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Novel anti-sepsis strategy targeting the endothelial cell-specific receptor Robo4

Research Project

Project/Area Number 26293014
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypePartial Multi-year Fund
Section一般
Research Field Biological pharmacy
Research InstitutionOsaka University

Principal Investigator

Okada Yoshiaki  大阪大学, 薬学研究科(研究院), 准教授 (50444500)

Co-Investigator(Kenkyū-buntansha) 土井 健史  大阪大学, 薬学研究科(研究院), 教授 (00211409)
Co-Investigator(Renkei-kenkyūsha) FUJIO Yasushi  大阪大学, 薬学研究科, 教授 (20359839)
KURODA Etsushi  大阪大学, 免疫学フロンティアセンター, 特任准教授 (10299604)
Research Collaborator Aird William  Harvard Medical School, 教授
Project Period (FY) 2014-04-01 – 2017-03-31
Project Status Completed (Fiscal Year 2016)
Budget Amount *help
¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000)
Fiscal Year 2016: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2015: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2014: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
KeywordsRobo4 / 敗血症 / 血管内皮細胞 / 炎症 / 単球 / インターロイキン6 / 治療薬 / 低分子化合物 / スクリーニング系 / HDAC阻害剤 / 免疫細胞 / 炎症性サイトカイン / シグナル伝達系
Outline of Final Research Achievements

The goal of our study is to develop a new drug to treat sepsis. Although antibiotics and steroids have been used for the treatment of sepsis, their effects are limited. To development new anti-sepsis drugs targeting vascular blood vessels, we focused on Robo4 that is a transmembrane receptor specifically expressed in endothelial cells. In this study we demonstrated that Robo4 downregulation suppresses IL-6 production not only from endothelial cells but also from monocytes though a crosstalk with GM-CSF, suggesting a new anti-sepsis strategy using molecules that inhibit Robo4 expression. To this end, we established a screening system for small molecules that suppress Robo4 expression.

Report

(4 results)
  • 2016 Annual Research Report   Final Research Report ( PDF )
  • 2015 Annual Research Report
  • 2014 Annual Research Report
  • Research Products

    (36 results)

All 2017 2016 2015 2014 Other

All Int'l Joint Research (2 results) Journal Article (8 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 8 results,  Open Access: 5 results,  Acknowledgement Compliant: 2 results) Presentation (22 results) (of which Int'l Joint Research: 3 results,  Invited: 3 results) Remarks (3 results) Patent(Industrial Property Rights) (1 results)

  • [Int'l Joint Research] Harvard Medical School(米国)

    • Related Report
      2016 Annual Research Report
  • [Int'l Joint Research] Harvard Medical School(米国)

    • Related Report
      2015 Annual Research Report
  • [Journal Article] Tumor Necrosis Factor α Induces the Expression of the Endothelial Cell-Specific Receptor Roundabout4 through the Nuclear Factor-κB Pathway2017

    • Author(s)
      Tanaka T, Maekawa N, Kashio T, Izawa K, Ishiba R, Shirakura K, Ishimoto K, Hino N, Aird WC, Doi T, Okada Y.
    • Journal Title

      Biological and Pharmaceutical Bulletin

      Volume: 40 Issue: 4 Pages: 504-509

    • DOI

      10.1248/bpb.b16-00938

    • NAID

      130005530067

    • ISSN
      0918-6158, 1347-5215
    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
  • [Journal Article] Adenovirus vector-based incorporation of a photo-cross-linkable amino acid into proteins in human primary cells and cancerous cell lines.2016

    • Author(s)
      Kita A, Hino N, Higashi S, Hirota K, Narumi R, Adachi J, Takafuji K, Ishimoto K, Okada Y, Sakamoto K, Tomonaga T, Takashima S, Mizuguchi H, Doi T.
    • Journal Title

      Sci Rep

      Volume: 6 Issue: 1 Pages: 36946-36946

    • DOI

      10.1038/srep36946

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Efficacy and safety evaluation of claudin-4-targeted antitumor therapy using a human and mouse cross-reactive monoclonal antibody.2016

    • Author(s)
      Hashimoto Y, Kawahigashi Y, Hata T, Li X, Watari A, Tada M, Ishii-Watabe A, Okada Y, Doi T, Fukasawa M, Kuniyasu H, Yagi K, Kondoh M
    • Journal Title

      Pharmacol Res Perspect

      Volume: 4 Issue: 5

    • DOI

      10.1002/prp2.266

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Generation and characterization of a human-mouse chimeric antibody against the extracellular domain of claudin-1 for cancer therapy using a mouse model.2016

    • Author(s)
      Hashimoto Y, Tada M, Iida M, Nagase S, Hata T, Watari A, Okada Y, Doi T, Fukasawa M, Yagi K, Kondoh M.
    • Journal Title

      Biochem Biophys Res Commun.

      Volume: 477(1) Issue: 1 Pages: 91-95

    • DOI

      10.1016/j.bbrc.2016.06.025

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Ubiquitination of Lysine 867 of the Human SETDB1 Protein Upregulates Its Histone H3 Lysine 9 (H3K9) Methyltransferase Activity.2016

    • Author(s)
      Ishimoto K, Kawamata N, Uchihara Y, Okubo M, Fujimoto R, Gotoh E, Kakinouchi K, Mizohata E, Hino N, Okada Y, Mochizuki Y, Tanaka T, Hamakubo T, Sakai J, Kodama T, Inoue T, Tachibana K, Doi T
    • Journal Title

      PLoS One

      Volume: 11 Issue: 10 Pages: e0165766-e0165766

    • DOI

      10.1371/journal.pone.0165766

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Expression of the Robo4 receptor in endothelial cells is regulated by two AP-1 protein complexes.2015

    • Author(s)
      Okada Y, Naruse H, Tanaka T, Funahashi N, Regan ER, Yamakawa K, Hino N, Ishimoto K, Doi T, Aird WC.
    • Journal Title

      Biochem Biophys Res Commun

      Volume: 467(4) Issue: 4 Pages: 987-991

    • DOI

      10.1016/j.bbrc.2015.10.029

    • Related Report
      2015 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Regulation of Endothelial Cell-specific Robo4 Gene Expression by DNA Methylation and Non-lineage Specific Transcription Factors2014

    • Author(s)
      Okada Y
    • Journal Title

      YAKUGAKU ZASSHI

      Volume: 134 Issue: 7 Pages: 817-821

    • DOI

      10.1248/yakushi.13-00258

    • NAID

      130004756442

    • ISSN
      0031-6903, 1347-5231
    • Year and Date
      2014-07-01
    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Endothelial cell-specific expression of roundabout 4 is regulated by differential DNA methylation of the proximal promoter2014

    • Author(s)
      Okada, Y., Funahashi, N., Tanaka, T., Nishiyama, Y., Yuan, L., Shirakura, K., Turjman, A. S., Kano, Y., Naruse, H., Suzuki, A., Sakai, M., Zhixia, J., Kitajima, K., Ishimoto, K., Hino, N., Kondoh, M., Mukai, Y., Nakagawa, S., Garcia-Cardena, G., Aird, W. C., Doi, T.
    • Journal Title

      Arterioscler Thromb. Vasc. Biol.

      Volume: 34 Issue: 7 Pages: 1531-1538

    • DOI

      10.1161/atvbaha.114.303818

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed
  • [Presentation] TNF-αはNF-κB経路を介して血管内皮細胞特異的受容体Robo4の発現を促進する2017

    • Author(s)
      前河直樹, 田中亨, 樫尾泰斗, William C. Aird, 岡田欣晃, 土井健史
    • Organizer
      日本薬学会第137回年会
    • Place of Presentation
      東北大学(宮城)
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 血管内皮細胞特異的なRobo4プロモーターのDNAメチル化パターン形成機構の解明2017

    • Author(s)
      田中亨
    • Organizer
      第三回日本血管生物医学会若手研究会
    • Place of Presentation
      淡路夢舞台国際会議場(兵庫)
    • Related Report
      2016 Annual Research Report
  • [Presentation] 炎症時の血管透過性を制御するRobo4細胞内シグナルの解明2017

    • Author(s)
      白倉圭佑
    • Organizer
      第三回日本血管生物医学会若手研究会
    • Place of Presentation
      淡路夢舞台国際会議場(兵庫)
    • Related Report
      2016 Annual Research Report
  • [Presentation] Novel anti-sepsis strategy targeting the endothelial cell-specific receptor Robo42016

    • Author(s)
      Yoshiaki Okada, Keisuke Shirakura, Kiichiro Yano, Naoya Shigesada, Yu Fukushima, Ryosuke Ishiba, Taito Kashio, William C. Aird, Takefumi Doi
    • Organizer
      第2 回春期特別日本血管生物医学会シンポジウム
    • Place of Presentation
      大阪大学微生物病研究所(大阪府)
    • Year and Date
      2016-06-03
    • Related Report
      2015 Annual Research Report
  • [Presentation] Claudin を標的とした創薬基盤技術の開発~claudin-4 を標的としたがん治療戦略の有効性及び安全性の評価~2016

    • Author(s)
      松田 基, 橋本洋佑, 川東祐美, 畑 智幸, 渡利彰浩, 近藤昌夫, 岡田欣晃,多田 稔, 石井明子, 深澤征義, 土井健史, 八木清仁
    • Organizer
      日本薬学会 第136年会
    • Place of Presentation
      横浜(神奈川県)
    • Year and Date
      2016-03-29
    • Related Report
      2015 Annual Research Report
  • [Presentation] Tricellular tight junction を標的とした新規バリア制御技術、angubindin-1 の開発2016

    • Author(s)
      山本浩樹, 井口大輔, 早石知浩, Susanne M. KRUG, Michael FROMM, 渡利彰浩, 岡田欣晃, 竹田浩之, 永浜政博, 土井健史, 澤崎達也, 近藤昌夫, 八木清仁
    • Organizer
      日本薬学会 第136年会
    • Place of Presentation
      横浜(神奈川県)
    • Year and Date
      2016-03-28
    • Related Report
      2015 Annual Research Report
  • [Presentation] 第二回血管生物医学会若手研究会2016

    • Author(s)
      岡田欣晃
    • Organizer
      Robo4発現抑制分子を用いた新規敗血症治療戦略の可能性
    • Place of Presentation
      東北大学(宮城県)
    • Year and Date
      2016-03-05
    • Related Report
      2015 Annual Research Report
  • [Presentation] 第二回血管生物医学会若手研究会2016

    • Author(s)
      白倉圭佑
    • Organizer
      Robo4強制発現が炎症下の血管透過性制御に与える影響について
    • Place of Presentation
      東北大学(宮城県)
    • Year and Date
      2016-03-05
    • Related Report
      2015 Annual Research Report
  • [Presentation] Novel anti-sepsis strategy targeting the endothelial cell-specific receptor Robo42016

    • Author(s)
      Yoshiaki Okada, Keisuke Shirakura, Kiichiro Yano, Naoya Shigesada, Yu Fukushima, Ryosuke Ishiba, Taito Kashio, William C. Aird, Takefumi Doi
    • Organizer
      第2回春期特別日本血管生物医学会シンポジウム
    • Place of Presentation
      大阪大学(大阪)
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Robo4が炎症時の血管透過性を制御するメカニズムの解析2016

    • Author(s)
      白倉圭佑, William Aird, 岡田欣晃, 土井健史
    • Organizer
      第17回 Pharmaco-Hematology シンポジウム
    • Place of Presentation
      帝京大学(東京)
    • Related Report
      2016 Annual Research Report
  • [Presentation] 血管内皮細胞特異的Robo4発現が生み出されるメカニズムの解明2016

    • Author(s)
      田中亨, 岡村麻紀, 川端健二, 岡田欣晃, 土井健史
    • Organizer
      第17回 Pharmaco-Hematology シンポジウム
    • Place of Presentation
      帝京大学(東京)
    • Related Report
      2016 Annual Research Report
  • [Presentation] 炎症下の血管透過性制御におけるRobo4の役割2016

    • Author(s)
      岡田 欣晃
    • Organizer
      Kansai Vascular Biology Meeting 2016
    • Place of Presentation
      ホテルグランビア大阪(大阪)
    • Related Report
      2016 Annual Research Report
    • Invited
  • [Presentation] 3.Roundabout4 suppresses TNFα-induced vascular hyperpermeability via TRAF72016

    • Author(s)
      Keisuke Shirakura, Toru Tanaka, William C. Aird, Takefumi Doi, Yoshiaki Okada
    • Organizer
      19th International Vascular Biology Meeting
    • Place of Presentation
      ボストン(アメリカ)
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 血管内皮細胞特異的受容体を標的とする新規全身性炎症治療薬の開発2015

    • Author(s)
      重定 直弥、真鍋 詩織、山本 奈那、William Aird、岡田 欣晃、土井 健史
    • Organizer
      第14回次世代を担う若手ファーマ・バイオフォーラム2015
    • Place of Presentation
      千葉大学亥鼻キャンパス(千葉県)
    • Year and Date
      2015-09-12
    • Related Report
      2015 Annual Research Report
  • [Presentation] Robo4プロモーターの血管内皮細胞特異的なDNAメチル化パターン形成に寄与する因子の探索2015

    • Author(s)
      田中亨、間庭佑典、岡田淳雅、川端健二、Aird WC、岡田欣晃、土井健史
    • Organizer
      第9回日本エピジェネティクス研究会年会
    • Place of Presentation
      学術総合センター一橋講堂(東京都)
    • Year and Date
      2015-05-25
    • Related Report
      2015 Annual Research Report
  • [Presentation] 血管内皮細胞特異的な遺伝子発現とDNAメチル化2015

    • Author(s)
      岡田欣晃、William Aird、土井健史
    • Organizer
      日本薬学会第135年会
    • Place of Presentation
      神戸学院大学(兵庫)
    • Year and Date
      2015-03-26
    • Related Report
      2014 Annual Research Report
    • Invited
  • [Presentation] 血管内皮細胞特異的受容体Robo4の敗血症治療標的としての可能性2015

    • Author(s)
      岡田欣晃
    • Organizer
      日本血管生物医学会若手研究会
    • Place of Presentation
      東京大学(東京)
    • Year and Date
      2015-02-06
    • Related Report
      2014 Annual Research Report
  • [Presentation] Robo4 発現抑制による炎症抑制機構の解析と敗血症治療薬開発への応用2014

    • Author(s)
      真鍋詩織、山本奈那、Aird WC、岡田欣晃、土井健史
    • Organizer
      第64回日本薬学会近畿支部総会・大会
    • Place of Presentation
      京都薬科大学(京都)
    • Year and Date
      2014-10-11
    • Related Report
      2014 Annual Research Report
  • [Presentation] 血管内皮細胞特異的受容体Robo4 の血管透過性制御における役割2014

    • Author(s)
      山内沙織、白倉圭佑、William C Aird、岡田欣晃、土井健史
    • Organizer
      第64回日本薬学会近畿支部総会・大会
    • Place of Presentation
      京都薬科大学(京都)
    • Year and Date
      2014-10-11
    • Related Report
      2014 Annual Research Report
  • [Presentation] Roles of Endothelial cell specific receptor, Robo4 in inflammatory response2014

    • Author(s)
      Keisuke Shirakura, Miki Sakai, Yu Fukushima, Shiori Manabe, William C. Aird, Yoshiaki Okada, Takefumi Doi
    • Organizer
      第8回SKOシンポジウム
    • Place of Presentation
      大阪大学銀杏会館(大阪)
    • Year and Date
      2014-06-10
    • Related Report
      2014 Annual Research Report
  • [Presentation] 血管内皮細胞特異的受容体Robo4 の炎症応答における役割2014

    • Author(s)
      白倉圭佑、酒井美貴、福島 優、真鍋詩織、William Aird、岡田欣晃、土井健史
    • Organizer
      第15回Pharmaco-Hematologyシンポジウム
    • Place of Presentation
      名古屋市立大学大学院薬学研究科(愛知)
    • Year and Date
      2014-05-24
    • Related Report
      2014 Annual Research Report
  • [Presentation] DNA methylation of the proximal promoter regulates endothelial cell-specific Robo4 gene expression2014

    • Author(s)
      Yoshiaki Okada, Nobuaki Funahashi, Yuji Nishiyama, Toru Tanaka, Keisuke Shirakura, Yusuke Maniwa, William C. Aird, Takefumi Doi
    • Organizer
      The 18th International Vascular Biology Meeting
    • Place of Presentation
      みやこめっせ(京都)
    • Year and Date
      2014-04-14
    • Related Report
      2014 Annual Research Report
  • [Remarks] 大阪大学薬学研究科生命情報解析学分野ホームページ

    • URL

      http://www.phs.osaka-u.ac.jp/homepage/b018/

    • Related Report
      2016 Annual Research Report
  • [Remarks] 大阪大学大学院薬学研究科生命情報解析学分野ホームページ

    • URL

      http://www.phs.osaka-u.ac.jp/homepage/b018/

    • Related Report
      2015 Annual Research Report 2014 Annual Research Report
  • [Remarks] 大阪大学大学院薬学研究科ホームページ

    • URL

      http://www.phs.osaka-u.ac.jp/index.cgi

    • Related Report
      2015 Annual Research Report
  • [Patent(Industrial Property Rights)] Claudin 5抗体、及びその抗体を含有する医薬品2016

    • Inventor(s)
      岡田欣晃, 近藤昌夫, ほか
    • Industrial Property Rights Holder
      大阪大学
    • Industrial Property Rights Type
      特許
    • Filing Date
      2016-12-07
    • Related Report
      2016 Annual Research Report

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Published: 2014-04-04   Modified: 2022-02-16  

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