (CF) is the most common hereditary disease in Caucasians, it is rare in East Asia. Clinical phenotype of Japanese CF patients is similar to European patients, but the prognosis is worse. The median survival age is about 25 years. The present study has demonstrated that the spectrum of CFTR variants in Japanese CF alleles is entirely different from that in European CF alleles. When 2 types of Japanese CFTR variants (H1085R and L441P) were expressed in CHO cells, the combination of tezacaftor and elexacaftor helped the glycosylation and membrane expression. In addition, we have successfully generated functional cholangiocytes from human pluripotent stem cells.

Academic Significance and Societal Importance of the Research Achievements

日本における嚢胞性線維症の実態は不明であったが、研究代表者が所属する研究室が事務局となって2012年に患者レジストリが始まり、2023年5月現在日本国内で約50名の患者を把握している。また、原因となるCFTR遺伝子バリアントのタイプがヨーロッパ人種とは全く異なること、日本人のCFはヨーロッパ人種に比べて重症が多いことが分かってきた。本研究は、日本人の嚢胞性線維症の予後を改善するための基盤である。

Report

(4 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (22 results)

All 2022 2021 2020 Other

All Journal Article (12 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 8 results,  Open Access: 3 results) Presentation (7 results) (of which Int'l Joint Research: 2 results,  Invited: 1 results) Book (2 results) Remarks (1 results)

  • [Journal Article] 膵導管細胞の病態生理と嚢胞性線維症2022

    • Author(s)
      石黒 洋、山口 誠、山本明子
    • Journal Title

      胆と膵

      Volume: 43(8) Pages: 743-750

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Viscoelastic Notch Signaling Hydrogel Induces Liver Bile Duct Organoid Growth and Morphogenesis2022

    • Author(s)
      Rizwan Muhammad、Ling Christopher、Guo Chengyu、Liu Tracy、Jiang Jia‐Xin、Bear Christine E.、Ogawa Shinichiro、Shoichet Molly S.
    • Journal Title

      Advanced Healthcare Materials

      Volume: 11 Issue: 23 Pages: 2200880-2200880

    • DOI

      10.1002/adhm.202200880

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Bicarbonate transport of airway surface epithelia in luminally perfused mice bronchioles2022

    • Author(s)
      Liu L, Yamamoto A, Yamaguchi M, Taniguchi I, Nomura N, Nakakuki M, Kozawa Y, Fukuyasu T, Higuchi M, Niwa E, Tamada T, Ishiguro H
    • Journal Title

      J Physiol Sci

      Volume: 72 Issue: 1 Pages: 1-16

    • DOI

      10.1186/s12576-022-00828-2

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Japanese siblings of cystic fibrosis with a novel large heterozygous deletion in the CFTR gene2022

    • Author(s)
      Kawase M, Ogawa M, Hoshina T, Kojiro M, Nakakuki M, Naruse S, Ishiguro H, Kusuhara K
    • Journal Title

      Front Pediatr

      Volume: 9 Pages: 1-7

    • DOI

      10.3389/fped.2021.800095

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cystic fibrosis with focal biliary cirrhosis and portal hypertension in Japan: a case report2021

    • Author(s)
      山本明子、伊藤孝一、成瀬 達、服部日出雄、中莖みゆき、藤木理代、石黒 洋
    • Journal Title

      Nippon Shokakibyo Gakkai Zasshi

      Volume: 118 Issue: 7 Pages: 686-697

    • DOI

      10.11405/nisshoshi.118.686

    • NAID

      130008064416

    • ISSN
      0446-6586, 1349-7693
    • Year and Date
      2021-07-10
    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Journal Article] Generation of functional ciliated cholangiocytes from human pluripotent stem cells2021

    • Author(s)
      Ogawa Mina、Jiang Jia-Xin、Xia Sunny、Yang Donghe、Ding Avrilynn、Laselva Onofrio、Hernandez Marcela、Cui Changyi、Higuchi Yuichiro、Suemizu Hiroshi、Dorrell Craig、Grompe Markus、Bear Christine E.、Ogawa Shinichiro
    • Journal Title

      Nature Communications

      Volume: 12 Issue: 1 Pages: 6504-6519

    • DOI

      10.1038/s41467-021-26764-0

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] 膵嚢胞線維症(嚢胞性線維症)2021

    • Author(s)
      成瀬 達、中莖みゆき、藤木理代、近藤志保、小澤祐加、山本明子、石黒 洋
    • Journal Title

      胆と膵

      Volume: 42 Pages: 937-941

    • Related Report
      2021 Research-status Report
  • [Journal Article] Regulation of Pancreatic Fluid and Electrolyte Secretion2021

    • Author(s)
      Ishiguro H, Yamaguchi M, Yamamoto A
    • Journal Title

      Pancreapedia Exocrine Pancreas Knowledge Base

      Volume: 1 Pages: 1-13

    • DOI

      10.3998/panc.2021.05

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Pancreatic Bicarbonate Secretion2020

    • Author(s)
      Ishiguro H, Yamamoto A, Steward MC
    • Journal Title

      Encyclopedia of Gastroenterology 2nd Edition

      Volume: 4 Pages: 24-29

    • DOI

      10.1016/b978-0-12-801238-3.65645-3

    • ISBN
      9780128187289
    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] 難病研究の進歩 嚢胞性線維症2020

    • Author(s)
      石黒 洋、相馬義郎、山本明子
    • Journal Title

      生体の科学

      Volume: 71 Pages: 436-437

    • Related Report
      2020 Research-status Report
  • [Journal Article] 患者さんと家族、医療関係者をつなぐ窓口に~NPO法人嚢胞性線維症支援ネットワークの取組み~2020

    • Author(s)
      石黒 洋、小澤祐加
    • Journal Title

      medical forum CHUGAI

      Volume: 24 Pages: 1-4

    • Related Report
      2020 Research-status Report
  • [Journal Article] 膵の生理と生化学2020

    • Author(s)
      石黒 洋
    • Journal Title

      膵臓病診療ガイドブック

      Volume: 1 Pages: 9-14

    • Related Report
      2020 Research-status Report
  • [Presentation] わが国のCF患者のCFTR variantの特徴 ワークショップ「胆膵疾患の遺伝子解析による病態解明・臨床展開」2022

    • Author(s)
      中莖みゆき、山本明子、石黒 洋
    • Organizer
      第108回日本消化器病学会総会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Effects of GLP-1, GIP, and glucagon on pancreatic fluid secretion in guinea-pig interlobular pancreatic duct.2022

    • Author(s)
      Higuchi M, Yamamoto A, Taniguchi I, Nomura N, Niwa E, Nakakuki M, Yamaguchi M, Liu L, Ishiguro H
    • Organizer
      第26回国際膵臓学会/第53回日本膵臓学会大会
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Roles of zinc in fluid secretion from pancreatic duct cells.2022

    • Author(s)
      Nomura N, Yamamoto A, Nakakuki M, Mochimaru Y, Taniguchi I, Liu L, Kozawa Y, Higuchi M, Niwa E, Ishiguro H
    • Organizer
      第26回国際膵臓学会/第53回日本膵臓学会大会
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Educational Lecture 膵の生理と生化学2022

    • Author(s)
      石黒 洋
    • Organizer
      第53回日本膵臓学会大会
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] 嚢胞性線維症に対する吸入療法 シンポジウム「難治性呼吸器疾患に対する吸入療法の新展開」2022

    • Author(s)
      石黒 洋
    • Organizer
      Japan Basic and Clinical Pharmacology Week 2022 第96回日本薬理学会年会/第43回日本臨床薬理学会学術集会
    • Related Report
      2022 Annual Research Report
  • [Presentation] パネルディスカッション「膵内外分泌機能障害の診断と治療」日本の嚢胞性線維症患者のCFTRバリアントと膵外分泌機能2021

    • Author(s)
      山本明子、中莖みゆき、成瀬 達、小澤祐加、藤木理代、近藤志保、竹山宜典、石黒 洋
    • Organizer
      第52回日本膵臓学会大会
    • Related Report
      2021 Research-status Report
  • [Presentation] 嚢胞性線維症患者の腸内細菌叢解析2021

    • Author(s)
      福安智哉、藤木理代、中村浩平、鈴木 徹、成瀬 達、山本明子、近藤志保、中莖みゆき、小澤祐加、石黒 洋
    • Organizer
      第52回日本膵臓学会大会
    • Related Report
      2021 Research-status Report
  • [Book] 小児科診療Controversy 小児の嚢胞性線維症はいかに診断すべきか?2022

    • Author(s)
      石黒 洋
    • Total Pages
      5
    • Publisher
      中外医学社
    • ISBN
      9784498145740
    • Related Report
      2022 Annual Research Report
  • [Book] Regulation of pancreatic fluid and electrolyte secretion, The Pancreas: Biology and Physiology2021

    • Author(s)
      Ishiguro H, Yamaguchi M, Yamamoto A
    • Total Pages
      11
    • Publisher
      American Pancreatic Association and Michigan Publishing
    • ISBN
      9781607857198
    • Related Report
      2021 Research-status Report
  • [Remarks] NPO法人嚢胞性線維症支援ネットワーク

    • URL

      https://www.cfnetworkjapan.org/

    • Related Report
      2022 Annual Research Report

URL: 

Published: 2020-04-28   Modified: 2024-01-30  

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