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Elucidation of molecular mechanism and development of novel diagnostic methods for aortic valve stenosis

Research Project

Project/Area Number 16K10631
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Cardiovascular surgery
Research InstitutionEhime University

Principal Investigator

Hironori Izutani  愛媛大学, 医学系研究科, 教授 (90419200)

Co-Investigator(Kenkyū-buntansha) 坂上 倫久  愛媛大学, 医学系研究科, 講師(特定教員) (20709266)
Project Period (FY) 2016-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywords大動脈弁狭窄症 / 大動脈弁 / 石灰化 / AS / 間質細胞 / VIC / 弁間質細胞 / 線維化 / 弁膜症 / HB-EGF / バイオマーカー / 心臓
Outline of Final Research Achievements

The main causes of AS are heart disorders such as bicuspid aortic valve and the degeneration of valves resulting from atherosclerosis. However, the medical therapy for prevention of calcification has not been established yet, because the molecular mechanism underlying calcium deposition remain unknown. In this study, we aimed to clarify the molecular mechanism and develop the novel diagnostic methods for aortic valve stenosis. As the results, we successfully identified COX-1 as a calcification-specific factor in aortic valves. When valve interstitial cells (VICs) were stimulated by osteogenic media, COX-1 was strongly induced. However, osteoblast differentiations were completely abrogated by COX1-depletion. Our data suggested that COX-1 might be novel drug target for AS treatment.

Academic Significance and Societal Importance of the Research Achievements

本邦において、ASの罹患率は増加傾向にある。心臓外科領域におけるAS治療は、TAVI(経カテーテル的大動脈弁留置術)の導入などにより飛躍的に進歩したが、AS発症の分子機序が不明であるため根治療法のための薬剤開発も未だ進んでいない。本研究で得られた新規知見は、この問題解決に資するものであり、今後の研究発展の可能性が大いに期待できる。

Report

(5 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • 2016 Research-status Report
  • Research Products

    (32 results)

All 2019 2018 2017 2016 Other

All Int'l Joint Research (1 results) Journal Article (5 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 5 results,  Open Access: 2 results) Presentation (21 results) (of which Int'l Joint Research: 5 results) Book (1 results) Remarks (4 results)

  • [Int'l Joint Research] セント・ビンセント病院(オーストラリア)

    • Related Report
      2017 Research-status Report
  • [Journal Article] Valve Interstitial Cell-Specific Cyclooxygenase-1 Associated With Calcification of Aortic Valves.2019

    • Author(s)
      Sakaue T, Hamaguchi M, Aono J, Nakashiro KI, Shikata F, Kawakami N, Oshima Y, Kurata M, Nanba D, Masumoto J, Yamaguchi O, Higashiyama S, Izutani H.
    • Journal Title

      Ann Thorac Surg.

      Volume: 19 Pages: 31717-5

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Biochemical and histological evidence of deteriorated bioprosthetic valve leaflets: the accumulation of fibrinogen and plasminogen2018

    • Author(s)
      Sakaue Tomohisa、Nakaoka Hirotomo、Shikata Fumiaki、Aono Jun、Kurata Mie、Uetani Teruyoshi、Hamaguchi Mika、Kojima Ai、Uchita Shunji、Yasugi Takumi、Higashi Haruhiko、Suzuki Jun、Ikeda Shuntaro、Higaki Jitsuo、Higashiyama Shigeki、Izutani Hironori
    • Journal Title

      Biology Open

      Volume: 7 Issue: 8

    • DOI

      10.1242/bio.034009

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Molecular-based analysis and therapeutic development of aortic valve stenosis.2018

    • Author(s)
      Sakaue T, Nakaoka H, Aono J、Kurata M, Oshima Y, Koga S, Namiguchi K Izutani H.
    • Journal Title

      Ehime Medical Journal.

      Volume: 37 (1) Pages: 05-09

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Perivascular Adipose Tissue Angiotensin II Type 1 Receptor Promotes Vascular Inflammation and Aneurysm Formation.2017

    • Author(s)
      Sakaue T, Suzuki J, Hamaguchi M, Suehiro C, Tanino A, Nagao T, Uetani T, Aono J, Nakaoka H, Kurata M, Sakaue T, Okura T, Yasugi T, Izutani H, Higaki J, Ikeda S.
    • Journal Title

      Hypertension

      Volume: 70(4) Issue: 4 Pages: 780-789

    • DOI

      10.1161/hypertensionaha.117.09512

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Proteomics-based analysis of lung injury-induced proteins in a mouse model of common bile duct ligation.2017

    • Author(s)
      Sakaue T, Shikata F, Utsunomiya K, Fukae S, Kurata M, Nakaoka H, Okazaki M, Kawanishi Y, Kojima A, Higashiyama S, Izutani H.
    • Journal Title

      Surgery

      Volume: 印刷中 Issue: 6 Pages: 1525-1535

    • DOI

      10.1016/j.surg.2016.12.017

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] Valve interstitial cell-specific cyclooxygenase1 is associated with calcification of aortic valves2019

    • Author(s)
      Tomohisa SAKAUE, Mika HAMAGUCHI, Fumiaki SHIKATA, Jun AONO, Koh-ichi NAKASHIRO, Hironori IZUTANI"
    • Organizer
      STS2019 第55回米国胸部外科学会
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 二次元電気泳動法を用いた石灰化大動脈弁のタンパク質解析2019

    • Author(s)
      坂上倫久、濱口美香、青野 潤、中岡裕智、倉田美恵、鹿田文昭、浪口謙治、打田俊司、八杉 巧、増本純也、東山繁樹、泉谷裕則
    • Organizer
      第49回日本心臓血管外科学会学術総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Identification of target molecules for anti-deterioration therapy against implanted tissue valve in aortic position utilizing proteomic technology2019

    • Author(s)
      Tomohisa Sakaue, Tadaaki Koyama, Yoshitugu Nakamura, Fumiaki Shikata, Izutani Hironori
    • Organizer
      第33回欧州心臓胸部外科学会 EACTS2019
    • Related Report
      2019 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 大動脈弁狭窄症患者由来の石灰化大動脈弁のタンパク質プロファイリング解析2019

    • Author(s)
      坂上倫久、濱口美香、青野 潤、鹿田文昭、浪口謙治、打田俊司、八杉 巧、東山繁樹、泉谷裕則
    • Organizer
      第72回日本胸部外科学会定期学術集会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 大動脈弁異所性石灰化の分子メカニズムの解明2019

    • Author(s)
      坂上倫久、濱口美香、青野潤、中城公一、倉田美恵、大嶋佑介、東山繁樹、泉谷裕則
    • Organizer
      第4回黒潮カンファレンス
    • Related Report
      2019 Annual Research Report
  • [Presentation] Valve interstitial cell-specific cyclooxygenase-1 associated with calcification of aortic valves2019

    • Author(s)
      Tomohisa Sakaue、Mika Hamaguchi、Jun Aono、Koh-ichi Nakashiro、Fumiaki Shikata、Hironori Izutani
    • Organizer
      STS 55th Annual Meeting
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] 大動脈弁狭窄症患者由来石灰化大動脈弁のプロテオミクス解析2018

    • Author(s)
      坂上倫久、濱口美香、青野潤、鹿田文昭、浪口謙治、中岡裕智、倉田美恵、東山繁樹、泉谷裕則
    • Organizer
      第91回日本生化学会大会
    • Related Report
      2018 Research-status Report
  • [Presentation] 摘出大動脈弁からの弁間質細胞の調製と網羅的遺伝子発現解析2018

    • Author(s)
      坂上倫久、濱口美香、青野潤、中城公一、鹿田文昭、浪口謙治、中岡裕智、倉田美恵、打田俊司、八杉巧、東山繁樹、泉谷裕則
    • Organizer
      第71回日本胸部外科学会定期学術集会
    • Related Report
      2018 Research-status Report
  • [Presentation] Comprehensive gene expression analysis of valve interstitial cells from surgically excised stenotic aortic valves2018

    • Author(s)
      Tomohisa Sakaue、Mika Hamaguchi、Jun Aono、Koh-ichi Nakashiro、Fumiaki Shikata、Kenji Namiguchi、Hirotomo Nakaoka、Mie Kurata、Shunji Uchita、Takumi Yasug、Ai Kojima、Hironori Izutani
    • Organizer
      Vascular Biology 2018
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] 大動脈弁置換術患者由来の摘出大動脈弁を用いた組織学的解析2017

    • Author(s)
      坂上 倫久、中岡 裕智、鹿田 文昭、村上 貴志、阪下 裕司、小嶋 愛、打田 俊司、八杉 巧、東山 繁樹、泉谷 裕則
    • Organizer
      第47回日本心臓血管外科学会学術総会
    • Place of Presentation
      東京都港区台場 グランドニッコー台場
    • Year and Date
      2017-02-26
    • Related Report
      2016 Research-status Report
  • [Presentation] 再弁置換術によって得られた摘出生体弁の組織学的解析2017

    • Author(s)
      中岡 裕智、坂上 倫久、村上 貴志、阪下 裕司、小嶋 愛、鹿田 文昭、打田 俊司、八杉 巧、泉谷 裕則
    • Organizer
      第47回日本心臓血管外科学会学術総会
    • Place of Presentation
      東京都港区台場 グランドニッコー台場
    • Year and Date
      2017-02-26
    • Related Report
      2016 Research-status Report
  • [Presentation] 摘出大動脈弁から弁細胞の調整とその特性解析2017

    • Author(s)
      坂上 倫久、中岡 裕智、倉田 美恵、青野 潤、鹿田 文昭、村上 貴志、浪口 謙治、小嶋 愛、打田 俊司、八杉 巧、泉谷 裕則
    • Organizer
      第46回日本心脈管作動物質学会年会
    • Place of Presentation
      琉球大学医学部
    • Year and Date
      2017-02-10
    • Related Report
      2016 Research-status Report
  • [Presentation] ヒト血管内皮機能障害関連疾患におけるアンジオテンシン変換酵素2 (ACE2)およびMas受容体の発現解析2017

    • Author(s)
      中岡 裕智、坂上 倫久、倉田 美恵、青野 潤、鹿田 文昭、村上 貴志、浪口 謙治、小嶋 愛、打田 俊司、八杉 巧、泉谷 裕則
    • Organizer
      第46回日本心脈管作動物質学会年会
    • Place of Presentation
      琉球大学医学部
    • Year and Date
      2017-02-10
    • Related Report
      2016 Research-status Report
  • [Presentation] 摘出大動脈弁由来間質細胞の調整とその特性解析2017

    • Author(s)
      坂上倫久、中岡裕智、倉田美恵、青野潤、鹿田文昭、村上貴志、浪口謙治、小嶋愛、打田俊司、八杉巧、泉谷裕則
    • Organizer
      第46回日本心脈管作動物質学会
    • Related Report
      2017 Research-status Report
  • [Presentation] ヒト血管内皮機能障害関連疾患におけるアンジオテンシン変換酵素2 (ACE2)およびMas受容体の発現解析2017

    • Author(s)
      中岡裕智、坂上倫久、倉田美恵、青野潤、村上貴志、浪口謙治、小嶋愛、鹿田文昭、打田俊司、八杉巧、泉谷裕則
    • Organizer
      第46回日本心脈管作動物質学会
    • Related Report
      2017 Research-status Report
  • [Presentation] 大動脈弁置換術患者由来の摘出大動脈弁を用いた組織学的解析2017

    • Author(s)
      坂上倫久、中岡裕智、鹿田文昭、村上 貴志、阪下裕司、小嶋愛、打田俊司、八杉巧、泉谷裕則
    • Organizer
      第47回日本心臓血管外科学会学術総会
    • Related Report
      2017 Research-status Report
  • [Presentation] 再弁置換術によって得られた摘出生体弁の組織学的解析2017

    • Author(s)
      中岡裕智、坂上倫久、村上貴志、阪下裕司、小嶋愛、鹿田文昭、打田俊司、八杉巧、泉谷裕則
    • Organizer
      第47回日本心臓血管外科学会学術総会
    • Related Report
      2017 Research-status Report
  • [Presentation] 弁置換術によって得られた摘出大動脈弁のプロテオミクス解析2017

    • Author(s)
      坂上倫久、中岡裕智、鹿田文昭、村上貴志、阪下裕司、小嶋愛、打田俊司、八杉巧、泉谷裕則
    • Organizer
      第117回日本外科学会定期学術集会
    • Related Report
      2017 Research-status Report
  • [Presentation] 大動脈弁置換術における摘出大動脈弁を用いたα-SMAの発現解析2017

    • Author(s)
      中岡裕智、坂上倫久、鹿田文昭、村上貴志、阪下裕司、小嶋愛、打田俊司、八杉巧、泉谷裕則
    • Organizer
      第117回日本外科学会定期学術集会
    • Related Report
      2017 Research-status Report
  • [Presentation] Plasminogen and fibrinogen promote calcification in bioprosthetic valve leaflets in aortic position2017

    • Author(s)
      Tomohisa Sakaue, Hirotomo Nakaoka, Fumiaki Shikata, Jun Aono, Mie Kurata, Teruyoshi Uetani, Takashi Murakami1, Yuji Sakashita, Ai Kojima, Shunji Uchita, Takumi Yasugi, Shigeki Higashiyama, Hironori Izutani.
    • Organizer
      31st EACTS 2017 Annual Meeting - European Association for Cardio-Thoracic Surgery
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] 大動脈弁狭窄症患者由来の摘出大動脈弁を用いたヘパリン結合性EGF様成長因子(HB-EGF)の解析2016

    • Author(s)
      坂上 倫久、中岡 裕智、鹿田 文昭、村上 貴志、阪下 裕司、小嶋 愛、打田 俊司、八杉 巧、東山 繁樹、泉谷 裕則
    • Organizer
      第69回日本胸部外科学会定期学術集会
    • Place of Presentation
      岡山市
    • Year and Date
      2016-09-28
    • Related Report
      2016 Research-status Report
  • [Book] 大動脈弁狭窄症の病態解明とその治療法の開発研究2018

    • Author(s)
      坂上倫久、中岡裕智、青野潤、倉田美恵、東山繁樹、泉谷裕則
    • Total Pages
      43
    • Publisher
      愛媛医学 37(1): 01-04
    • Related Report
      2018 Research-status Report
  • [Remarks] 愛媛大学医学部心臓血管・呼吸器外科学HP

    • URL

      https://www.m.ehime-u.ac.jp/school/surgery2/

    • Related Report
      2019 Annual Research Report
  • [Remarks] 愛媛大学医学部心臓血管・呼吸器外科HP

    • URL

      https://www.m.ehime-u.ac.jp/school/surgery2/

    • Related Report
      2018 Research-status Report
  • [Remarks] 愛媛大学大学院 医学系研究科 心臓血管・呼吸器外科

    • URL

      https://www.m.ehime-u.ac.jp/school/surgery2/

    • Related Report
      2017 Research-status Report
  • [Remarks] 愛媛大学大学院医学系研究科心臓血管・呼吸器外科学

    • URL

      http://www.m.ehime-u.ac.jp/school/surgery2/

    • Related Report
      2016 Research-status Report

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Published: 2016-04-21   Modified: 2021-02-19  

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