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Congenital pituitary hypoplasia modeling using induced pluripotent cells

Research Project

Project/Area Number 16H05332
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Endocrinology
Research InstitutionKobe University

Principal Investigator

Takahashi Yutaka  神戸大学, 医学研究科, 准教授 (70301281)

Co-Investigator(Kenkyū-buntansha) 長谷川 奉延  慶應義塾大学, 医学部(信濃町), 教授 (20189533)
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000)
Fiscal Year 2018: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2017: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2016: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Keywords疾患iPS細胞 / 下垂体 / 先天性下垂体形成不全 / 下垂体機能低下症 / 疾患特異的iPS細胞 / 遺伝子異常 / iPS細胞 / 下垂体疾患モデル / 病態モデル / 下垂体疾患
Outline of Final Research Achievements

Anterior pituitary develops from oral ectoderm in contact with adjacent neural ectoderm that differentiates into hypothalamus with a close interaction. Here, we demonstrate iPSC-based disease modeling for congenital pituitary hypoplasia and investigated its underlying mechanisms. Using exome analysis in a patient with combined pituitary hormone deficiency, we identified a novel OTX2 mutation, of which gene product showed impaired nuclear translocation. The differentiation into pituitary in the patient-derived iPSCs (OTX2mut-iPSCs) was severely impaired. As the underlying mechanisms, the expression of an essential transcription factor for pituitary development, was diminished in OTX2mut-iPSCs. Interestingly, addition of the growth factor to the media restored the expression of transcription factor, indicating that OTX2-dependent expression of growth factor in the hypothalamus plays an important role in the pituitary differentiation.

Academic Significance and Societal Importance of the Research Achievements

先天性下垂体形成不全は小児下垂体機能低下症の中で比較的頻度が高く重症化しうる疾患であるが、その原因、病態は十分に明らかになっていない。本研究では、エクソーム解析による網羅的な解析に加えて疾患特異的iPS細胞を用いたin vitroモデルによる病態解析によりその原因を明らかにすることを目的として行なった。今回疾患iPS細胞が下垂体疾患に応用可能であることを世界で初めて示しただけではなく、これまでのノックアウトマウスでは明らかにしえなかった詳細な機序の解明に繋がるとともに、表現型をレスキューする方法を見出したことから、最終的には治療応用も期待される。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Annual Research Report
  • 2016 Annual Research Report
  • Research Products

    (53 results)

All 2019 2018 2017 2016 Other

All Journal Article (17 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 16 results,  Open Access: 9 results,  Acknowledgement Compliant: 1 results) Presentation (20 results) (of which Int'l Joint Research: 5 results,  Invited: 20 results) Book (14 results) Remarks (2 results)

  • [Journal Article] IgG4-related hypophysitis in patients with autoimmune pancreatitis2019

    • Author(s)
      Kanie Keitaro、Bando Hironori、Iguchi Genzo、Shiomi Hideyuki、Masuda Atsuhiro、Fukuoka Hidenori、Nishizawa Hitoshi、Fujita Yasunori、Sakai Arata、Kobayashi Takashi、Shiomi Yuuki、Yoshida Kenichi、Matsumoto Ryusaku、Suda Kentaro、Kodama Yuzo、Ogawa Wataru、Takahashi Yutaka
    • Journal Title

      Pituitary

      Volume: 22 Issue: 1 Pages: 54-61

    • DOI

      10.1007/s11102-018-00930-y

    • NAID

      120006767933

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] The Essential Role of SIRT1 in Hypothalamic-Pituitary Axis2018

    • Author(s)
      Yamamoto Masaaki、Takahashi Yutaka
    • Journal Title

      Frontiers in Endocrinology

      Volume: 9 Pages: 605-605

    • DOI

      10.3389/fendo.2018.00605

    • NAID

      120006534501

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Isolated adrenocorticotropic hormone deficiency as a form of paraneoplastic syndrome2018

    • Author(s)
      Bando Hironori、Iguchi Genzo、Kanie Keitaro、Nishizawa Hitoshi、Matsumoto Ryusaku、Fujita Yasunori、Odake Yukiko、Yoshida Kenichi、Suda Kentaro、Fukuoka Hidenori、Tanaka Keiko、Ogawa Wataru、Takahashi Yutaka
    • Journal Title

      Pituitary

      Volume: 21 Issue: 5 Pages: 480-489

    • DOI

      10.1007/s11102-018-0901-7

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Impact of preoperative pasireotide therapy on invasive octreotide-resistant acromegaly2018

    • Author(s)
      Yamamoto Reina、Robert Shima Kosuke、Igawa Hirobumi、Kaikoi Yuka、Sasagawa Yasuo、Hayashi Yasuhiko、Inoshita Naoko、Fukuoka Hidenori、Takahashi Yutaka、Takamura Toshinari
    • Journal Title

      Endocrine Journal

      Volume: 65 Issue: 10 Pages: 1061-1067

    • DOI

      10.1507/endocrj.EJ17-0487

    • NAID

      130007501515

    • ISSN
      0918-8959, 1348-4540
    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Multiple salivary cortisol measurements are a useful tool to optimize metyrapone treatment in patients with Cushing’s syndromes treatment; case presentations.2018

    • Author(s)
      Yoshida K, Fukuoka H, Odake Y, Nakajima S, Tachibana M, Ito J, Hosokawa Y, Yamada T, Miura H, Suematsu N, Matsumoto R, Bando H, Suda K, Nishizawa H, Iguchi G, Ogawa W, Takahashi Y
    • Journal Title

      Front Endocrinol

      Volume: 8 Pages: 375-375

    • DOI

      10.3389/fendo.2017.00375

    • NAID

      120006382334

    • Related Report
      2018 Annual Research Report 2017 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Factors correlated with serum insulin-like growth factor-I levels in health check-up subjects.2018

    • Author(s)
      Matsumoto R, Koga M, Kasayama S, Fukuoka H, Iguchi G, Odake Y, Yoshida K, BandoH, Suda K, Nishizawa H, Takahashi M, Ogawa W, Takahashi Y
    • Journal Title

      Growth Horm IGF Res.

      Volume: in press Pages: 55-60

    • DOI

      10.1016/j.ghir.2018.01.003

    • Related Report
      2018 Annual Research Report 2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A novel thymoma-associated autoimmune disease: Anti-PIT-1 antibody syndrome.2017

    • Author(s)
      Bando H, Iguchi G, Okimura Y, Odake Y, Yoshida K, Matsumoto R, Suda K, Nishizawa H, Fukuoka H, Mokubo A, Tojo K, Maniwa Y, Ogawa W, Takahashi Y.
    • Journal Title

      Sci Rep.

      Volume: 20 Issue: 1 Pages: 43060-43067

    • DOI

      10.1038/srep43060

    • NAID

      120005997120

    • Related Report
      2017 Annual Research Report 2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Hypothalamic-pituitary germinoma presenting as generalized hypohidorosis.2017

    • Author(s)
      Fukunaga A, Tajima S, Sasayama T, Tanaka K, Takahashi Y, Nishigori C
    • Journal Title

      Eur J Dermotol.

      Volume: 27 Issue: 3 Pages: 297-299

    • DOI

      10.1684/ejd.2017.2975

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Cross-sectional prevalence of pancreatic cystic lesions in patients with acromegaly, a single-center experience2017

    • Author(s)
      Odake Yukiko、Fukuoka Hidenori、Yamamoto Masaaki、Arisaka Yoshifumi、Konishi Junya、Yoshida Kenichi、Matsumoto Ryusaku、Bando Hironori、Suda Kentaro、Nishizawa Hitoshi、Iguchi Genzo、Yamada Shozo、Ogawa Wataru、Takahashi Yutaka
    • Journal Title

      Pituitary

      Volume: 20 Issue: 5 Pages: 509-514

    • DOI

      10.1007/s11102-017-0810-1

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Insulin Secretion and Insulin Sensitivity Before and After Surgical Treatment of Pheochromocytoma or Paraganglioma2017

    • Author(s)
      Komada Hisako、Hirota Yushi、So Anna、Nakamura Tomoaki、Okuno Yoko、Fukuoka Hidenori、Iguchi Genzo、Takahashi Yutaka、Sakaguchi Kazuhiko、Ogawa Wataru
    • Journal Title

      The Journal of Clinical Endocrinology & Metabolism

      Volume: 102 Issue: 9 Pages: 3400-3405

    • DOI

      10.1210/jc.2017-00357

    • NAID

      120006554638

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Two Cases of Atezolizumab-Induced Hypophysitis2017

    • Author(s)
      Kanie Keitaro、Iguchi Genzo、Bando Hironori、Fujita Yasunori、Odake Yukiko、Yoshida Kenichi、Matsumoto Ryusaku、Fukuoka Hidenori、Ogawa Wataru、Takahashi Yutaka
    • Journal Title

      Journal of the Endocrine Society

      Volume: 2 Issue: 1 Pages: 91-95

    • DOI

      10.1210/js.2017-00414

    • NAID

      120006767927

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The role of GH and insulin-like growth factor-I in the liver.2017

    • Author(s)
      Takahashi Y.
    • Journal Title

      Int J Mol Sci

      Volume: 18 Issue: 7 Pages: 1447-1447

    • DOI

      10.3390/ijms18071447

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 医学と医療の最前線 成長ホルモンから見た脂肪肝/NASHの病態と治療2017

    • Author(s)
      高橋 裕
    • Journal Title

      日本内科学会雑誌

      Volume: 106 Pages: 2254-2257

    • Related Report
      2017 Annual Research Report
  • [Journal Article] Prevalence of Simple Renal Cysts in Acromegaly2016

    • Author(s)
      Yamamoto M, Matsumoto R, Fukuoka H, Iguchi G, Takahashi M, Nishizawa H, Suda K, Bando H, Takahashi Y.
    • Journal Title

      Internal Medicine

      Volume: 55 Issue: 13 Pages: 1685-1690

    • DOI

      10.2169/internalmedicine.55.6560

    • NAID

      130005161015

    • ISSN
      0918-2918, 1349-7235
    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] The influence of type 2 diabetes on serum GH and IGF-I levels in hospitalized Japanese patients.2016

    • Author(s)
      Suda K, Matsumoto R, Fukuoka H, Iguchi G, Hirota Y, Nishizawa H, Bando H, Yoshida K, Odake Y, Takahasi M, Sakaguchi K, Ogawa W, Takahashi Y
    • Journal Title

      Growth Hormone and IGF-I Research.

      Volume: 印刷中 Pages: 4-10

    • DOI

      10.1016/j.ghir.2016.03.002

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Genetic and clinical characteristics of Japanese patients with sporadic somatotropinoma2016

    • Author(s)
      Matsumoto R, Izawa M, Fukuoka H, Iguchi G, Odake Y, Yoshida K, Bando H, Suda K, Nishizawa H, Takahashi M, Yamada S, Ogawa W, Takahashi Y.
    • Journal Title

      Endocrine Journal

      Volume: 63 Issue: 11 Pages: 953-963

    • DOI

      10.1507/endocrj.EJ16-0075

    • NAID

      130005170483

    • ISSN
      0918-8959, 1348-4540
    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] IGF-I induces senescence of hepatic stellate cells and limits fibrosis in a p53-dependent manner.2016

    • Author(s)
      Nishizawa H, Iguchi G, Fukuoka H, Takahashi M, Suda K, Bando H, Matsumoto R, Yoshida K, Odake Y, Ogawa W, Takahashi Y※ IGF-I induces senescence of hepatic stellate cells and limits fibrosis in a p53-dependent manner.
    • Journal Title

      Sci Rep.

      Volume: 6 Issue: 1 Pages: 34605-34605

    • DOI

      10.1038/srep34605

    • NAID

      120005866886

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] Immunotherapy-induced Pituitary Damage2019

    • Author(s)
      Takahashi Y
    • Organizer
      the 16th International Pituitary Congress
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 機能性下垂体腺腫Update2019

    • Author(s)
      高橋 裕
    • Organizer
      第29回日本間脳下垂体腫瘍学会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] 下垂体機能低下症を呈する新たな疾患の発見と発症機序の解明2019

    • Author(s)
      高橋 裕
    • Organizer
      第29回日本間脳下垂体腫瘍学会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] Pituitary autoimmunity: a journey for the discovery of novel diseases2018

    • Author(s)
      Takahashi Y
    • Organizer
      18th International Congress of Endocrinology
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 自己免疫性下垂体疾患の新たな病態2018

    • Author(s)
      井口元三、坂東弘教、高橋 裕
    • Organizer
      第28回間脳下垂体腫瘍学会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] 新たな自己免疫性下垂体疾患:抗PIT-1抗体症候群の病態2018

    • Author(s)
      井口元三、坂東弘教、高橋 裕
    • Organizer
      第91回内分泌学会学術総会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] 下垂体update 機能性下垂体腫瘍の病理と薬物治療2018

    • Author(s)
      高橋 裕
    • Organizer
      第22回日本内分泌病理学会学術総会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] 機能性下垂体腫瘍薬物療法Update2018

    • Author(s)
      高橋 裕
    • Organizer
      第91回内分泌学会学術総会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] 日常診療からいかに新しい疾患を見出すのか?2018

    • Author(s)
      高橋 裕
    • Organizer
      第91回内分泌学会学術総会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] 下垂体機能低下症を呈する新たな疾患の発見と発症機序の解明2018

    • Author(s)
      高橋 裕
    • Organizer
      第91回内分泌学会学術総会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] 下垂体機能低下症を呈する新たな疾患の発見と発症機序の解明2018

    • Author(s)
      高橋 裕
    • Organizer
      第18回日本内分泌学会北陸支部学術総会
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] GH and the liver2017

    • Author(s)
      Takahashi Y
    • Organizer
      The 15th International Pituitary Congress
    • Place of Presentation
      Olando
    • Year and Date
      2017-03-29
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] プレゼンの奥義を伝授します2017

    • Author(s)
      高橋 裕
    • Organizer
      第90回日本内分泌学会学術総会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] 内分泌学の面白さを若手にどのように伝えるのか2017

    • Author(s)
      高橋 裕
    • Organizer
      第90回日本内分泌学会学術総会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] 中枢性甲状腺機能低下症を呈する新たな疾患の発見とその機序の解明2017

    • Author(s)
      高橋 裕
    • Organizer
      第60回日本甲状腺学会学術総会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] 先端巨大症の新たな病態と治療戦略2017

    • Author(s)
      高橋 裕
    • Organizer
      第21回日本臨床内分泌病理学会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] 下垂体機能低下症を呈する新たな疾患の発見と機序の解明2017

    • Author(s)
      高橋 裕
    • Organizer
      第17回北海道支部内分泌集会
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] 内分泌学の過去、現在、未来-Case-oriated-researchの魅力とPhysician scientistの重要性2017

    • Author(s)
      高橋 裕
    • Organizer
      日本内分泌学会創設90周年記念式典
    • Related Report
      2017 Annual Research Report
    • Invited
  • [Presentation] The essential role of GH/IGF-I in liver.2016

    • Author(s)
      Takahashi Y
    • Organizer
      The 58th Annual Congress of the Spanish Society of Endocrinology and Nutrition
    • Place of Presentation
      Malaga
    • Year and Date
      2016-10-19
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 下垂体疾患のパールとピットフォール-症例から学ぶ2016

    • Author(s)
      高橋 裕
    • Organizer
      第36回日本脳神経外科コングレス学術総会
    • Place of Presentation
      大阪国際会議場
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research / Invited
  • [Book] 今日の疾患辞典2019

    • Author(s)
      高橋 裕
    • Total Pages
      300
    • Publisher
      プレシジョン
    • Related Report
      2018 Annual Research Report
  • [Book] 今日の治療指針2018

    • Author(s)
      高橋 裕
    • Total Pages
      2160
    • Publisher
      医学書院
    • Related Report
      2018 Annual Research Report
  • [Book] 内分泌機能検査実施マニュアル改訂第3版2018

    • Author(s)
      高橋 裕
    • Total Pages
      109
    • Publisher
      診断と治療社
    • Related Report
      2018 Annual Research Report
  • [Book] 内分泌症候群(第3版)2018

    • Author(s)
      高橋 裕
    • Total Pages
      561
    • Publisher
      日本臨床
    • Related Report
      2018 Annual Research Report
  • [Book] 内分泌代謝専門医ガイドブック2018

    • Author(s)
      高橋 裕
    • Total Pages
      763
    • Publisher
      診断と治療社
    • Related Report
      2018 Annual Research Report 2017 Annual Research Report
  • [Book] 内科学書2018

    • Author(s)
      高橋 裕
    • Total Pages
      3000
    • Publisher
      中山書店
    • ISBN
      9784521737751
    • Related Report
      2017 Annual Research Report
  • [Book] 今日の治療指針2018年度版2018

    • Author(s)
      高橋 裕
    • Total Pages
      2066
    • Publisher
      医学書院
    • ISBN
      4260032348
    • Related Report
      2017 Annual Research Report
  • [Book] 新臨床内科学2018

    • Author(s)
      高橋 裕
    • Total Pages
      1882
    • Publisher
      医学書院
    • ISBN
      4260102524
    • Related Report
      2017 Annual Research Report
  • [Book] Frontiers in Hormone Research2017

    • Author(s)
      Iguchi G, Bando H, Takahashi Y
    • Total Pages
      180
    • Publisher
      Karger
    • ISBN
      3318060135
    • Related Report
      2017 Annual Research Report
  • [Book] Nova Science Hypopituitarism2017

    • Author(s)
      Iguchi G, Takahashi Y
    • Total Pages
      303
    • Publisher
      Nova Science Pub Inc
    • ISBN
      1624179266
    • Related Report
      2017 Annual Research Report
  • [Book] 今日の治療指針2017年度版2017

    • Author(s)
      高橋 裕
    • Total Pages
      1999
    • Publisher
      医学書籍社
    • Related Report
      2016 Annual Research Report
  • [Book] 糖尿病 医師・医療スタッフのための臨床総合誌 別冊プラクティス「糖尿病検査マニュアル」2016

    • Author(s)
      高橋 裕
    • Total Pages
      216
    • Publisher
      医歯薬出版株式会社
    • Related Report
      2016 Annual Research Report
  • [Book] 内分泌代謝専門医ガイドブック2016

    • Author(s)
      高橋 裕
    • Total Pages
      479
    • Publisher
      診断と治療社
    • Related Report
      2016 Annual Research Report
  • [Book] 下垂体診療マニュアル2016

    • Author(s)
      高橋 裕
    • Total Pages
      283
    • Publisher
      診断と治療社
    • Related Report
      2016 Annual Research Report
  • [Remarks] 神戸大学医学部糖尿病内分泌内科神経内分泌グループ

    • URL

      http://www.med.kobe-u.ac.jp/im2/doctor/activity/acti-04.html

    • Related Report
      2018 Annual Research Report
  • [Remarks] 神戸大学大学院医学研究科 糖尿病内分泌内科学 神経内分泌グループ

    • URL

      http://www.med.kobe-u.ac.jp/im2/doctor/activity/acti-04.html

    • Related Report
      2017 Annual Research Report 2016 Annual Research Report

URL: 

Published: 2016-04-21   Modified: 2020-03-30  

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