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Development of plasma steroid precursor-based new differential diagnosis and molecular targeted therapies for hyperaldosteronism

Research Project

Project/Area Number 26670174
Research Category

Grant-in-Aid for Challenging Exploratory Research

Allocation TypeMulti-year Fund
Research Field Human pathology
Research InstitutionKyoto University

Principal Investigator

MASAO Doi  京都大学, 薬学研究科(研究院), 准教授 (20432578)

Co-Investigator(Renkei-kenkyūsha) OKAMURA Hitoshi  京都大学, 大学院薬学研究科, 教授 (60158813)
FUSTIN Jean-Michel  京都大学, 大学院薬学研究科, 特定講師 (50711818)
SASANO Hironobu  東北大学, 医学部, 教授 (50187142)
NAKAMURA Yasuhiro  東北大学, 医学部, 准教授 (80396499)
SATO Fumitoshi  東北大学, 医学部, 講師 (70343051)
Research Collaborator OTA Takumi  
YARIMIZU Daisuke  
NAKAGAWA Yuuki  
Project Period (FY) 2014-04-01 – 2015-03-31
Project Status Completed (Fiscal Year 2014)
Budget Amount *help
¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Fiscal Year 2014: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
Keywordsアルドステロン / 副腎 / ステロイド合成酵素
Outline of Final Research Achievements

We previously showed that the enzyme 3β-hydroxysteroid dehydrogenase (3β-HSD) is involved in the development of primary aldosteronism (PA) in mice (Nat Med 2010) and found that this enzyme is indeed inappropriately expressed in the lesions of PA in humans (JCEM 2014). Here we measured plasma concentrations of steroid precursors and demonstrated that adrenal vein samples from PA patients exhibit a significant increase in 3β-HSD enzymatic activity, compared with that of contralateral, nondiseased adrenal glands. These data clearly show that enhanced activity of 3β-HSD is involved in human PA pathology. We also revealed that angiotensin II can stimulate expression of this enzyme through de novo protein synthesis of the orphan nuclear receptor NGFIB (Mol Cell Biol 2014). Thus, 3β-HSD appears to play a key role in the regulation of aldosterone synthesis in normal physiology and pathophysiology.

Report

(2 results)
  • 2014 Annual Research Report   Final Research Report ( PDF )
  • Research Products

    (27 results)

All 2015 2014 2013 Other

All Journal Article (9 results) (of which Peer Reviewed: 6 results,  Open Access: 2 results,  Acknowledgement Compliant: 3 results) Presentation (16 results) (of which Invited: 6 results) Remarks (1 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] 3ß-hydroxysteroid dehydrogenase isoforms in human aldosterone-producing adenoma2015

    • Author(s)
      Konosu-Fukaya S, Nakamura Y, Satoh F, Ono Y, Felizola SJ, Ise K, Maekawa T, Takeda K, Katsu K, Fujishima F, Kasajima A, Watanabe M, Arai Y, Gomez-Sanchez EP, Gomez-Sanchez CE, Doi M, Okamura H, and Sasano H
    • Journal Title

      Mol. Cell. Endocrinol.

      Volume: 印刷中 Pages: 205-212

    • DOI

      10.1016/j.mce.2014.10.008

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Steroidogenic enzymes, their related transcription factors and nuclear receptors in human sebaceous glands under normal and pathological conditions2014

    • Author(s)
      Azmahani A, Nakamura Y, Felizola SJ, Ozawa Y, Ise K, Inoue T, McNamara KM, Doi M, Okamura H, Zouboulis CC, Aiba S, and Sasano H
    • Journal Title

      J. Steroid Biochem. Mol. Biol.

      Volume: 144 Pages: 268-279

    • DOI

      10.1016/j.jsbmb.2014.07.010

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Angiotensin II Triggers Expression of the Adrenal Gland Zona Glomerulosa-Specific 3β-Hydroxysteroid Dehydrogenase Isoenzyme through de novo Protein Synthesis of the Orphan Nuclear Receptors NGFIB and NURR1.2014

    • Author(s)
      Takumi Ota, Masao Doi, Fumiyoshi Yamazaki, Daisuke Yarimizu, Kazuki Okada, Iori Murai, Hida Hayashi, Sumihiro Kunisue, Yuuki Nakagawa, Hitoshi Okamura
    • Journal Title

      Molecular and Cellular Biology

      Volume: 34 Issue: 20 Pages: 3880-3894

    • DOI

      10.1128/mcb.00852-14

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Acknowledgement Compliant
  • [Journal Article] Isoform-specific monoclonal antibodies against 3beta-hydroxysteroid dehy drogenase/isomerase family provide markers for subclassification of hum an primary aldosteronism. .2014

    • Author(s)
      Doi M, Satoh F, Maekawa T, N akamura Y, Fustin JM, Tainaka M, Hotta Y, Takahashi Y, Morimoto R, Takase K, Ito S, Sasano H, and Okamura H
    • Journal Title

      J Clin Endocrinol Metab

      Volume: 99 Issue: 2 Pages: 257-62

    • DOI

      10.1210/jc.2013-3279

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Immunolocalization of murine type VI 3β-hydroxysteroid dehydrogenase in the adrenal gland, testis, skin, and placenta2014

    • Author(s)
      Koki Yamamura, Magao Doi, Hida Hayashi, Takumi Ota, Iori Murai, Yunhong Hotta, Rie Komatsu, Hitoshi Okamura
    • Journal Title

      Molecular and Cellular Endocrinology

      Volume: 382 Issue: 1 Pages: 131-138

    • DOI

      10.1016/j.mce.2013.09.014

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 時計遺伝子 Clock genes2014

    • Author(s)
      土居雅夫, 岡村均
    • Journal Title

      医学のあゆみ

      Volume: 249 Pages: 373-373

    • Related Report
      2014 Annual Research Report
  • [Journal Article] 体内時計とアンギオテンシンIIにより制御される新規アルドステロン合成酵素と高血圧2014

    • Author(s)
      岡村均, 土居雅夫
    • Journal Title

      最新医学

      Volume: 11月 Pages: 133-144

    • Related Report
      2014 Annual Research Report
  • [Journal Article] 生体リズムと高血圧2014

    • Author(s)
      岡村均, 土居雅夫
    • Journal Title

      循環Plus

      Volume: 14 Pages: 10-12

    • NAID

      40019184089

    • Related Report
      2014 Annual Research Report
  • [Journal Article] Chronic hyperaldosteronism in Cryptochrome null mice induces high-salt- and blood pressure-independent kidney damage in mice.2013

    • Author(s)
      Nugrahaningsih DAA, Emoto N, Vignon-Zellweger N, Purnomo E, Yagi K, Nakayama K, Doi M, Okamura H, Hirata KI.
    • Journal Title

      Hypertens Res.

      Volume: 37 Issue: 3 Pages: 202-209

    • DOI

      10.1038/hr.2013.143

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed
  • [Presentation] Identification of a new class of GPCR signalling that tunes the central clock2015

    • Author(s)
      Masao Doi
    • Organizer
      The 4th International Symposium on Molecular Clock
    • Place of Presentation
      Kyoto, Japan
    • Year and Date
      2015-03-27
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] A New Class of G-protein Signaling in the Suprachiasmatic Nucleus2015

    • Author(s)
      Masao Doi
    • Organizer
      International Symposium on RNA and Clock 2015
    • Place of Presentation
      Awaji, Japan
    • Year and Date
      2015-03-25
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] Stimulus-selective induction of the orphan nuclear receptor NGFIB underlies different influences of angiotensin II and potassium on the human adrenal zona glomerulosa 3ß-HSD isoform in H295R cells.2014

    • Author(s)
      Daisuke Yarimizu, Masao Doi, Takumi Ota, and Hitoshi Okamura
    • Organizer
      第37回日本分子生物学会
    • Place of Presentation
      横浜
    • Year and Date
      2014-11-25
    • Related Report
      2014 Annual Research Report
  • [Presentation] Angiotensin II-regulatable cell-autonomous circadian oscillators in adrenocortical zona glomerulosa cells2014

    • Author(s)
      Daisuke Yarimizu, Masao Doi, Takumi Ota, Yuuki Nakagawa,and Hitoshi Okamura
    • Organizer
      第21回日本時間生物学会年会
    • Place of Presentation
      福岡
    • Year and Date
      2014-11-08
    • Related Report
      2014 Annual Research Report
  • [Presentation] 時間生物学の次世代を切り拓く新技術:植物からヒトまで2014

    • Author(s)
      明石真、土居雅夫
    • Organizer
      第21回日本時間生物学会年会
    • Place of Presentation
      福岡
    • Year and Date
      2014-11-08
    • Related Report
      2014 Annual Research Report
  • [Presentation] Atlas of circadian clock gene expression in the body2014

    • Author(s)
      Masao Doi and Hitoshi Okamura
    • Organizer
      平成26年度 自然科学研究機構 生理学研究所研究会
    • Place of Presentation
      岡崎
    • Year and Date
      2014-09-27
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] 時計遺伝子のその先にあるもの:視交叉上核神経ネットワークがつくる哺乳類の時計機構2014

    • Author(s)
      本間さと、土居雅夫
    • Organizer
      第37回日本神経科学大会
    • Place of Presentation
      横浜
    • Year and Date
      2014-09-11
    • Related Report
      2014 Annual Research Report
  • [Presentation] Agonist-independent basal activity of G-protein coupled receptor GPRS leads to reduced intracellular cAMP levels.2014

    • Author(s)
      Sumihiro Kunisue, Masao Doi, and Hitoshi Okamura
    • Organizer
      第37回日本神経科学大会
    • Place of Presentation
      横浜
    • Year and Date
      2014-09-11
    • Related Report
      2014 Annual Research Report
  • [Presentation] 生体リズム異常に伴う高血圧発症メカニズム -原発性アルドステロン症の原因診断学の再構築を目指して-2014

    • Author(s)
      土居雅夫
    • Organizer
      第9回神戸生活習慣病研究会
    • Place of Presentation
      神戸
    • Year and Date
      2014-07-26
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] 原発性アルドステロン症の病態鑑別を可能にするヒト3β-HSD酵素サブタイプ選択的モノクローナル抗体の樹立2014

    • Author(s)
      土居雅夫、中村保宏、佐藤文俊、笹野公伸、岡村均
    • Organizer
      第32回内分泌代謝学サマーセミナー
    • Place of Presentation
      河口湖
    • Year and Date
      2014-07-11
    • Related Report
      2014 Annual Research Report
  • [Presentation] 核内オーファン受容体NGFIBの新規合成を介したAngiotensinIIによる副腎球状層特異的3β-HSDアイソザイムの発現誘導メカニズム2014

    • Author(s)
      鑓水大介、土居雅夫、太田拓巳、岡村均
    • Organizer
      第32回内分泌代謝学サマーセミナー
    • Place of Presentation
      河口湖
    • Year and Date
      2014-07-11
    • Related Report
      2014 Annual Research Report
  • [Presentation] he gene encoding the type I 3ß-hydroxysteroid dehydrogenase is acutely induced by Angiotensin II through orphan nuclear receptor NGFIB signaling in human adrenocortical H295R cells2014

    • Author(s)
      Takumi Ota, Masao Doi, and Hitoshi Okamura
    • Organizer
      The 8th SKO Joint Symposium on Biology
    • Place of Presentation
      Osaka, Japan
    • Year and Date
      2014-06-10
    • Related Report
      2014 Annual Research Report
  • [Presentation] Mechanism of circadian transcription of clock core gene Per22014

    • Author(s)
      Yuta Atobe, Masao Doi, and Hitoshi Okamura
    • Organizer
      The 8th SKO Joint Symposium on Biology
    • Place of Presentation
      Osaka, Japan
    • Year and Date
      2014-06-10
    • Related Report
      2014 Annual Research Report
  • [Presentation] Isoform-specific monoclonal antibodies against 3ß-hydroxysteroid dehydrogenase/ isomerase family provide markers for subclassification of human primary aldosteronism2014

    • Author(s)
      Hida Hayashi, Masao Doi, and Hitoshi Okamura
    • Organizer
      The 7th International Aldosterone Forum in Japan
    • Place of Presentation
      Yokohama, Japan
    • Year and Date
      2014-05-31
    • Related Report
      2014 Annual Research Report
  • [Presentation] Angiotensin II triggers transcription of the adrenal gland zona glomerulosa-specific 3ß-HSD isoenzyme through de novo synthetic NGFIB pathway.2014

    • Author(s)
      Takumi Ota, Masao Doi, and Hitoshi Okamura
    • Organizer
      The 7th International Aldosterone Forum in Japan
    • Place of Presentation
      Yokohama, Japan
    • Year and Date
      2014-05-31
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] 生体リズム異常に伴う高血圧発症メカニズム-原発性アルドステロン症の原因診断学の再構築を目指して-2014

    • Author(s)
      土居雅夫, 岡村均
    • Organizer
      第87回日本内分泌学会学術総会
    • Place of Presentation
      福岡
    • Year and Date
      2014-04-26
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Remarks] 研究室ホームページ

    • URL

      http://www.pharm.kyoto-u.ac.jp/system-biology/doimasao/

    • Related Report
      2014 Annual Research Report
  • [Patent(Industrial Property Rights)] 原発性アルドステロン症の検出方法及びモノクローナル抗体2015

    • Inventor(s)
      岡村均, 土居雅夫, 佐藤文俊, 笹野公伸, 森本玲ら
    • Industrial Property Rights Holder
      国立大学法人京都大学
    • Industrial Property Rights Type
      特許
    • Filing Date
      2015-03-27
    • Related Report
      2014 Annual Research Report

URL: 

Published: 2014-04-04   Modified: 2016-06-03  

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