聴覚におけるガングリオシドの機能解明

• Project Area: Deciphering sugar chain-based signals regulating integrative neuronal functions
• Project/Area Number: 26110717
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Tohoku Pharmaceutical University
• Principal Investigator: 井ノ口 仁一 東北薬科大学, 薬学部, 教授 (70131810)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥8,320,000 (Direct Cost: ¥6,400,000、Indirect Cost: ¥1,920,000); Fiscal Year 2015: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2014: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
• Keywords: 聴覚 / ガングリオシド / 視床下部 / レプチン抵抗性 / GM3合成酵素 / KKAyマウス / メラノコルチン受容体MC4R / Agoutiタンパク / 難聴 / 内耳有毛細胞 / ラフト / 聴毛

Outline of Annual Research Achievements

私は、平成２６年度から２７年度の公募班員として参加し、その間、２度の国際シンポジウムで発表の機会を得た。2014年には、ハワイでの日米合同糖質シンポジウムでGanglioside GM3 is essential for the structural integrity and function of cochlear hair cells. というタイトルで講演し、Human Molecular Geneticsに2015年に掲載された。この研究で、１）マウス蝸牛の聴覚機能は、生後２週間で成熟する。この生後直後から２週の間に蝸牛のガングリオシド発現が著しく増加し、ガングリオシドは聴覚機能の成熟に必須であること。２）GM3合成酵素欠損症のヒトでは聴覚機能が消失することを、米国のClinic for Sick Children(CSC)のKevin Strauss博士の研究グループとの共同研究により明らかにした。2016年１月には、淡路島での本領域の最後の国際シンポジウムで視床下部接触中枢におけるレプチンーメラノコルチンシグナルにおけるガングリオシド関与について、我々の最新の知見について発表した。肥満・糖尿病モデルマウスのKKAyでは、メラノコルチン受容体MC4Rに対して抑制効果を示すAgoutiタンパクの高発現によって、視床下部の食欲中枢におけるレプチンシグナル抑制され、摂餌量の亢進し肥満による糖尿病病態を示す。GM3合成酵素を欠損させたKKAyマウスでは、摂餌量が正常化し、糖尿病の発症が抑制されていることを見出している。これらの結果から。ガングリオシド発現異常は、脂肪組織のインスリン抵抗性発症のみならず、中枢のレプチン抵抗性にも関わっていることを示すことができた。

Research Progress Status

27年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

27年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Targeting ceramide synthase 6-dependent metastasis-prone phenotype in lung cancer cells. (2016)
  • Author(s): Suzuki M, et al.
  • Journal Title: J. Clin. Invest. Volume: 126 Issue: 1 Pages: 254-265
  • DOI: 10.1172/jci79775
  • Peer Reviewed / Open Access
• [Journal Article] The regulation of ER export and Golgi retention of ST3Gal5 (GM3/GM4 synthase) and B4GalNAcT1 (GM2/GD2/GA2 synthase) by arginine/lysine-based motif adjacent to the transmembrane domain (2015)
  • Author(s): Satoshi Uemura, Fumi Shishido, Madoka Kashimura, Jin-ichi Inokuchi
  • Journal Title: Glycobiology Volume: 25 Issue: 12 Pages: 1410-1422
  • DOI: 10.1093/glycob/cwv071
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Identification of Ganglioside GM3 Molecular Species in Human Serum Associated with Risk Factors of Metabolic Syndrome. (2015)
  • Author(s): Veillon L, Go S, Matsuyama W, Suzuki A, *Nagasaki M*, Yatomi Y, Inokuchi J
  • Journal Title: PLoS One Volume: 2015 Jun 23;10(6) Issue: 6 Pages: 1-15
  • DOI: 10.1371/journal.pone.0129645
  • Peer Reviewed / Open Access
• [Journal Article] Ganglioside GM3 is essential for the structural integrity and function of cochlear hair cells (2015)
  • Author(s): Misato Yoshikawa, Shinji Go, Shuichi Suzuki, Akemi Suzuki, Thierry Morlet, Kevin Strauss, Michihiro Fujiwara, Katsunori Iwasaki, Jin-ichi Inokuchi
  • Journal Title: Hum. Mol. Genet. Volume: 24 Issue: 10 Pages: 2796-2807
  • DOI: 10.1093/hmg/ddv041
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Control of Homeostatic and Pathogenic Balance in Adipose Tissue by Ganglioside GM3 (2015)
  • Author(s): Nagafuku, M., Sato, T., Sato, S., Shimizu, K., Taira, T., Inokuchi, J.
  • Journal Title: Glycobiology Volume: 25 Issue: 3 Pages: 303-318
  • DOI: 10.1093/glycob/cwu112
  • Peer Reviewed
• [Journal Article] Membrane lipid therapy: Modulation of the cell membrane composition and structure as a molecular base for drug discovery and new disease treatment (2015)
  • Author(s): Pablo V. Escribá, Xavier Busquets, Jin-ichi Inokuchi, Gábor Balogh, Zsolt Török, Ibolya Horváth, John L. Harwood, László Vígh
  • Journal Title: Prog. Lipid Res. Volume: 59 Pages: 38-53
  • DOI: 10.1016/j.plipres.2015.04.003
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Distinct selectivity of gangliosides required for CD4+ T and CD8+ T cell activation (2015)
  • Author(s): Inokuchi, J., Nagafuku, M., Ohno, I., Suzuki, A.
  • Journal Title: Biochim Biophys Acta. Volume: 1851 Issue: 1 Pages: 98-106
  • DOI: 10.1016/j.bbalip.2014.07.013
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Functional mapping and implications of substrate specificity of the yeast high-affinity leucine permease Bap2 (2014)
  • Author(s): 上村 聡志，井ノ口 仁一 他
  • Journal Title: Biochimica et Biophysica Acta Volume: 1838 Issue: 7 Pages: 1719-1729
  • DOI: 10.1016/j.bbamem.2014.03.018
  • Peer Reviewed / Open Access
• [Journal Article] Loss of hydroxyl groups from the ceramide moiety can modify the lateral diffusion of membrane proteins in S. cerevisiae. (2014)
  • Author(s): Uemura, S., Shishido, F., Tani, M., Mochizuki, T., Abe, F., and Inokuchi, J.
  • Journal Title: J. Lipid Res. Volume: 55 Issue: 7 Pages: 1343-1356
  • DOI: 10.1194/jlr.m048637
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] GM3 and Diabetes. (2014)
  • Author(s): Inokuchi J.
  • Journal Title: Glycoconj. J Volume: 31 Issue: 3 Pages: 193-197
  • DOI: 10.1007/s10719-013-9516-4
  • Peer Reviewed
• [Presentation] Control of Homeostatic and Pathogenic Balance in Adipose Tissue by Ganglioside GM3 (2015)
  • Author(s): Inokuchi Jin-ichi
  • Organizer: 2015 Annual meeting of Consorciam for Functional Glycomics
  • Place of Presentation: Sanfrancisco, USA
  • Year and Date: 2015-12-01
  • Int'l Joint Research / Invited
• [Presentation] レプチンおよびメラノコルチンシグナルにおけるガングリオシドの役割の検討 (2015)
  • Author(s): 稲森 啓一郎，伊藤 英樹，楊 燕華，二瓶 渉，突田 壮平，山田 哲也，片桐 秀樹，井ノ口 仁一
  • Organizer: BMB2015 第38回日本分子生物学会年会・第８８回日本生化学会大会 合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-01
• [Presentation] mouse ST3Gal5(GM3/GM4 synthase)のarginine/lysine-based motifによる細胞内輸送機構の解析 (2015)
  • Author(s): 宍戸 史，上村 聡志，樫村 まどか，井ノ口 仁一
  • Organizer: BMB2015 第38回日本分子生物学会年会・第８８回日本生化学会大会 合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-01
• [Presentation] O-GlcNAc修飾によるスフィンゴ糖脂質代謝制御機構 (2015)
  • Author(s): 郷 慎司、井ノ口 仁一
  • Organizer: BMB2015 第38回日本分子生物学会年会・第８８回日本生化学会大会 合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-01
• [Presentation] 分子種依存的に糖脂質が制御する筋分化過程の解明 (2015)
  • Author(s): 新井詩織、郷慎司、Lucas Veillon、佐藤ちひろ、北島健、井ノ口仁一
  • Organizer: BMB2015 第38回日本分子生物学会年会・第８８回日本生化学会大会 合同大会
  • Place of Presentation: 神戸
  • Year and Date: 2015-12-01
• [Presentation] Establishment of mutant Jurkat cell lineslacking different glycosphingolipid species (2015)
  • Author(s): Yamamoto Hiroyuki, Nagafuku Masakazu, Inamori Kei-ichiro, Ito Hideki, Inokuchi Jin-ichi
  • Organizer: 第44回日本免疫学会
  • Place of Presentation: 札幌
  • Year and Date: 2015-11-18
• [Presentation] Sphingomyelin is indispensable for successful thymocyte development (2015)
  • Author(s): Toshima Kaoru, Nagafuku Masakazu, Okazaki Toshiro, Inokuchi Jin-ichi
  • Organizer: 第44回日本免疫学会
  • Place of Presentation: 札幌
  • Year and Date: 2015-11-18
• [Presentation] Role of gangliosides in B cell development (2015)
  • Author(s): Mao Nanjo, Erika Saito, Masakazu Nagafuku, Jin-ichi Inokuchi
  • Organizer: 7th Asian Community of Glycoscience and Glycotechnology Conference
  • Place of Presentation: Matsushima, Japan
  • Year and Date: 2015-11-14
• [Presentation] Ablation of the GM3 synthase gene in KK-Ay mice improved the obese phenotype: implication for its role in leptin and melanocortin signaling (2015)
  • Author(s): Kei-ichiro Inamori, Hideki Ito, Xiaohua Yang, Wataru Nihei, Sohei Tsukitaa, Tetsuya Yamadaa, Hideki Katagiria, Jin-ichi Inokuchi
  • Organizer: 7th Asian Community of Glycoscience and Glycotechnology Conference
  • Place of Presentation: Matsushima, Japan
  • Year and Date: 2015-11-12
  • Int'l Joint Research
• [Presentation] The regulation of ER export and Golgi retention of ST3Gal5 (GM3/GM4 synthase) and B4GalNAcT1 (GM2/GD2/GA2 synthase) by arginine/lysine-based motif adjacent to the transmembrane domain (2015)
  • Author(s): Uemura Satoshi, Shishido Fumi, Kashimura Madoka, Inokuchi Jin-ichi
  • Organizer: 7th Asian Community of Glycoscience and Glycotechnology Conference
  • Place of Presentation: Matsushima, Japan
  • Year and Date: 2015-11-12
  • Int'l Joint Research
• [Presentation] The expression of glycosphingolipids in insulin - target organ of High Fat Diet - induced obesity mice (2015)
  • Author(s): Wakana Matsuyama, Shinji Go, Lucas Veillon, Kei-ichiro Inamori, Jin-ichi Inokuchi
  • Organizer: 7th Asian Community of Glycoscience and Glycotechnology Conference
  • Place of Presentation: Matsushima, Japan
  • Year and Date: 2015-11-12
  • Int'l Joint Research
• [Presentation] Gangliosides regulate intestinal cholesterol absorption (2015)
  • Author(s): Wataru Nihei, Masakazu Nagafuku, Yui Kikuchi, Jin-ichi Inokuchi
  • Organizer: 7th Asian Community of Glycoscience and Glycotechnology Conference
  • Place of Presentation: Matsushima, Japan
  • Year and Date: 2015-11-12
  • Int'l Joint Research
• [Presentation] Establishment of mutant Jurkat T-cell lines lacking different glycosphingolipid species (2015)
  • Author(s): Hiroyuki Yamamoto, Masakazu Nagafuku, Kei-ichiro Inamori, Fumi Shishido, Hideki Ito, Jin-ichi Inokuchi
  • Organizer: 7th Asian Community of Glycoscience and Glycotechnology Conference
  • Place of Presentation: Matsushima, Japan
  • Year and Date: 2015-11-12
  • Int'l Joint Research
• [Presentation] Investigation of the role of gangliosides in leptin and melanocortin signaling (2015)
  • Author(s): Hideki Ito, Kei-ichiro Inamori, Xiaohua Yang, Wataru Nihei, Sohei Tsukita, Tetsuya Yamada, Hideki Katagiri, Jin-ichi Inokuchi
  • Organizer: 7th Asian Community of Glycoscience and Glycotechnology Conference
  • Place of Presentation: Matsushima, Japan
  • Year and Date: 2015-11-12
  • Int'l Joint Research
• [Presentation] Analysis of GM3 synthase-gene knockout cell lines generated from mouse hypothalamic neuronal cells (2015)
  • Author(s): Yumi Tamura, Kei-ichiro Inamori, Hideki Ito, Hikaru Chiba, Jin-ichi Inokuchi
  • Organizer: 7th Asian Community of Glycoscience and Glycotechnology Conference
  • Place of Presentation: Matsushima, Japan
  • Year and Date: 2015-11-12
  • Int'l Joint Research
• [Presentation] Regulation of glycosphingolipid expression by O-GlcNAc modification (2015)
  • Author(s): Shinji Go and Jin-ichi Inokuchi
  • Organizer: 7th Asian Community of Glycoscience and Glycotechnology Conference
  • Place of Presentation: Matsushima, Japan
  • Year and Date: 2015-11-12
  • Int'l Joint Research
• [Presentation] 脂肪組織の生理的制御因子としてのガングリオシドGM3 (2015)
  • Author(s): 井ノ口 仁一、永福 正和、稲森 啓一郎、狩野 裕考
  • Organizer: 第36回日本肥満学会
  • Place of Presentation: 名古屋
  • Year and Date: 2015-10-02
• [Presentation] mouse ST3Gal5(GM3/GM4 synthase)のarginine/lysine-based motifによる細胞内輸送機構の解析 (2015)
  • Author(s): 宍戸 史，上村 聡志，樫村 まどか，井ノ口 仁一
  • Organizer: 第54回日本薬学会東北支部大会
  • Place of Presentation: 盛岡市矢巾
  • Year and Date: 2015-09-25
• [Presentation] 糖尿病研究における糖脂質メタボロミクス (2015)
  • Author(s): 井ノ口 仁一
  • Organizer: 第３７回日本薬学会九州支部コロキウム
  • Place of Presentation: 福岡県福岡市
  • Year and Date: 2015-09-11
  • Invited
• [Presentation] 高脂肪食餌誘発性肥満モデルマウスのインスリン感受性組織におけるスフィンゴ糖脂質発現 (2015)
  • Author(s): 松山和佳奈、郷慎司、Lucas Veillon、稲森啓一郎、井ノ口仁一
  • Organizer: 第９回東北糖鎖研究会
  • Place of Presentation: 仙台市
  • Year and Date: 2015-09-04
• [Presentation] スフィンゴ脂質は胸腺における自己反応性T細胞の除去に関与するか？ (2015)
  • Author(s): 豊島 かおる，永福 正和，神 麗美，岡崎 俊郎，井ノ口 仁一
  • Organizer: 第９回東北糖鎖研究会
  • Place of Presentation: 仙台市
  • Year and Date: 2015-09-04
• [Presentation] スフィンゴ糖脂質合成酵素欠損Jurkat T細胞株の樹立とその機能解析 (2015)
  • Author(s): 山本 博之 , 永福 正和 , 稲森 啓一郎 , 宍戸 史 , 伊藤 英樹 , 井ノ口 仁一
  • Organizer: 第９回東北糖鎖研究会
  • Place of Presentation: 仙台市
  • Year and Date: 2015-09-04
• [Presentation] ガングリオシドは腸管からのコレステロール吸収を制御する (2015)
  • Author(s): 二瓶 渉, 永福 正和, 菊地 唯, 井ノ口 仁一
  • Organizer: 第９回東北糖鎖研究会
  • Place of Presentation: 仙台市
  • Year and Date: 2015-09-04
• [Presentation] B細胞分化におけるガングリオシドの機能的意義 (2015)
  • Author(s): 齋藤 恵梨香, 永福 正和, 髙橋 遥茄, 吉田 純人, 南條 真央, 井ノ口 仁一
  • Organizer: 第９回東北糖鎖研究会
  • Place of Presentation: 仙台市
  • Year and Date: 2015-09-04
• [Presentation] レプチン及びメラノコルチンシグナルにおけるガングリオシドの役割の検討 (2015)
  • Author(s): 伊藤英樹，稲森啓一郎，楊燕華，二瓶渉，突田壮平，山田哲也，片桐秀樹，井ノ口仁一
  • Organizer: 第９回東北糖鎖研究会
  • Place of Presentation: 仙台市
  • Year and Date: 2015-09-04
• [Presentation] スフィンゴ糖脂質合成酵素の細胞内トラフィック機構の解析 (2015)
  • Author(s): 宍戸 史，上村 聡志，樫村 まどか，井ノ口 仁一
  • Organizer: 第９回東北糖鎖研究会
  • Place of Presentation: 仙台市
  • Year and Date: 2015-09-04
• [Presentation] mouse ST3Gal5(GM3/GM4 synthase)のarginine/lysine-based motifによる細胞内輸送機構の解析 (2015)
  • Author(s): 宍戸 史，上村 聡志，樫村 まどか，井ノ口 仁一
  • Organizer: 第34回日本糖質学会年会
  • Place of Presentation: 東京
  • Year and Date: 2015-08-31
• [Presentation] Control of Homeostatic and Pathogenic Balance in Adipose Tissue by Ganglioside GM3 ; Development of Membrane Microdomain Ortho-Signaling Therapy (2015)
  • Author(s): Jin-ichi Inokuchi
  • Organizer: Bioactive Lipids in Cancer, Inflammation & Related Diseases
  • Place of Presentation: Budapest, Hungary
  • Year and Date: 2015-07-12
  • Int'l Joint Research / Invited
• [Presentation] Membrane Microdomain Ortho-Signaling Therapy (2015)
  • Author(s): 井ノ口 仁一
  • Organizer: 第10回スフィンゴテラピー研究会
  • Place of Presentation: 石川県加賀
  • Year and Date: 2015-06-16
• [Presentation] Rearrangement of raft constituents during T cell development (2015)
  • Author(s): 永福 正和、豊島 かおる、井ノ口 仁一
  • Organizer: 第10回スフィンゴテラピー研究会
  • Place of Presentation: 石川県加賀
  • Year and Date: 2015-06-16
• [Presentation] Identification of Ganglioside GM3 Molecular Species in Human Serum Associated With Risk Factors of Metabolic Syndrome (2015)
  • Author(s): Lucas Veillon、郷慎司、松山和佳奈、鈴木明身、長崎実佳、矢冨裕、井ノ口仁一
  • Organizer: 第57回日本脂質生化学会
  • Place of Presentation: 東京
  • Year and Date: 2015-05-28
• [Presentation] ガングリオシドGM3合成酵素の細胞内トラフィック機構の解析 (2015)
  • Author(s): 宍戸 史，上村 聡志，樫村 まどか，井ノ口 仁一
  • Organizer: 日本生化学会東北支部第81回例会・シンポジウム
  • Place of Presentation: 仙台市
  • Year and Date: 2015-05-21
• [Presentation] GM3は脂肪組織の恒常性と病態発症のバランスをインスリンシグナルを制御することにより支配している (2015)
  • Author(s): 井ノ口 仁一
  • Organizer: 第５８回日本糖尿病学会
  • Place of Presentation: 山口県 下関市
  • Year and Date: 2015-05-21
• [Presentation] Control of Homeostatic and Pathogenic Balance in Adipose Tissue by Ganglioside GM3. (2014)
  • Author(s): Inokuchi J
  • Organizer: 6th Asian Communications of Glycobiology an Glycotechnology conference
  • Place of Presentation: Hyderabad, India
  • Year and Date: 2014-12-09 – 2014-12-12
  • Invited
• [Presentation] Ganglioside GM3 is essential for the structural integrity and function of cochlear hair cells. (2014)
  • Author(s): Inokuchi J
  • Organizer: J. Society for Glycobiology & Japanese Society of Carbohydrate Research 2014 Joint Annual Meeting
  • Place of Presentation: Honolulu, HI, USA
  • Year and Date: 2014-11-16 – 2014-11-19
  • Invited
• [Presentation] ガングリオシドGM3は蝸牛有毛細胞の構造と機能維持に必須である。 (2014)
  • Author(s): 井ノ口仁一、吉川 弥里、郷 慎司
  • Organizer: 第33回日本糖質学会
  • Place of Presentation: 名古屋大学
  • Year and Date: 2014-08-10 – 2014-08-12
• [Presentation] Lipid Membranes and Insulin Signaling. (2014)
  • Author(s): Inokuchi J
  • Organizer: ISSFAL (International Society for the Study of Fatty Acid and Lipids)
  • Place of Presentation: Stockholm, Sweden
  • Year and Date: 2014-06-28 – 2014-07-02
  • Invited
• [Book] Sugar Chains (Macrophages govern ganglioside GM3 expression in adipocytes to regulate adipogenesis and insulin signaling in homeostatic and pathogenic conditions) (2015)
  • Author(s): Jin-ichi Inokuchi
  • Publisher: Springer
• [Book] Sugar Chains (Gangliosides and T cell immunity) (2015)
  • Author(s): Masakazu Nagafuku, Jin-ichi Inokuchi
  • Publisher: Springer
• [Book] Macrophages govern ganglioside GM3 expression in adipocytes to regulate adipogenesis and insulin signaling in homeostatic and pathogenic conditions (2015)
  • Author(s): Inokuchi J
  • Total Pages: 16
  • Publisher: Springer
• [Book] Gangliosides and T cell immunity (2015)
  • Author(s): Nagafuku M and Inokuchi J
  • Total Pages: 20
  • Publisher: Springer
• [Book] Synthesis of O-Linked Glycoconjugates in the Nervous System. (2014)
  • Author(s): Inokuchi J, Go S and Hirabayashi Y
  • Total Pages: 17
  • Publisher: Springer Science+Business Media New York
• [Book] ST3 beta-galactoside alpha-2,3-sialyltransferase 5;ST3GAL5. Handbook of Glycosyltransferases and Related Genes, 2nd Ed (2014)
  • Author(s): Inokuchi J and Uemura S
  • Total Pages: 12
  • Publisher: Springer
• [Book] Biosynthetic Pathways of Glycosphingolipids. Handbook of Glycosyltransferases and Related Genes, 2nd Ed (2014)
  • Author(s): Inokuchi J and Go S
  • Total Pages: 7
  • Publisher: Springer
• [Remarks] 東北薬科大学
  • URL: http://www.tohoku-pharm.ac.jp/new/index.cgi?eid=323