Bioprotection mechanisms by specific binding of globo-series glycosphingolipids to LPS receptors

• Project/Area Number: 23659171
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Pathological medical chemistry
• Research Institution: Nagoya University
• Principal Investigator: FURUKAWA Koichi 名古屋大学, 医学(系)研究科(研究院), 教授 (80211530)
• Project Period (FY): 2011 – 2012
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2012: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2011: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: グロボシド / LPS / エンドトキシンショック / A4GALT / TLR-4 / エンドトシンショック / TLR4 / MD2 / 脂質ラフト / 内因性リガンド / 血管内皮 / 糖脂質 / エンドトキシン / ミクロドメイン / シグナル

Research Abstract

Bioprotective functions and action mechanisms of glycosphingolipids induced by LPS were analyzed. In particular, demonstration of novel functions of glycolipids was aimed by analyzing binding specificity and interaction between LPS receptors and Gb4 with focus on the suppressive function of globo-series glycolipids to LPS cytotoxicity. Specific binding of Gb4 to TLR-4/MD2 and the suppression of LPS signals with Gb4 were observed. The fact that only Gb4 with saturated forms of fatty acids bound to TLR-4/MD2 as well as results of immunocytochemistry and of fractionation of membrane molecules suggested that the binding occurred in lipid rafts. Administration of Gb4 into LPS-injected mice could restore them from endotoxin shock, suggesting the possibility of therapeutic application of Gb4 in the clinical fields.

Research Products

• [Journal Article] Neuronal expression of GalNAc transferase is sufficient to prevent the age-related neurodegenerative phenotype of complex ganglioside deficient mice. (2014)
  • Author(s): Yao, D., McGonigal, R., Barrie, J.A., Cappell, J., Cunningham, M.E., Meehan, G.R., Fewou, S.N., Edgar, J.M., Rowan, E., Ohmi, Y., Furukawa, K., Furukawa, K., Brophy, P.J., Willison, H.J.
  • Journal Title: J. Neurosci. Volume: 34 Pages: 880-891
  • Peer Reviewed
• [Journal Article] TLR4-MD-2complex is negativerly regulated by an endogenous ligand, globotetrasylceramide in vascular endothelial cells (2013)
  • Author(s): Kondo, Y., Tokuda, N., Nishitani, C., Ohto, U., Akashi-takaura, S., Ito, Y., Uchikawa, M., Kuroki, Y., Miyake, K., Zhang, Q., Furukawa, K., Furukawa, K
  • Journal Title: Proc. Natl. Acad. Sci. USA Volume: 110 Pages: 4714-4719
• [Journal Article] β4GalT6 is involved in the synthesis of lactosylceramide with less intensity than β4GalT5 (2013)
  • Author(s): Tokuda N, Numata S, Li X, Nomura T, Takizawa M, Kondo Y, Yamashita Y, Hashimoto N, Kiyono T, Urano T, Furukawa K, Furukawa K
  • Journal Title: Glycobiology Volume: 23 Issue: 10 Pages: 1175-1183
  • DOI: 10.1093/glycob/cwt054
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Trimeric Tn antigen on Syndecan-1 binds to integrins and enhances cancer metastasis via dynamic changes of membrane microdomains. (2013)
  • Author(s): Matsumoto, Y., Zhang, Q., Akita, K., Nakada, H., Hamamura, K., Tsuchida, A., Okajima, T., Furukawa, K., Urano, T., Furukawa, K
  • Journal Title: J. Biol. Chem. Volume: 288 Pages: 24264-24276
  • Peer Reviewed
• [Journal Article] TLR4-MD-2 complex is negatively regulated by an endogenous ligand, globotetraosylceramide in vascular endothelial cells. (2013)
  • Author(s): Kondo, Y., Tokuda, N., Nishitani, C., Ohto, U., Akashi-TakKondo, Y., Tokuda, N., Nishitani, C., Ohto, U., Akashi-Takamura, S., Ito, Y., Uchikawa, M., Kuroki, Y., Miyake, K., Zhang, Q., Furukawa, K., Furukawa, K
  • Journal Title: Proc. Natl. Acad. Sci. USA Volume: 110 Issue: 12 Pages: 4714-4719
  • DOI: 10.1073/pnas.1218508110
  • Peer Reviewed
• [Journal Article] Protemic analysis of ganglioside-associated membrane molecules : Substantial basis for molecular clustering (2012)
  • Author(s): Hashimoto, N., Hamamura, K., Kotani, N., Furukawa, K., Kaneko, K., Honke, K., Furukawa, K
  • Journal Title: Proteomics Volume: 12 Pages: 3154-3163
• [Journal Article] Clostridium perfringens Alpha-toxin Recognnezies the GM1a/TrkA Complex (2012)
  • Author(s): Oda, M., Kabura, M., Takagishi, T., Suzue, A., Tominaga, K., Urano, S., Nagahama, M., Kobayashi, K., Furukawa, K., Sakurai, J
  • Journal Title: J. Biol. Chem Volume: 287 Pages: 33070-33079
  • Peer Reviewed
• [Journal Article] Clostridium perfringens Alpha-toxin Recognizes the GM1a/TrkA Complex. (2012)
  • Author(s): Oda, M., Kabura, M., Takagishi, T., Suzue, A., Tominaga, K., Urano, S., Nagahama, M., Kobayashi, K., Furukawa, K., Furukawa, K., Sakurai, J.
  • Journal Title: J. Biol. Chem Volume: 287 Pages: 33070-33079
  • Peer Reviewed
• [Journal Article] Proteomic analysis of ganglioside-associated membrane molecules: Substantial basis for molecular clustering. (2012)
  • Author(s): Hashimoto, N., Hamamura, K., Kotani, N., Furukawa, K., Kaneko, K., Honke, K., Furukawa, K.
  • Journal Title: Proteomics Volume: 12 Issue: 21 Pages: 3154-3163
  • DOI: 10.1002/pmic.201200279
  • Peer Reviewed
• [Journal Article] Expression of LY6D is induced at the surface of MCF10A cells by X-ray irradiation. (2012)
  • Author(s): Kurosawa, M., Jeyasekharan, A., Surmann, E.-M., Hashimoto, N., Kurosawa, G., Furukawa, K., Venkitaraman, A., Kurosawa, Y.
  • Journal Title: FEBS J. Volume: 279 Issue: 24 Pages: 4479-4491
  • DOI: 10.1111/febs.12034
  • Peer Reviewed
• [Journal Article] C9-R95X Polymorphism in Patients with Neovascular Age-Related Macular Degeneration. (2012)
  • Author(s): Nishiguchi KM
  • Journal Title: Invest Ophthalmol Vis Sci. Volume: 53(1) Issue: 1 Pages: 508-512
  • DOI: 10.1167/iovs.11-8425
  • Peer Reviewed
• [Journal Article] Molecular mechanisms for the regulation of nervous systems with glycosphingolipids (2011)
  • Author(s): Furukawa K, Ohmi Y, Ohkawa Y, Tokuda N, Tajima O, Furukawa K
  • Journal Title: Seikagaku Volume: 83(3) Pages: 169-173
  • NAID: 10029067618
• [Journal Article] Regulatory mechanisms of nervous systems with glycosphingolipids. (2011)
  • Author(s): Furukawa K.
  • Journal Title: Neurochem Res. Volume: 36 Issue: 9 Pages: 1578-1586
  • DOI: 10.1007/s11064-011-0494-2
  • Peer Reviewed
• [Journal Article] Molecular mechanisms for the regulation of nervous systems with glycosphingolipids. (2011)
  • Author(s): Furukawa K, Ohmi Y, Ohkawa Y, Tokuda N, Tajima O, Furukawa K
  • Journal Title: Seikagaku. Volume: 83(3) Pages: 169-173
  • NAID: 10029067618
  • Peer Reviewed
• [Presentation] Spatio-temporal dynamics of the interaction between glycosphingolipids and memebrane molecules (2014)
  • Author(s): Koichi Furukawa
  • Organizer: Gordon Research Conference & Glycolipids Sphingolipid Biology
  • Place of Presentation: アメリカ・カリフォルニア州 Four Points by Sheraton Ventura Harbor Hotel
  • Year and Date: 2014-01-14
  • Invited
• [Presentation] Spatio-temporal dynamics of the interaction between glycosphingolipids and membrane molecules. (2014)
  • Author(s): Koichi Furukawa
  • Organizer: Gordon Research Conference, Glycolipid & and Sphingolipid Biology.
  • Place of Presentation: Ventura, CA, USA.
  • Invited
• [Presentation] 糖鎖フィールド : 糖鎖がシグナル伝達を制御する原理 (2013)
  • Author(s): 古川鋼一, 近藤裕史, 松本康之, 古川圭子
  • Organizer: 第86回日本生化学会大会
  • Place of Presentation: パシフィコ横浜 横浜市
  • Year and Date: 2013-09-12
• [Presentation] 複合糖質と糖鎖認識分子との相互作用の時空間的ダイナミクス (2013)
  • Author(s): 古川鋼一, 近藤裕史, 松本康之, 古川圭子
  • Organizer: 第86回日本生化学会大会
  • Place of Presentation: パシフィコ横浜 横浜市
  • Year and Date: 2013-09-12
• [Presentation] 複合糖質と糖鎖認識分子との相互作用の時空間的ダイナミクス (2013)
  • Author(s): 古川鋼一、近藤裕史、松本康之、古川圭子
  • Organizer: 第86回日本生化学会大会
  • Place of Presentation: パシフィコ横浜（横浜市）
• [Presentation] 鎖フィールド：糖鎖がシグナル伝達を制御する原理 (2013)
  • Author(s): 古川鋼一、近藤裕史、松本康之、古川圭子
  • Organizer: 第86回日本生化学会大会
  • Place of Presentation: パシフィコ横浜（横浜市）
• [Presentation] 糖鎖による悪性形質の制御機構 (2013)
  • Author(s): 古川鋼一、松本康之、橋本 登、大川祐樹、大海雄介、古川圭子
  • Organizer: 第35回日本糖質学会
  • Place of Presentation: 大阪国際センター（大阪市）
• [Presentation] 癌細胞の発症と進展に関わる糖鎖の作用機構 (2013)
  • Author(s): 古川鋼一、松本康之、橋本 登、大川祐樹、大海雄介、古川圭子
  • Organizer: 第35回日本糖質学会
  • Place of Presentation: 大阪国際センター（大阪市）
• [Presentation] TLR4-MD-2 Complex is Negatively Regulated by Endgenous Ligand, Globotetraosylceramide in Vascular Endothelial Cells (2012)
  • Author(s): Furukawa, K., Kondo, Y., Ohto, U., Akashi-Takamura, S., Ito, Y., Miyabe, K., Furukawa, K
  • Organizer: Symposium in the 35th Annual Meeting of the Molecular Biology Society of Japan "Glycans as disease modifier"
  • Place of Presentation: 福岡国際会議場 福岡市
  • Year and Date: 2012-12-12
  • Invited
• [Presentation] Roles of globo-series glycolipids in the regulation of LPS-TLR4 signals (2012)
  • Author(s): Furukawa, K., Kondo, Y., Tokuda, N., Ito, Y., Akashi-Takamura, S., Miyabe, K., Furukawa, K
  • Organizer: ICHC2012 14th International Congress of Histochemistry and Cytochemistry
  • Place of Presentation: 京都国際会議場 京都市
  • Year and Date: 2012-08-26
  • Invited
• [Presentation] Roles of globo-series glycolipids in the regulation of LPS-TLR4 signals. (2012)
  • Author(s): Koichi Furukawa, Yuji Kondo, Noriyo Tokuda, Yasutomo Ito, Sachiko Akashi- Takamura, Kensuke Miyake, Keiko Furukawa
  • Organizer: ICHC 2012 14th International Congress of Histochemistry and Cytochemistry
  • Place of Presentation: 京都国際会議場（京都市）
  • Invited
• [Presentation] TLR4-MD-2 Complex is Negatively Regulated by Endogenous Ligand, Globotetraosylceramide in Vascular Endothelial Cells. (2012)
  • Author(s): Koichi Furukawa, Yuji Kondo, Umeharu Ohto, Sachiko Akashi-Takamura, Yasutomo Ito, Kensuke Miyake, Keiko Furukawa
  • Organizer: Symposium in the 35th Annual Meeting of the Molecular Biology Society of Japan “Glycans as disease modifier”.
  • Place of Presentation: 福岡国際会議場（福岡市）
  • Invited
• [Presentation] 病理学におけるグライコーム研究-神経・筋, 感染症, がん, 再生医学-医学における糖鎖研究の重要性 (2011)
  • Author(s): 古川鋼一
  • Organizer: 第8回日本病理学会2011 カンファレンス松本
  • Place of Presentation: ホテルブエナビスタ松本 松本市
  • Year and Date: 2011-08-05
  • Invited
• [Presentation] 病理学におけるグライコーム研究ー神経・筋、感染症、がん、再生医学ー医学における糖鎖研究の重要性 (2011)
  • Author(s): 古川鋼一
  • Organizer: 第８回日本病理学会２０１１カンファレンス松本(招待講演)
  • Place of Presentation: ホテルブエナビスタ
• [Book] α4-galactsyltoranceferase(A4GALT). In Handbook of Glycosyltrasferases and Related Genes (2014)
  • Author(s): Koichi Furukawa, Yuji Kondo, Keiko Furukawa
  • Publisher: (in press)
• [Book] α4-galactosyltransferase (A4GALT). In Handbook of Glycosyltransferases and Related Genes. (2014)
  • Author(s): Koichi Furukawa, Yuji Kondo, Keiko Furukawa
  • Publisher: Springer
• [Book] beta-1,4 N-acetylgalactosaminyl- transferase 1,2 (B4GALNT1,2). In Handbook of Glycosyltransferases and Related Genes. (2014)
  • Author(s): Koichi Furukawa, Keiko Furukawa, Yuhsuke Ohmi, Yuki Ohkawa, Yoshio Yamauchi, Noboru Hashimoto, Orie Tajima
  • Publisher: Springer
• [Book] 神経疾患と糖鎖の関わり、Annual Revie神経 2013 (2013)
  • Author(s): 古川鋼一、大海雄介、大川祐樹、古川圭子、田島織絵
  • Total Pages: 277
  • Publisher: （株）中外医学
• [Book] 肺転移モデル, 転移浸潤モデルシリーズ モデル動物利用マニュアル 疾患モデルの作製と利用 がん (2012)
  • Author(s): 古川鋼一, 松本康之, 章青, 古川圭子
  • Total Pages: 633
  • Publisher: エル・アイ・シー
• [Book] 肺転移モデル、転移浸潤モデルシリーズ モデル動物利用マニュアル 疾患モデルの作製と利用 がん (2012)
  • Author(s): 古川鋼一、松本康之、章 青、古川圭子
  • Publisher: エル・アイ・シー
• [Book] グロボ系糖脂質欠損マウス 糖鎖関連遺伝子ノックアウトマウスシリーズモデル動物利用マニュアル 生物機能モデルと新しいリソース・リサーチツール (2011)
  • Author(s): 近藤裕史, 奥田徹哉, 古川圭子
  • Total Pages: 671
  • Publisher: エル・アイ・シー
• [Book] ガングリオシド合成酵素, 糖鎖関連遺伝子ノックアウトマウスシリーズ モデル動物利用マニュアル 生物機能モデルと新しいリソース・リサーチツール (2011)
  • Author(s): 古川鋼一, 大海雄介, 大川祐樹, 徳田典代, 田島織絵, 古川圭子
  • Total Pages: 671
  • Publisher: エル・アイ・シー
• [Book] ガングリオシド合成酵素, 糖鎖関連遺伝子ノックアウトマウス シリーズ モデル動物利用マニュアル 生物機能モデルと新しいリソース・リサーチツール (2011)
  • Author(s): 古川鋼一、大海雄介、大川祐樹、徳田典代、田島織絵、古川圭子
  • Publisher: エル・アイ・シー
• [Book] グロボ系糖脂質素欠損マウス, 糖鎖関連遺伝子ノックアウトマウス シリーズ モデル動物利用マニュアル 生物機能モデルと新しいリソース・リサーチツール (2011)
  • Author(s): 古川鋼一、近藤裕史、奥田徹哉、古川圭子
  • Publisher: エル・アイ・シー