Regulation of vascular cell function through control of membrane traffic by cellular lipid signaling

• Project/Area Number: 15H04673
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General physiology
• Research Institution: Kanazawa University
• Principal Investigator: Takuwa Yoh 金沢大学, 医学系, 教授 (60171592)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2017: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2015: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: イノシトールリン脂質 / PI3-キナーゼ / スフィンゴ脂質 / スフィンゴシンキナーゼ / 細胞内小胞輸送 / エンドソーム / エンドサイトーシス / シグナル伝達 / PI 3-キナーゼ / ホスファターゼ / PI-3-P / ノックアウト / 小胞輸送 / 脂質 / 生体分子 / 生理学 / ノックアウトマウス

Outline of Final Research Achievements

We studied the functions of class II phosphoinositide 3-kinase (PI3K) isoforms and their functional difference, by analyzing PI3K-C2α- and PI3K-C2β-knockout (KO) mice. Single KO mice of either gene apparently exhibited normal phenotypes whereas the PI3K-C2α/ PI3K-C2β double KO mice showed abnormalities in two different tissues. We also generated KO mice of the degrading enzyme, PI3Pase, of the class II PI3K product PI-3-P. Tissue-specific homozygous KO mice of PI3Pase showed the similar phenotypes to global KO mice, and the analyses of PI3Pase-deficient cells demonstrated abnormalities in membrane traffic. Homozygous KO mice of sphingolipid metabolizing enzyme, sphingosine kinase, showed exacerbation of vascular lesions. This was mediated by impaired membrane traffic.

Research Products

• [Journal Article] Photoacoustic imaging of tumor vascular permeability with indocyanine green in a mouse model. (2018)
  • Author(s): Okumura K, Yoshida K, Yoshioka K, Aki S, Yoneda N, Inoue D, Kitao A, Ogi T, Kozaka K, Minami T, Koda W, Kobayashi S, Takuwa Y and Gabata T
  • Journal Title: European Radiology Experimental Volume: 2: 5 Issue: 1 Pages: 1-9
  • DOI: 10.1186/s41747-018-0036-7
  • Peer Reviewed / Open Access
• [Journal Article] Neuronal SphK1 acetylates COX2 and contributes to pathogenesis in a model of Alzheimer’s Disease. (2018)
  • Author(s): Lee J-Y, Han S-H, Par M-H, Baek B, Song I-S, Choi M-K, Takuwa Y, Ryu H, He X, Schuchman E, Bae J-S, Jin H-K, Kim S-H.
  • Journal Title: Nat Commun Volume: 印刷中
  • Peer Reviewed / Open Access
• [Journal Article] Pancreas lineage allocation and specification are regulated by sphingosine-1-phosphate signalling. (2017)
  • Author(s): Serafimidis I, Rodriguez-Aznar E, Lesche M, Yoshioka K, Takuwa Y, Dahl A, Pan D and Gavalas A.
  • Journal Title: PLOS Biology Volume: 15 (3) Issue: 3 Pages: e2000949-e2000949
  • DOI: 10.1371/journal.pbio.2000949
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Early endothelialization associated with a biolimus A9 bioresorbable polymer stent in a porcine coronary model. (2017)
  • Author(s): Mori M, Sakata K, Nakanishi C, Nakahashi T, Kawashiri MA, Yoshioka K, Takuwa Y, Okada H, Yokawa JI, Shimojima M, Yoshimuta T, Yoshida S, Yamagishi M, Hayashi K.
  • Journal Title: Heart Vessels. Volume: 32 Issue: 10 Pages: 1244-1252
  • DOI: 10.1007/s00380-017-0992-5
  • Peer Reviewed
• [Journal Article] Augmented sphingosine 1 phosphate receptor-1 signaling in cardiac fibroblasts induces cardiac hypertrophy and fibrosis through angiotensin II and interleukin-6. (2017)
  • Author(s): Ohkura SI, Usui S, Takashima SI, Takuwa N, Yoshioka K, Okamoto Y, Inagaki Y, Sugimoto N, Kitano T, Takamura M, Wada T, Kaneko S, Takuwa Y.
  • Journal Title: PLoS One. Volume: 12 Issue: 8 Pages: e0182329-e0182329
  • DOI: 10.1371/journal.pone.0182329
  • Peer Reviewed / Open Access
• [Journal Article] Peretinoin, an acyclic retinoid, inhibits hepatocarcinogenesis by suppressing sphingosine kinase 1 expression in vitro and in vivo. (2017)
  • Author(s): Funaki M, Kitabayashi J, Shimakami T, Nagata N, Sakai Y, Takegoshi K, Okada H, Murai K, Shirasaki T, Oyama T, Yamashita T, Ota T, Takuwa Y, Honda M, Kaneko S.
  • Journal Title: Sci Rep Volume: 7 Issue: 1 Pages: 16978-16978
  • DOI: 10.1038/s41598-017-17285-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Sphingosine-1-phosphate receptor type 2 (S1P_2) inhibits bleomycin-induced cellular senescence in murine lung fibroblasts. (2016)
  • Author(s): Zhao J, Okamoto Y, Takuwa Y.
  • Journal Title: 金沢大学十全医学会雑誌 Volume: 125 Pages: 2-13
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [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
  • Peer Reviewed / Open Access
• [Presentation] Myotubularin-related protein 4 (MTMR4), a phosphoinositide 3'-phosphatase, regulates endolysosome integrity and autophagy flux in human lung alveolar epithelial A549 cells (2018)
  • Author(s): Pham Quynh Hoa, Yoshioka Kazuaki, Azadul Sarker Kabir, Aung Thuzar Khin, Islam Shahidul, Aki Sho, Ishimaru Kazuhiro, Takuwa Noriko, Takuwa Yoh
  • Organizer: 第 95 回日本生理学会大会
• [Presentation] Indispensable role of α and β isoforms of class II phosphoinositide 3-kinases (PI3K) in the uterine smooth muscle contraction during labor (2018)
  • Author(s): Sarker Kabir Azadul, Sho Aki, Yoshioka Kazuaki, Kuno Koji, Okamoto Yasuo, Aung Thuzar Khin, Pham Quynh Hoa, Islam Shahidul, Takuwa Noriko, Takuwa Yoh
  • Organizer: 第 95 回日本生理学会大会
• [Presentation] Class II phosphoinositide 3-kinase isoforms PI3K-C2α and PI3K-C2β play essential roles in pinocytosis in vascular endothelial cells (2018)
  • Author(s): Aung Thuzar Khin, Yoshioka Kazuaki, Aki Sho, Pham Quynh Hoa, Sarker Kabir Azadul, Islam Shahidul, Ishimaru Kazuhiro, Takuwa Noriko, Takuwa Yoh
  • Organizer: 第 95 回日本生理学会大会
• [Presentation] Phosphotidylinositol 3-kinase Class II isoforms, PI3K-C2α and PI3K-C2β are necessary for Pinocytosis in Endothelial Cells (2017)
  • Author(s): Khin Thuzar Aung, Sho Aki, Kazuaki Yoshioka, Pham Hoa Quynh , MD Azadul Kabir Sarker, Islam Shahidul, Noriko Takuwa, Yoh Takuwa.
  • Organizer: 第94回日本生理学会大会
  • Place of Presentation: アクトシティ浜松
  • Year and Date: 2017-03-29
• [Presentation] Phosphoinositide-specific 3'-phosphatase, myotubularin-related protein 4 (MTMR4), regulates lysosomal activity and autophagy (2017)
  • Author(s): Pham Quynh Hoa, Kazuaki Yoshioka, Sato Nakamura, MD Azadul Kabir Sarker, Khin Thuzar Aung, Shahidul Islam, Sho Aki, Noriko Takuwa and Yoh Takuwa
  • Organizer: 第94回日本生理学会大会
  • Place of Presentation: アクトシティ浜松
  • Year and Date: 2017-03-28
• [Presentation] Endothelial Class II PI3K-C2α is Necessary for Vasucular Formation and Integrity through Regulating Endocytic Membrane Trafficking (2017)
  • Author(s): Kazuaki Yoshioka, Sho Aki:, Noriko Takuwa:, Yoh Takuwa
  • Organizer: 第81回日本循環器学会学術集会 Topic 3 「Endothelium, Health and Diseases」
  • Place of Presentation: 金沢都ホテル
  • Year and Date: 2017-03-17
• [Presentation] 抗がん剤による臓器障害におけるスフィンゴシン-1-リン酸（S1P）情報伝達系の関与 (2017)
  • Author(s): 多久和 典子、石丸 和宏、岡本 安雄、多久和 陽
  • Organizer: 第27回日本病態生理学会大会
• [Presentation] Myotubularin - related protein 4 (MTMR4), a phosphoinositide 3-- specific phosphatase, regulates endolysosome integrity and autophagy flux in A549 human lung carcinoma cells (2017)
  • Author(s): Quynh Hoa Pham , Kazuaki Yoshioka , Azadul Kabir Sarker , Khin Thuzar Aung , Shahidul Islam , Sho Aki , Sato Nakamura , Noriko Takuwa, Yoh Takuwa
  • Organizer: 第40回日本分子生物学会年会
• [Presentation] Phosphatidylinositol 3-kinase class II α isoform PI3K-C2α is required for transforming growth factor β-induced receptor endocytosis and endosomal signaling in endothelial cells (2016)
  • Author(s): Sho Aki, Kazuaki Yoshioka, Yasuo Okamoto, Noriko Takuwa , Pham Hoa Quynh , MD Azadul Kabir Sarker, Khin Thuzar Aung, Islam Shahidul, Yoh Takuwa
  • Organizer: 第39回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜
  • Year and Date: 2016-11-30
• [Presentation] S1P2, A Receptor for the Lysophospholipid Mediator Sphingosine 1-phosphate, Protects Against Vascular Barrier Disruption (2016)
  • Author(s): Yasuo Okamoto, Hong Cui, Kazuaki Yoshioka, Noriko Takuwa, Toshishige Shibamoto, Yoh Takuwa
  • Organizer: International Shock Congress Symposium "Microcirculation and endothelial damage in sepsis and shock"
  • Place of Presentation: 東京ドームホテル
  • Year and Date: 2016-10-03
• [Presentation] S1P2 による血管新生と血管障壁機能の制御 (2016)
  • Author(s): 岡本安雄、杜娃、崔弘、吉岡和晃、多久和典子、多久和陽
  • Organizer: 第58回 日本脂質生化学会
  • Place of Presentation: にぎわい交流館AU（あう）
  • Year and Date: 2016-06-09
• [Presentation] PI3K-C2α is required for TGFβ-induced receptor endocytosis and endosomal signaling inendothelial cells (2016)
  • Author(s): Aki Sho, Yoshioka Kazuaki, Okamoto Yasuo, Takuwa Noriko, Takuwa Yoh
  • Organizer: 第93回日本生理学会
  • Place of Presentation: 札幌コンベンションセンター（札幌市）
  • Year and Date: 2016-03-22
  • Invited
• [Presentation] he announcement title: Deletion of sphingosine 1-phospahte (S1P) receptor-2 (S1P2) inhibitslung fibrosis throughaltering alveolar macrophage polarization and senescence in mice (2016)
  • Author(s): Juanjuan Zhao, Yasuo Okamoto, Yoh Takuwa.
  • Organizer: Gorden research conference “Glycolipid and Sphingolipid Biology”
  • Place of Presentation: Renaissance Tuscany Il Ciocco （Lucca (Barga), Italy）
  • Year and Date: 2016-03-06
  • Int'l Joint Research
• [Presentation] クラス II 型 PI3K-C2αはエンドソーム上での TGF/Smad2/3 シグナリングに必須である (2016)
  • Author(s): 安藝 翔
  • Organizer: 第２回 血管生物若手研究会
  • Place of Presentation: 東北大学加齢医学研究所スマートエージング国際共同研究センター 国際会議室（宮城県仙台市）
  • Year and Date: 2016-03-04
• [Presentation] Sphingosine 1-phospahte (S1P) receptor-2 (S1P2) aggravates lung fibrosis through altering alveolar macrophage polarization and cellular senescence in mice (2016)
  • Author(s): JuanJuan Zhao, Yasuo Okamoto, Kazuaki Yoshioka, Noriko Takuwa, Takashi Wada, Yutaka Inagaki, Chiaki Takahashi,Yoh Takuwa
  • Organizer: 日本生化学会北陸支部第３４回大会
  • Place of Presentation: 金沢大学宝町キャンパス 医学部記念館
• [Presentation] Phosphatidylinositol 3-kinase class IIαisoform PI3K-C2α is required for transforming growth factor β-induced receptor endocytosis and endosomal signaling in endothelial cells (2016)
  • Author(s): 2.Sho Aki, Kazuaki Yoshioka, Yasuo Okamoto, Noriko Takuwa and Yoh Takuwa
  • 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谷口記念講堂
  • Invited
• [Presentation] Deletion of sphingosine 1-phospahte (S1P) receptor-2 (S1P-2-) inhibits lung fibrosis through altering alveolar macrophage polarization and senescence in mice. (2015)
  • Author(s): Juan juan Zhao Yasuo Okamoto Kazuaki Yoshioka Sho Aki Pham Quynh Hoa Azadul MD Kabir Sarker Khin Thuzar Aung Noriko Takuwa Yutaka Inagaki Chiaki Takahashi Takashi Wada Yoh Takuwa
  • Organizer: BMB2015（第38回日本分子生物学会・第88回日本生化学会）
  • Place of Presentation: 神戸ポートアイランド（神戸ポートピアホテル 神戸国際会議場 神戸国際展示場 神戸商工会議所）(兵庫県神戸市)
  • Year and Date: 2015-12-01
• [Presentation] クラス II PI3-キナーゼ PI3K-C2αはエンドソーム上でのTGFβ/Smad2/3シグナリングに必須である (2015)
  • Author(s): 安藝 翔、吉岡 和晃、岡本 安雄、多久和 典子、多久和 陽
  • Organizer: 第62回 中部日本生理学会
  • Place of Presentation: 富山大学 五福キャンパス 黒田講堂(富山県富山市)
  • Year and Date: 2015-11-13
• [Presentation] Role of S1P2 in inflammation and fibrosis (2015)
  • Author(s): Yoh Takuwa Juanjuan Zhao, Yasuo, Okamoto, Kazuaki Yoshioka and Noriko Takuwa. Role of S1P2 in inflammation and fibrosis
  • Organizer: 14 th International Conference on Bioactive Lipids in Cancer, Inflammation, and Related Diseases Plenary Lecture
  • Place of Presentation: ハンガリーアカデミーオブサイエンス（ハンガリー ブタペスト）
  • Year and Date: 2015-07-12
  • Int'l Joint Research / Invited
• [Presentation] Phosphatidylinositol 3-kinase class II a isoform PI3K-C2a is required for transforming growth factor b-induced receptor endocytosis and endosomal signaling in endothelial cells (2015)
  • Author(s): Sho Aki
  • Organizer: 14 th International Conference on Bioactive Lipids in Cancer, Inflammation, and Related Diseases
  • Place of Presentation: ハンガリーアカデミーオブサイエンス（ハンガリー ブタペスト）
  • Year and Date: 2015-07-12
  • Int'l Joint Research
• [Presentation] Sphingosine 1-phosphate receptor-2 plays a protective role against anaphylaxis and acute lung injury (2015)
  • Author(s): Yasuo Okamoto, Hong Cui, Kazuaki Yoshioka, Noriko Takuwa, Yoh Takuwa
  • Organizer: 第10回スフィンゴテラピィ（STC）研究会
  • Place of Presentation: ホテルアローレ（石川県加賀市）
  • Year and Date: 2015-06-16
• [Presentation] クラスII α型PI3K-C2αはエンドソーム上でのTGFβ/Smad2/3 シグナリングに必須である (2015)
  • Author(s): 安藝 翔、吉岡 和晃、岡本 安雄、多久和 典子、多久和 陽
  • Organizer: 第57回 日本脂質生化学会
  • Place of Presentation: 一橋大学一橋講堂(東京)
  • Year and Date: 2015-05-28
• [Book] なるほどなっとく！解剖生理学 (2017)
  • Author(s): 多久和典子、多久和陽
  • Total Pages: 297
  • Publisher: 南山堂
  • ISBN: 9784525121617
• [Book] Bioactive Lipid Mediators: Current Reviews and Protocols. (2015)
  • Author(s): Takuwa N, OkamotoY, Yoshioka K and Takuwa Y
  • Total Pages: 426
  • Publisher: Springer Japan
• [Book] サイトカイン・増殖因子キーワード (2015)
  • Author(s): 多久和 陽
  • Total Pages: 422
  • Publisher: 羊土社
• [Remarks] 血管分子生理学教室（旧生理学第一講座）
  • URL: http://physiology1.w3.kanazawa-u.ac.jp/
• [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/
• [Patent(Industrial Property Rights)] マクロファージの増殖・分化阻害又はマクロファージの老化促進による肺線維症の抑制 (2015)
  • Inventor(s): 多久和 陽、岡本 安雄
  • Industrial Property Rights Holder: 金沢大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2015-013793
  • Filing Date: 2015-07-09