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Mechanisms for the regulation of vascular homeostasis by functional lipid molecules

Research Project

Project/Area Number 24390051
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypePartial Multi-year Fund
Section一般
Research Field General physiology
Research InstitutionKanazawa University

Principal Investigator

TAKUWA Yoh  金沢大学, 医学系, 教授 (60171592)

Co-Investigator(Renkei-kenkyūsha) OKAMOTO Yasuo  金沢大学, 医学系, 准教授 (80293877)
YOSHIOKA Kazuaki  金沢大学, 医学系, 助教 (80333368)
TAKUWA Noriko  石川県立看護大学, 看護学部, 教授 (70150290)
Project Period (FY) 2012-04-01 – 2015-03-31
Project Status Completed (Fiscal Year 2014)
Budget Amount *help
¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000)
Fiscal Year 2014: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2013: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
Fiscal Year 2012: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000)
Keywords脂質メディエーター / スフィンゴシンー1-リン酸 / イノシトールリン脂質 / PI3-キナーゼ / シグナル伝達 / 血管新生 / 血管障壁 / 血管医学 / 脂質 / 循環器・高血圧 / 生体分子 / 生理学 / 循環器疾患
Outline of Final Research Achievements

We studied the mechanisms by which sphingosine-1-phosphate receptor S1P2 and phosphatidylinositol 3-kinase (PI3K) class II α-isoform (PI3K-C2α). S1P2 in the vascular endothelium protected the vasculature from acute disruption of vascular barrier integrity induced by anaphylactic mediators and lipopolysaccharide. This effect was mediated by S1P2-mediated inhibition of Akt and eNOS. S1P2 decreased the generation of nitric oxide (NO) by eNOS, resulting in inhibition of NO-mediated disruption of adherens junctions. Genetic deletion of PI3K-C2α impaired developmental and pathological angiogenesis. PI3K-C2α was necessary for VE-cadherin transport to the cell-cell junction, VEGF receptor endocytosis and endosomal receptor signaling, through which PI3K-C2α served an essential role in angiogenesis.

Report

(4 results)
  • 2014 Annual Research Report   Final Research Report ( PDF )
  • 2013 Annual Research Report
  • 2012 Annual Research Report
  • Research Products

    (50 results)

All 2015 2014 2013 2012 Other

All Journal Article (16 results) (of which Peer Reviewed: 13 results,  Open Access: 4 results) Presentation (28 results) (of which Invited: 7 results) Book (1 results) Remarks (4 results) Patent(Industrial Property Rights) (1 results)

  • [Journal Article] Phosphatidylinositol 3-kinase Class II α-Isoform PI3K-C2α Is Required for Transforming Growth Factor β-induced Smad Signaling in Endothelial Cells.2015

    • Author(s)
      Aki S, Yoshioka K, Okamoto Y, Takuwa N, Takuwa Y.
    • Journal Title

      J Biol Chem.

      Volume: 290 Issue: 10 Pages: 6086-6105

    • DOI

      10.1074/jbc.m114.601484

    • NAID

      120005593954

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Selenoprotein P as a diabetes-associated hepatokine that impairs angiogenesis by inducing VEGF resistance in vascular endothelial cells.2014

    • Author(s)
      Ishikura K, Misu H, Kumazaki M, Takayama H, Matsuzawa-Nagata N, Tajima N, Chikamoto K, Lan F, Ando H, Ota T, Sakurai M, Takeshita Y, Kato K, Fujimura A, Miyamoto K, Saito Y, Kameo S, Okamoto Y, Takuwa Y, Takahashi K, Kidoya H, Takakura N, Kaneko S, Takamura T
    • Journal Title

      Diabetologia

      Volume: 57 Issue: 9 Pages: 1968-1976

    • DOI

      10.1007/s00125-014-3306-9

    • NAID

      120005463349

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Involvement of S1P1 receptor pathway in angiogenic effects of a novel adenosine-like nucleic acid analog COA-Cl in cultured human vascular endothelial cells2014

    • Author(s)
      Igarashi J, Hashimoto T, Kubota Y, Shoji K, Maruyama T, Sakakibara N, TakuwaY, Ujihara Y, Katanosaka Y, Mohri S, Naruse K, Yamashita T, Okamoto R, Hirano K, Kosaka H, Takata M, Konishi R, Tsukamoto I.
    • Journal Title

      Pharmacology Research & Perspectives

      Volume: 2 Issue: 5 Pages: 68-68

    • DOI

      10.1002/prp2.68

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Receptor for advanced glycation end products - membrane type1 matrix metalloprotease axis regulates tissue factor expression via RhoA and Rac1 activation in high-mobility group box-1 stimulated endothelial Cells.2014

    • Author(s)
      Sugimoto K, Ohkawara H, Takuwa Y, Ishibashi T and Takeishi Y .
    • Journal Title

      PLoS One.

      Volume: 9 Issue: 12 Pages: 1-13

    • DOI

      10.1371/journal.pone.0114429

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] スフィンゴシン-1-リン酸の炎症における多彩な役割2014

    • Author(s)
      多久和 陽
    • Journal Title

      実験医学

      Volume: 32 Pages: 138-146

    • Related Report
      2014 Annual Research Report
  • [Journal Article] Sphingosine-1-Phosphate Signaling and Cardiac Fibrosis.2013

    • Author(s)
      Takuwa N, Okamoto Y, Yoshioka K, Takuwa Y.
    • Journal Title

      Inflammation and Regeneration

      Volume: 33 Pages: 96-108

    • NAID

      130004943837

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] CCL2/CCR2 augments the production of transforming growth factor-beta1, type 1 collagen and CCL2 by human CD45-/collagen 1-positive cells under high glucose concentrations.2013

    • Author(s)
      Hara A, Sakai N, Furuichi K, Sakai Y, Takeya M, Bucala R, Mukaida N, Takuwa Y, Matsushima K, Kaneko S, Wada T.
    • Journal Title

      Clin Exp Nephrol.

      Volume: 17 Issue: 6 Pages: 793-804

    • DOI

      10.1007/s10157-013-0796-6

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Sphingosine-1-phosphate receptor-2 protects against anaphylactic shock through suppression of eNOS in mice.2013

    • Author(s)
      Cui H, Okamoto Y, Yoshioka K, et al.
    • Journal Title

      J. Allergy Clin. Immunol.

      Volume: 132 Issue: 5 Pages: 1205-1214

    • DOI

      10.1016/j.jaci.2013.07.026

    • Related Report
      2013 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Sphingosine-1-phosphate as a mediator involved in development of fibrotic diseases2013

    • Author(s)
      Takuwa Y
    • Journal Title

      Biochim Biophys Acta

      Volume: 183 Issue: 1 Pages: 185-192

    • DOI

      10.1016/j.bbalip.2012.06.008

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Essential role of class II PI3K-C2α in sphingosine-1-phosphate receptor-1 mediated signaling and migration in endothelial cells2013

    • Author(s)
      Biswas K, Yoshioka K, Asanuma K, Okamoto Y, Takuwa N, Sasaki T, TakuwaY
    • Journal Title

      J. Biol. Chem

      Volume: 288 Issue: 4 Pages: 2325-2339

    • DOI

      10.1074/jbc.m112.409656

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Sphingosine -1 -Phosphate Signaling and Cardiac Fibrosis.2013

    • Author(s)
      Takuwa N
    • Journal Title

      Inflammation and Regeneration

      Volume: 33 Pages: 96-108

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] P13キナーゼ・ファミリーの血管における生理機能:クラスIIα型P13キナーゼC2aによる新たな血管恒常性維持機構2013

    • Author(s)
      吉岡 和晃
    • Journal Title

      血管

      Volume: 36 Pages: 1-9

    • Related Report
      2012 Annual Research Report
  • [Journal Article] 血管新生の基礎と臨床2013

    • Author(s)
      多久和 陽
    • Journal Title

      Bio Clinica

      Volume: 28 Pages: 16-17

    • Related Report
      2012 Annual Research Report
  • [Journal Article] Sphingosine-1 -phosphate signaling in physiology and diseases2012

    • Author(s)
      Takuwa Y
    • Journal Title

      BioFactors

      Volume: 38 Pages: 329-337

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Overexpression of sphingosine kinase 1 prevents ceramide accumulation and ameliorates muscle insulin resistance in high fat-fed mice.2012

    • Author(s)
      Bruce C
    • Journal Title

      Diabetes.

      Volume: 61 Pages: 3148-3155

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Essential role of endothelial class II PI3K-C2αin angiogenesis and vascular barrier function2012

    • Author(s)
      Yoshioka K, Yoshida K, Cui H, Wakayama T, Takuwa N, Okamoto Y, Du W, Qi X, Asanuma K, Sugihara K, Aki S, Miyazawa H, Biswas K, Nagakura C, Ueno M, Iseki S, Schwartz JR, Okamoto H, Sasaki T,Matsui O, Asano M, Adams HR, Takakura N, Takuwa Y.
    • Journal Title

      Nature med

      Volume: 18 Issue: 10 Pages: 1560-1569

    • DOI

      10.1038/nm.2928

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Presentation] Sphingosine 1-phosphate receptor-2 plays a protective role against lipopolysaccharide (LPS)-induced acute lung injury2015

    • Author(s)
      Yasuo Okamoto, Hong Cui, Kazuaki Yoshioka, Noriko Takuwa, Sho Aki, JuanJuan Zhao, Hoa Quynh Pham, Md. Azadul Kabir Sarker, Saori Koizumi, Yoh Takuwa
    • Organizer
      第92回日本生理学会大会
    • Place of Presentation
      神戸国際会議場・展示場(兵庫県・神戸市)
    • Year and Date
      2015-03-21 – 2015-03-23
    • Related Report
      2014 Annual Research Report
  • [Presentation] Essential role of PI3K class II α for endosomal signaling of S1P1 and other receptors2015

    • Author(s)
      Yoh Takuwa
    • Organizer
      6th international conference on Phospholipase A2 and Lipid Mediators
    • Place of Presentation
      京王プラザホテル(東京都・新宿区)
    • Year and Date
      2015-02-10 – 2015-02-12
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] クラスIIα型PI3K-C2αはALK5 内在化及び足場タンパクSARA のエンドソームへの動員を制御しTGF-1-Smad2/3 を介した血管新生を調節する2014

    • Author(s)
      安藝 翔、吉岡 和晃、岡本 安雄、多久和 典子、多久和 陽
    • Organizer
      第56回 日本脂質生化学会
    • Place of Presentation
      近畿大学東大阪キャンパス(大阪府・東大阪市)
    • Year and Date
      2014-06-06 – 2014-06-07
    • Related Report
      2014 Annual Research Report
  • [Presentation] Sphingosine-1-phosphate receptor-2 (S1P2) negatively regulates eNOS and protects against acute vascular barrier disruption2014

    • Author(s)
      Yasuo Okamoto, Cui Hong, Kazuaki Yoshioka, Noriko Takuwa, Toshishige Shibamoto, Yoh Takuwa
    • Organizer
      The 18th International Vascular Biology Meeting 2014 (IVBM 2014)
    • Place of Presentation
      みやこめっせ(京都府・京都市)
    • Year and Date
      2014-04-14 – 2014-04-17
    • Related Report
      2014 Annual Research Report
  • [Presentation] Distinct role of S1P2 in the functional regulation of vascular endothelium and smooth muscle2014

    • Author(s)
      Yoh Takuwa, Yasuo Okamoto, Kazuaki Yoshioka, Noriko Takuwa
    • Organizer
      The 18th International Vascular Biology Meeting 2014 (IVBM 2014)
    • Place of Presentation
      みやこめっせ(京都府・京都市)
    • Year and Date
      2014-04-14 – 2014-04-17
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] Sphingosine-1-phosphate receptor-2 protects against anaphylactic shock through inhibiting eNOS2014

    • Author(s)
      Yasuo Okamoto, Hong Cui, Kazuaki Yoshioka, Noriko Takuwa, Juanjuan Zhao, Yoh Takuwa
    • Organizer
      第91回日本生理学会大会  Symposium “Mechanisms on distributive shock and other blood pressure control failures
    • Place of Presentation
      鹿児島大学 郡元キャンパス(鹿児島県鹿児島市)
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] クラスII 型PI3K-C2αはメンブレン・トラフィック調節を介して血管バリア機能を制御する2014

    • Author(s)
      吉岡 和晃,岡本 安雄,多久和 典子,多久和 陽
    • Organizer
      第91回日本生理学会大会 シンポジウム「心血管系の形態・機能研究の最前線」
    • Place of Presentation
      鹿児島大学 郡元キャンパス(鹿児島県鹿児島市)
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] S1P2は内皮型一酸化窒素合成酵素を抑制することによりアナフラキシーショックに対して防御的に働く2013

    • Author(s)
      岡本 安雄 崔 弘 吉岡 和晃 多久和 典子 多久和 陽
    • Organizer
      第55回日本脂質生化学会
    • Place of Presentation
      ホテル松島大観荘(宮城県宮城郡)
    • Related Report
      2013 Annual Research Report
  • [Presentation] Phosphatidylinositol 3-kinase classII α-isoform contols vesicular trafficking in endothelial cells to serve the essential role in angiogenesis and vascular barrier integrity2013

    • Author(s)
      Yoh Takuwa
    • Organizer
      第45回動脈硬化学会
    • Place of Presentation
      京王プラザホテル(東京都新宿区)
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] Sphingosine-1-phosphate receptor-2 negatively regulates eNOS and protects against acute vascular barrier disruption2013

    • Author(s)
      Yoh Takuwa
    • Organizer
      2013FASEB Summer Research Conference Lysophospholipid and Other Related Mediators - From Bench to Clinic
    • Place of Presentation
      Hilton Niseko Village(北海道虻田郡)
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] S1P受容体はeNOS-NO経路を抑制することによりアナフラキシーショックに対して抑制的に働く2013

    • Author(s)
      岡本安雄、崔弘、吉岡和晃、多久和典子、多久和陽
    • Organizer
      第21回日本血管生物医学会
    • Place of Presentation
      千里阪急ホテル(大阪府豊中市)
    • Related Report
      2013 Annual Research Report
  • [Presentation] TGFβ1-Smad2/3シグナル伝達系を介した血管新生調節におけるクラスIIαPI3キナーゼPI3K-C2αの機能的役割2013

    • Author(s)
      安藝 翔、吉岡 和晃、多久和 典子、岡本 安雄、多久和 陽
    • Organizer
      第21回日本血管生物医学会
    • Place of Presentation
      千里阪急ホテル(大阪府豊中市)
    • Related Report
      2013 Annual Research Report
  • [Presentation] クラスIIα型PI3キナーゼ-C2αによる血管新生・バリア機能調節メカニズム2013

    • Author(s)
      吉岡 和晃、多久和 典子、岡本 安雄、多久和 陽
    • Organizer
      第21回日本血管生物医学会 シンポジウム「血管機能を抑制するシグナリング機構」
    • Place of Presentation
      千里阪急ホテル(大阪府豊中市)
    • Related Report
      2013 Annual Research Report
    • Invited
  • [Presentation] クラスII 型PI3K-C2αはSARA のエンドソームへの動員を制御しTGFß1-Smad2/3シグナル伝達系を介した血管新生を調節する2013

    • Author(s)
      安藝 翔,吉岡 和晃,岡本 安雄,多久和 典子,多久和 陽
    • Organizer
      第36回日本分子生物学会
    • Place of Presentation
      神戸国際会議場/神戸国際展示場/神戸ポートピアホテル(兵庫県神戸市)
    • Related Report
      2013 Annual Research Report
  • [Presentation] ClassII P13-kinase, PI3K-C2alpha, mediates S1P-induced endothelial cell migration through endosomal Rac1 activation2013

    • Author(s)
      Kuntal Biswas
    • Organizer
      Gordon Research Conference Vascular Cell Biology
    • Place of Presentation
      Four Points Sheraton / Holiday Inn Express (USA)
    • Related Report
      2012 Annual Research Report
  • [Presentation] Endothelial PI3K-C2a, a class II PI3K, has an essential role in angiogenesis and vascular barrier function.2013

    • Author(s)
      Yoshioka K
    • Organizer
      Gordon Research Conference Vascular CeU Biology
    • Place of Presentation
      Four Points Sheraton / Holiday Inn Express (USA)
    • Related Report
      2012 Annual Research Report
  • [Presentation] Endothelial P13K-C2a, a class II PI3K in angiogenesis and vascular barrier function2013

    • Author(s)
      Yoh Takuwa
    • Organizer
      Gordon Research Conference Vascular CeU Biology
    • Place of Presentation
      Four Points Sheraton / Holiday Inn Express (USA)(招待講演)
    • Related Report
      2012 Annual Research Report
  • [Presentation] スフィンゴシン-1-リン酸特異的2型受容体は内皮型一酸化窒素合成酵素を抑制することによりアナフィラキシーショックに対して保護的に働く2013

    • Author(s)
      崔 弘
    • Organizer
      第90回日本生理学会
    • Place of Presentation
      タワーホール船堀(東京都)
    • Related Report
      2012 Annual Research Report
  • [Presentation] クラスII型P13キナーゼC2aはエンドソーム上でのSIPによるRacl活性化を制御して内皮細胞遊走を調節する2013

    • Author(s)
      Kuntal Biswas
    • Organizer
      第90回日本生理学会
    • Place of Presentation
      タワーホール船堀(東京都)
    • Related Report
      2012 Annual Research Report
  • [Presentation] クラスII型P13キナーゼC2aはメンブレン・トラフィツキング調節を介する血管形成及び恒常性維持に必須である2013

    • Author(s)
      吉岡和晃
    • Organizer
      第90回日本生理学会
    • Place of Presentation
      タワーホール船堀(東京都)
    • Related Report
      2012 Annual Research Report
  • [Presentation] Role of sphingosine-1'phosphate in cardiac remodeling and protection2012

    • Author(s)
      Yoh Takuwa
    • Organizer
      The 1st International Symposium Oil Lipid Mediators
    • Place of Presentation
      九州大学医学部百年講堂(福岡県)(招待講演)
    • Related Report
      2012 Annual Research Report
  • [Presentation] クラスII ・型P13キナーゼC2・は血管形成に必須である2012

    • Author(s)
      吉岡和晃
    • Organizer
      第54回日本脂質生化学会
    • Place of Presentation
      九州大学医学部百年講堂(福岡県)
    • Related Report
      2012 Annual Research Report
  • [Presentation] Essential role of class IIα-isoform P13 kinase (PI3K-C2a) in sphingosine-1-phosphate(SlP-induced endothelial cell migration2012

    • Author(s)
      多久和 陽
    • Organizer
      第7回 スフィンゴテラピィ研究会
    • Place of Presentation
      能登ロイヤルホテル(石川県)
    • Related Report
      2012 Annual Research Report
  • [Presentation] Class II PI3K"C2&alphai is essential for vascular barrier integrity2012

    • Author(s)
      Kazuaki Yoshioka
    • Organizer
      International Endotoxin and Innate Immunity Society Meeting 2012
    • Place of Presentation
      学術総合センター(東京都)
    • Related Report
      2012 Annual Research Report
  • [Presentation] クラスII型P13キナーゼC2aは血管新生・恒常性維持に必須である2012

    • Author(s)
      吉岡和晃
    • Organizer
      第59回中部生理学会
    • Place of Presentation
      自然科学研究機構岡崎コンファレンスセンター(愛知県)
    • Related Report
      2012 Annual Research Report
  • [Presentation] Class II P13 kinase C2α has a crucial role in vascular formation and barrier integrity2012

    • Author(s)
      Kazuaki Yoshioka
    • Organizer
      20回日本血管生物医学会
    • Place of Presentation
      あわぎんホール(徳島県)
    • Related Report
      2012 Annual Research Report
  • [Presentation] クラスII型P13キナーゼC2αは血管形成・血管恒常性維持に必須である2012

    • Author(s)
      吉岡和晃
    • Organizer
      第35回日本分子生物学会
    • Place of Presentation
      福岡国際会議場・マリンメッセ福岡(福岡県)(招待講演)
    • Related Report
      2012 Annual Research Report
  • [Presentation] クラスII型P13キナーゼC2aはエンドソーム上でのRacl活性化を制御してスフィンゴシン・1-リン酸(SIP)による血管内皮細胞遊走・管腔形成を調節する。2012

    • Author(s)
      Kuntal Biswas
    • Organizer
      第35回日本分子生物学会
    • Place of Presentation
      福岡国際会議場・マリンメッセ福岡(福岡県)(招待講演)
    • Related Report
      2012 Annual Research Report
  • [Book] サイトカイン・増殖因子キーワード2015

    • Author(s)
      宮園浩平 他
    • Total Pages
      420
    • Publisher
      羊土社
    • Related Report
      2014 Annual Research Report
  • [Remarks] 血管分子生理学教室(旧生理学第一講座) 金沢大学大学院 医学系研究科 循環医科学専攻

    • URL

      http://physiology1.w3.kanazawa-u.ac.jp/

    • Related Report
      2014 Annual Research Report
  • [Remarks] 金沢大学情報リポジトリ

    • URL

      http://dspace.lib.kanazawa-u.ac.jp/dspace/

    • Related Report
      2013 Annual Research Report
  • [Remarks] 血管分子生理学教室(旧生理学第一講座) 金沢大学大学院 医学系研究科 循環医科学専攻

    • URL

      http://physiology1.w3.kanazawa-u.ac.jp/

    • Related Report
      2013 Annual Research Report
  • [Remarks]

    • URL

      http://physiology1.w3.kanazawa-u.ac.jp/

    • Related Report
      2012 Annual Research Report
  • [Patent(Industrial Property Rights)] 血管内皮関門障害に関連した疾患又は症状を予防及び/又は治療するための候補物質のスクリーニング方法2013

    • Inventor(s)
      多久和 陽
    • Industrial Property Rights Holder
      多久和 陽
    • Industrial Property Number
      2013-033893
    • Filing Date
      2013-02-22
    • Related Report
      2012 Annual Research Report

URL: 

Published: 2012-04-24   Modified: 2019-07-29  

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