Regulation of sphingolipid signal by acid-β-glucosidase

• Project/Area Number: 21890144
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Pathological medical chemistry
• Research Institution: Tottori University
• Principal Investigator: KITATANI Kazuyuki Tottori University, 医学部・附属病院, 助教 (40539235)
• Project Period (FY): 2009 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000); Fiscal Year 2010: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2009: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: 酸性グルコセレブロシダーゼ / セラミド / 炎症 / p38 / スフィンゴ脂質 / ゴーシェ病 / GBA1 / サイトカイン

Research Abstract

Acid-β-glucocerebrosidase (GBA1) contributes to the formation of ceramide and signal that suppresses p38δ activation and IL6 formation. In this project, the PI uncovered that p38δ is involved in inducing the formation of proteases including MMP1 and MMP13. Moreover, in GBA1-deficient Gaucher disease model, the activation of inflammatory kinase p38 was significantly increased. Taken together, GBA1-ceramide pathway is suggested to account for suppressing p38δ-mediated inflammatory responses.

Research Products

• [Journal Article] Isofagomine in vivo effects in a neuropathic Gaucher disease mouse (2011)
  • Author(s): Sun Y., Ran H., Liou B., Quinn B., Zamzow M., Zhang W., Bielawski J., Kitatani K., Setchell K.D., Hannun Y.A., Witte D.P., Xu Y., Grabowski G.A.
  • Journal Title: PLoS One in press
• [Journal Article] Regulation of CC ligand 5/rantes by acid sphingomyelinase (2011)
  • Author(s): Jenkins R.W., Clarke C.J., Canal D., Snider A.J., Gault C.R., Heffernan-Stroud L., Wu B.X., Simbari F., Roddy P., Kitatani K., Obeid L.M., Hannun Y.A.
  • Journal Title: J.Biol.Chem. 286 Pages: 13292-13303
• [Journal Article] Selective knockdown of ceramide synthases reveals complex inte -regulation of sphingolipid metabolism (2011)
  • Author(s): Mullen T.D., Spassieva S., Jenkins R.W., Kitatani K., Bielawski J., Hannun Y.A., Obeid L.M.
  • Journal Title: J.Lipid Res. 52 Pages: 68-77
• [Journal Article] Inhibitory effects of dietary glucosylceramides on squamous cell carcinoma of the head and neck in NOD/SCID mice (2011)
  • Author(s): Fujiwara K., Kitatani K., Fukushima K., Yazama H., Umehara H., Kikuchi M., Igarashi Y., Kitano H., Okazaki T.
  • Journal Title: Int.J.Clin.Oncol. 16 Pages: 133-140
  • NAID: 10029366450
• [Journal Article] Inhibitory effects of dietary glucosylceramides on squamous cell carcinoma of the head and neck in NOD/SCID mice (2011)
  • Author(s): Fujiwara K., et al
  • Journal Title: Int.J.Clin.Oncol. Volume: 16 Pages: 133-144
  • Peer Reviewed
• [Journal Article] Selective knockdown of ceramide synthases reveals complex inter-regulation of sphingolipid metabolism (2011)
  • Author(s): Mullen T.D., et al
  • Journal Title: J.Lipid Res. Volume: 52 Pages: 68-77
  • Peer Reviewed
• [Journal Article] Regulation of CC ligand 5/rantes by acid sphingomyelinase (2011)
  • Author(s): Jenkins R.W., et al
  • Journal Title: J.Biol.Chem. Volume: 286 Pages: 13292-13303
  • Peer Reviewed
• [Journal Article] Regulated secretion of acid sphingomyelinase : implications for selectivity of ceramide formation (2010)
  • Author(s): Jenkins R.W., Canal D., Idkowiak-Baldys J., Simbari F., Roddy P. Perry D.M., Kitatani K., Luberto C., Hannun Y.A.
  • Journal Title: J.Biol.Chem. 285 Pages: 35706-35718
• [Journal Article] Neuronopathic Gaucher disease in the mouse : Viable combined selective saposin C deficiency and mutant glucocerebrosidase (V394L) with CNS glucosylsphingosine and glucosylceramide accumulation (2010)
  • Author(s): Sun Y., Liou B., Ran H., Skelton M.R., Williams M.T., Vorhees C.V., Kitatani K., Hannun Y.A., Witte D.P., Xu Y., Grabowski G.A.
  • Journal Title: Human Mol.Genet. 19 Pages: 1088-1097
• [Journal Article] Specific saposin C deficiency : CNS impairment and aci -β-glucosidase effects in the mouse (2010)
  • Author(s): Sun Y., Ran H., Zamzow M., Kitatani K., Skelton M.R., Williams M.T., Vorhees C.V., Witte D.P., Hannun Y.A., Grabowski G.A.
  • Journal Title: Human Mol.Genet. 19 Pages: 634-647
• [Journal Article] Inhibitory effects of dietary glucosylceramides on squamous cell carcinoma of the head and neck in NOD/SCID mice (2010)
  • Author(s): Jenkins R.W., et al
  • Journal Title: J.Biol.Chem. Volume: 285 Pages: 35706-35718
  • Peer Reviewed
• [Journal Article] Specific saposin C deficiency : CNS impairment and acid-β-glucosidase effects in the mouse (2010)
  • Author(s): Sun Y., Ran H., Zamzow M., Kitatani K., Skelton M.R., Williams M.T., Vorhees C.V., Witte D.P., Hannun Y.A., Grabowski G.A.
  • Journal Title: Human Mol.Genet. 15 Pages: 634-647
  • Peer Reviewed
• [Journal Article] Acid-β-glucosidase 1 counteracts p38δ-dependent induction of interleukin-6 : possible role for ceramide as an anti-inflammatory lipid. (2009)
  • Author(s): Kitatani K., Sheldon, K., Anelli, V., Jenkins, R. W., Sun, Y., Grabowski, G. A., Obeid, L. M., Hannun, Y. A.
  • Journal Title: J.Biol.Chem. 284 Pages: 12979-12988
• [Journal Article] Involvement of acid-β-glucosidase 1 in the salvage pathway of ceramide formation. (2009)
  • Author(s): Kitatani K., Sheldon, K., Anelli, V., Jenkins, R. W., Sun, Y., Grabowski, G. A., Obeid, L. M., Hannun, Y. A.
  • Journal Title: J.Biol.Chem 284 Pages: 12972-12978
• [Journal Article] Isofagomine in vivo effects in a neuropathic Gaucher disease mouse
  • Author(s): Sun Y., et al
  • Journal Title: PLoS One Volume: (印刷中)
  • Peer Reviewed
• [Presentation] Regulation of the pro-inflammatory kinase p38 by ceramide generated from acid-β-glucosidase-1 (GBA1) : implications for Gaucher disease. (2010)
  • Author(s): 北谷和之
  • Organizer: Gordon Research Conference
  • Place of Presentation: Ventura, CA, USA
  • Year and Date: 2010-02-09
• [Presentation] Regulation of the pro-inflammatory kinase p38 by ceramide generated from acid-β-glucosidase 1 (GBA1) : implications for Gaucher disease (2010)
  • Author(s): 北谷和之
  • Organizer: The 27^<th> NAITO conference on Membrane Dynamics and Lipid Biology [I]
  • Place of Presentation: 札幌
• [Presentation] セラミド依存的なATM活性化によるアポトーシス誘導 (2010)
  • Author(s): 橋本真由美, 田口佳光, 北谷和之, 谷口真, 浅野智志, ルーシー・ワルダハニ, 武谷浩之, 岡崎俊朗
  • Organizer: 第83回日本生化学会
  • Place of Presentation: 神戸
• [Presentation] 細胞間相互作用によるSMSの新たな機能細胞遊走能,浸潤/転移,homingにおける役割 (2010)
  • Author(s): 岡崎俊朗, 北谷和之, 谷口真, 橋本真由美, 浅野智志, ルーシー・ワルダハニ
  • Organizer: 第5回スフィンゴテラピー研究会
  • Place of Presentation: 鳥取県米子市
• [Presentation] スフィンゴシン-1-リン酸(S1P)によるmTOR活性化を介したオートファジー抑制機構 (2010)
  • Author(s): 谷口真, 北谷和之, 近藤忠一, 橋本真由美, 浅野智志, 五十嵐靖之, 梅原久範, 武谷浩之, 岡崎俊朗
  • Organizer: 第5回スフィンゴテラピー研究会
  • Place of Presentation: 鳥取県米子市
• [Presentation] セラミド依存的なATM活性化によるアポトーシス誘導 (2010)
  • Author(s): 橋本真由美, 北谷和之, 浅野智志, 五十嵐靖之, 武谷浩之, 岡崎俊朗
  • Organizer: 第5回スフィンゴテラピー研究会
  • Place of Presentation: 鳥取県米子市
• [Presentation] スフィンゴミエリンによる走化性運動の制御 (2010)
  • Author(s): 浅野智志, 北谷和之, 谷口真, 橋本真由美, 武谷浩之, 座間宏太, 光武進, 五十嵐靖之, 岡崎俊朗
  • Organizer: 第5回スフィンゴテラピー研究会
  • Place of Presentation: 鳥取県米子市
• [Presentation] Regulation of the pro-inflammatory kinase p38 by ceramide generated from acid-β-glucosidase 1 (GBA1) : implications for Gaucher disease (2010)
  • Author(s): Kazuyuki Kitatani
  • Organizer: The 27^<th> NAITO conference on Membrane Dynamics and Lipid Biology [I]
  • Place of Presentation: 札幌市 シャトレーゼガトーキングダム 札幌
• [Presentation] Suppression of ceramide-, mediated autophagy by sphingosine-1 phosphate
  • Author(s): M.Taniguchi, K.Kitatani, K.Ko ndo, M.Hashimoto, S.Asano, Y.Igarashi, H.Umehara, H.Takeya, T Okazaki
• [Book] Advances in Experimental Medicine and Biology("Tools and Techniques for sphingolipid research" Sphingolipids as Signaling and Regulatory Molecules) (2010)
  • Author(s): Kitatani K., Luberto, C.
  • Publisher: LANDES BIOSCIENCE
• [Book] Seibutsu-kogaku Kaishi(Functional liposomes using sphingolipids)88 (2010)
  • Author(s): Kitatani K.
  • Total Pages: 678
  • Publisher: The Society for Biotechnology, Japan
• [Book] The Lipids(Ceramide and Tumors)20 (2009)
  • Author(s): Kitatani K.., Okazaki T.
  • Publisher: Tokyo
• [Book] The Cell(Regulation of ceramide by sphingomyelin synthase) (2009)
  • Author(s): Kitatani K., Hashimoto M., Sugimoto Y., Taniguchi M., Okazaki T.
  • Publisher: Tokyo
• [Book] Sphingolipids as Signaling and Regulatory Molecules
  • Author(s): Kitatani K., Luberto
  • Publisher: LANDES BIOSCIENCE(印刷中)