研究室紹介LABORATORY

分子細胞化学

KEYWORDS

  • Notch
  • O-GlcNAc
  • 糖鎖生物学
  • 血管内皮細胞
  • 血液脳関門
  • 小胞体
  • 分子標的治療薬
  • 糖転移酵素

HEAD

岡島 徹也

教授

研究者総覧

LAB MEMBER

構成員名 役職 研究者総覧
田嶌 優子 講師 研究者総覧
近藤 裕史 講師 研究者総覧
橋本 登 特任助教 研究者総覧

CONTACT

Email tokajima◎med.nagoya-u.ac.jp（送信の際は◎を@に変更してください）
HP 分子細胞化学 独自ホームページ

OUTLINE

癌細胞、神経細胞、そして、周囲に存在する血管系細胞を中心に、細胞機能の制御や細胞増殖・分化を制御する糖タンパク質の解析を行い、癌や神経系などの難治疾患の治療応用を目指している。そのために、

  • Notch受容体のO型糖鎖による品質管理機構を解明し、CADASILなどの遺伝性血管性認知症に対する新たな治療戦略を構築する。
  • 腫瘍組織におけるEGFR受容体の糖鎖変化を解析し、糖鎖構造に基づくEGFシグナルの制御と腫瘍抑制法を開発する。
  • 質量分析を用いたグライコプロテオミクス解析により疾患に関連する糖鎖構造を同定し、診断や創薬に活用可能なバイオマーカーとしての意義を検証する。
  • 糖鎖異常に関連した遺伝性疾患に着目し、発生プロセス制御における糖鎖の役割を、ゲノム編集細胞やマウスモデルを用いて分子レベルで解明する。
  • DepMapなどのデータベースを活用し、がんにおいて重要な糖鎖関連遺伝子を特定し、低副作用の新規治療法を提案する。
  • 糖鎖認識分子シグレックを介した免疫細胞と癌細胞間の双方向シグナル伝達を解析し、免疫応答と腫瘍進展の制御機構を明らかにする。

当研究室は、文部科学省による「大規模学術フロンティア促進事業」の一環として始動したヒューマングライコームプロジェクトを推進する基幹研究室です。
本プロジェクトでは、ヒトの体内に存在する「糖鎖（とうさ）」と呼ばれる分子の働きや構造を詳しく調べることで、病気の原因解明や新たな治療法の開発につなげることを目指しています。
糖鎖は、細胞間の情報伝達や免疫機能など、生命活動の多くに関わる重要な要素ですが、その全容はまだ十分に解明されていません。当研究室では、最先端の研究技術を活用し、糖鎖の全体像を明らかにすることで、医学・生命科学の発展に貢献してまいります。    

RESEARCH PROJECTS

  1. Notch受容体O型糖鎖の品質管理と血管性認知症への関与
  2. EGFシグナルと腫瘍抑制におけるO型糖鎖の役割
  3. グライコプロテオミクスによる疾患バイオマーカー探索と創薬応用
  4. 糖鎖関連疾患の分子病態の解明
  5. 公共データベースを活用した糖鎖関連遺伝子の治療標的探索
  6. 糖鎖免疫チェックポイント分子シグレックを介した免疫・癌双方向シグナルの解析

以上のようなテーマのもとに、基礎医学・生物学の研究成果を臨床の場で応用・展開することを目指している。

BIBLIOGRAPHY

2025
  1. Osada A, Tanaka M, Sugiura Y, Yuan X, Yamashita S, Ochi K, Kohda H, Ito A, Go S, Okajima T, Kadomatsu K, Yanagita M, Furuhashi K, Maruyama S, Suganami T. Altered glycolipid metabolism during acute kidney injury exacerbates renal inflammation. Sci Rep. 2025 Dec 2;16(1):147. doi: 10.1038/s41598-025-28897-4.
  2. Kondo Y, Jiang Y, Geng X, Song J, Simeroth S, McDaniel JM, Yu P, Srinivasan RS, Xia L. Site-1 protease-mediated cholesterol metabolism is essential for lymphatic development in mice. JCI Insight. 2025 Oct 22;10(20).
  3. Yang Xu, Noboru Hashimoto, Fumiya Kano, Linze Xia, Cheng Ding, Houjun Lao, Yifei Wang, Takahiro Arai, Tomonori Iwasaki, Akihito Yamamoto Conditioned medium from stem cells of human exfoliated deciduous teeth ameliorates mouse ovalbumin-specific allergic dermatitis. Stem cell research & therapy, 16(1) 605-605, Oct 31, 2025
  4. Tashima Y, Tsukamoto Y, Tsukamoto N, Kondo Y, Uddin E, Furukawa W, Go S, Arakawa H, Kaji H, Takeuchi H, Okajima T.Retention of DLK1 in the endoplasmic reticulum identifies roles for EGF-like-domain-specific O-glycans in the secretory pathway.FEBS J. 2025 Oct;292(20):5355-5381. doi: 10.1111/febs.70168. Epub 2025 Jul 10.
  5. Tsukamoto Y, Aoki K, Kama Y, Hosokawa H, Saiki W, Tsukamoto N, Kato K, Hosokawa Y, Sato R, Uesugi N, Fujita Y, Fukazawa K, Funada D, Suzuki F, Kurebayashi Y, Urata Y, Uchiyama S, Wang W, Minami A, Takahashi T, Tiemeyer M, Narimatsu Y, Okajima T, Takeuchi H.Differential O-glucose elongation on a specific EGF repeat within the canonical ligand-binding domain regulates DLL1/4-NOTCH1 signaling.Proc Natl Acad Sci U S A. 2025 Oct 28;122(43):e2504827122. doi: 10.1073/pnas.2504827122. Epub 2025 Oct 23.
  6. Wang W, Saiki W, Tsukamoto Y, Uchiyama S, Kondo Y, Okajima T, Takeuchi H.XXYLT1 inhibits NOTCH1 activation in Jurkat cells while promoting cell proliferation.Nagoya J Med Sci. 2025 Aug;87(3):431-450. doi: 10.18999/nagjms.87.3.431.
  7. Tsukamoto Y, Okajima T.O-GlcNAc glycans in the mammalian extracellular environment.Carbohydr Res. 2025 Mar;549:109378. doi: 10.1016/j.carres.2025.109378. Epub 2025 Jan 10.
  8. Cheng Ding, Noboru Hashimoto, Fumiya Kano, Hirofumi Tenshin, Takahiro Arai, Linze Xia, Yang Xu, Houjun Lao, Yifei Wang, Tomonori Iwasaki.Factors secreted from the stem cells of human exfoliated deciduous teeth inhibit osteoclastogenesis through the activation of the endogenous antioxidant system. Journal of oral biosciences, 100618-100618, Jan 22, 2025
  9. Tsukamoto Y, Okajima T. O-GlcNAc glycans in the mammalian extracellular environment. Carbohydr Res. 2025 Jan 10;549:109378. doi: 10.1016/j.carres.2025.109378. Online ahead of print.PMID: 39813972
2024
  1. Noboru Hashimoto, Shizuka Ito, Akira Harazono, Akiko Tsuchida, Yasuhiro Mouri, Akihito Yamamoto, Tetsuya Okajima, Yuhsuke Ohmi, Keiko Furukawa, Yasusei Kudo Bidirectional signals generated by Siglec-7 and its crucial ligand tri-sialylated T to escape of cancer cells from immune surveillance. iScience, 27(11) 111139-111139, Nov 15, 2024
  2. Tsukamoto Y, Tsukamoto N, Saiki W, Tashima Y, Furukawa JI, Kizuka Y, Narimatsu Y, Clausen H, Takeuchi H, Okajima T. Characterization of galactosyltransferase and sialyltransferase genes mediating the elongation of the extracellular O-GlcNAc glycans. Biochem Biophys Res Commun. 2024 Apr 9;703:149610. doi: 10.1016/j.bbrc.2024.149610. Epub 2024 Feb 1. PMID: 38359610.
  3. Kondo Y. Innate Immune Sensing of Lysosomal Dysfunction Drives Multiple Lysosomal Storage Disorders. Trends in Glycoscience and Glycotechnology. 36 (212), E78-E78.
  4. Kondo Y, Li Y, Okajima T. Efficient Escorting Strategy for Aggregation-Prone Notch EGF Repeats with Sparcl1. Molecules. 2024 Feb 27;29(5):1031. doi: 10.3390/molecules29051031. PMID: 38474544.
  5. Sharma P, Zhang X, Ly K, Zhang Y, Hu Y, Ye AY, Hu J, Kim JH, Lou M, Wang C, Celuzza Q, Kondo Y, Furukawa K, Bundle DR, Furukawa K, Alt FW, Winau F. The lipid globotriaosylceramide promotes germinal center B cell responses and antiviral immunity. Science. 2024 Feb 16;383(6684):eadg0564. doi: 10.1126/science.adg0564. Epub 2024 Feb 16. PMID: 38359115.
  6. Huang L*, Kondo Y*, Cao L, Han J, Li T, Zuo B, Yang F, Li Y, Ma Z, Bai X, Jiang M, Ruan C, Xia L. Novel GNE missense variants impair de novo sialylation and cause defective angiogenesis in the developing brain in mice. Blood Adv. 2024 Feb 27;8(4):991-1001. doi: 10.1182/bloodadvances.2023011490. PMID: 38237079. *Equal co-first.
  7. Tashima Y, Tsukamoto Y, Tsukamoto N, Kondo Y, Uddin E, Furukawa W, Go S, Takeuchi H, Okajima T. Retention of DLK1 in the endoplasmic reticulum identifies roles for EGF domain-specific O-glycans in the secretory pathway. bioRxiv. 2024. doi: 10.1101/2024.08.31.610613.
  8. Kondo Y. Two new mutations identified as possible causes of rare blood disorder. EurekAlert! https://www.eurekalert.org/news-releases/1039061, 2024.
  9. Kondo Y, Jing W, Xia L Site-1 Protease Deficiency Causes Human Skeletal Dysplasia. Trends in Glycoscience and Glycotechnology 36 (210), E17-E20, 2024.
  10. ファルマシア　2024.9. 総説 紅林佑希、塚本庸平、竹内英之　O-結合型糖鎖修飾と感染症
  11. Suzuki S, Mashiko T, Tsukamoto Y, Oya M, Kotani Y, Okawara S, Matsumoto T, Mizue Y, Takeuchi H, Okajima T, Itoh M. The N-acetylglucosaminyltransferase Radical fringe contributes to defects in JAG1-dependent turnover and signaling of NOTCH3 CADASIL mutants. .J Biol Chem. 2024 Oct;300(10):107787. doi: 10.1016/j.jbc.2024.107787. Epub 2024 Sep 19.PMID: 39303912 Free PMC article.
2023
  1. Kondo Y, Okajima T. Inhibitory machinery for the functional dystroglycan glycosylation. J Biochem. 2023 Apr 26;173(5):333-335. doi: 10.1093/jb/mvad003. PMID: 36760122.
  2. Kakuo M, Horii T, Tonomura N, Sato R, Ogawa M, Okajima T, Kamemura K. Evidence that only EWS among the FET proteins acquires a low partitioning property for the hyperosmotic stress response by O-GlcNAc glycosylation on its low-complexity domain. Exp Cell Res. 2023 Mar 1;424(1):113504. doi: 10.1016/j.yexcr.2023.113504. Epub 2023 Feb 2.PMID: 36736606
2022
  1. Shao B, Hoover C, Shi H, Kondo Y, Lee RH, Chen J, Shan X, Song J, McDaniel JM, Zhou M, McGee S, Vanhoorelbeke K, Bergmeier W, López JA, George JN, Xia. Deletion of platelet CLEC-2 decreases GPIbα-mediated integrin αIIbβ3 activation and decreases thrombosis in TTP. Blood. 2022 Apr 21;139(16):2523-2533. doi: 10.1182/blood.2021012896. PMID: 35157766.
  2. Kakuo M, Horii T, Tonomura N, Sato R, Ogawa M, Okajima T, Kamemura K. Evidence that only EWS among the FET proteins acquires a low partitioning property for the hyperosmotic stress response by O-GlcNAc glycosylation on its low-complexity domain. Exp Cell Res. 2023 Mar 1;424(1):113504. doi: 10.1016/j.yexcr.2023.113504. Epub 2023 Feb 2. PMID: 36736606.
  3. Tsukamoto Y, Ogawa M, Yogi K, Tashima Y, Takeuchi H, Okajima T. Glycoproteomics of NOTCH1 EGF repeat fragments overexpressed with different glycosyltransferases in HEK293T cells reveals insights into O-GlcNAcylation of NOTCH1. Glycobiology. 2022 Jun 13;32(7):616-628. doi: 10.1093/glycob/cwac015. PMID: 35290457.
  4. Furukawa K, Okajima T. Galactosyltransferase I is a gene responsible for progeroid variant of Ehlers-Danlos syndrome: molecular cloning and identification of mutations. Biochim Biophys Acta. 2002 Dec 19;1573(3):377-81. doi: 10.1016/s0304-4165(02)00406-3. PMID: 12417421 Review.
  5. Zhang A, Tsukamoto Y, Takeuchi H, Nishiwaki K, Tashima Y, Okajima T. Secretory expression of mammalian NOTCH tandem epidermal growth factor-like repeats based on increased O-glycosylation. Anal Biochem. 2022 Nov 1;656:114881. doi: 10.1016/j.ab.2022.114881. Epub 2022 Sep 5. PMID: 36067866.
  6. Haltiwanger RS, Wells L, Freeze HH, Jafar-Nejad H, Okajima T, Stanley P.In: Varki A, Cummings RD, Esko JD, Stanley P, Hart GW, Aebi M, Mohnen D, Kinoshita T, Packer NH, Prestegard JH, Schnaar RL, Seeberger PH, editors. Other Classes of Eukaryotic Glycans. Essentials of Glycobiology [Internet]. 4th edition. Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press; 2022. Chapter 13.PMID: 35536928 Free Books & Documents. Review.
  7. Wang W, Okajima T, Takeuchi H. Significant Roles of Notch O-Glycosylation in Cancer. Molecules. 2022 Mar 9;27(6):1783. doi: 10.3390/molecules27061783. PMID: 35335147. Review.
  8. Furukawa K, Ohmi Y, Hamamura K, Kondo Y, Ohkawa Y, Kaneko K, Hashimoto N, Yesmin F, Bhuiyan RH, Tajima O, Furukawa K. Signaling domains of cancer-associated glycolipids. Glycoconj J. 2022 Apr;39(2):145-155. doi: 10.1007/s10719-022-10051-1. Epub 2022 Mar 22. PMID: 35315508 Review.
  9. Tashima Y, Hirata T, Maeda Y, Murakami Y, Kinoshita T. Differential use of p24 family members as cargo receptors for the transport of glycosylphosphatidylinositol-anchored proteins and Wnt1. J Biochem. 2022 Jan 7;171(1):75-83. doi: 10.1093/jb/mvab108. PMID: 34647572.
2021
  1. Saiki W, Ma C, Okajima T, Takeuchi H. Current Views on the Roles of O-Glycosylation in Controlling Notch-Ligand Interactions. Biomolecules. 2021 Feb 18;11(2):309. doi: 10.3390/biom11020309. PMID: 33670724. Review.
  2. Ohmi Y, Nishikaze T, Kitaura Y, Ito T, Yamamoto S, Sugiyama F, Matsuyama M, Takahashi Y, Takeda A, Kawahara T, Okajima T, Furukawa K, Furukawa K. Majority of alpha2,6-sialylated glycans in the adult mouse brain exist in O-glycans: SALSA-MS analysis for knockout mice of alpha2,6-sialyltransferase genes. Glycobiology. 2021 Jun 3;31(5):557-570. doi: 10.1093/glycob/cwaa105. PMID: 33242079.
  3. Barua R, Mizuno K, Tashima Y, Ogawa M, Takeuchi H, Taguchi A, Okajima T. Bioinformatics and Functional Analyses Implicate Potential Roles for EOGT and L-fringe in Pancreatic Cancers. Molecules. 2021 Feb 7;26(4):882. doi: 10.3390/molecules26040882. PMID: 33562410.
  4. Yesmin F, Bhuiyan RH, Ohmi Y, Yamamoto S, Kaneko K, Ohkawa Y, Zhang P, Hamamura K, Cheung NV, Kotani N, Honke K, Okajima T, Kambe M, Tajima O, Furukawa K, Furukawa K. Ganglioside GD2 Enhances the Malignant Phenotypes of Melanoma Cells by Cooperating with Integrins. Int J Mol Sci. 2021 Dec 31;23(1):423. doi: 10.3390/ijms23010423. PMID: 35008849.
  5. Zhang P, Ohkawa Y, Yamamoto S, Momota H, Kato A, Kaneko K, Natsume A, Farhana Y, Ohmi Y, Okajima T, Bhuiyan RH, Wakabayashi T, Furukawa K, Furukawa K. St8sia1-deficiency in mice alters tumor environments of gliomas, leading to reduced disease severity. Nagoya J Med Sci. 2021 Aug;83(3):535-549. doi: 10.18999/nagjms.83.3.535. PMID: 34552288.
  6. Mishima Y, Hamamura K, Kato H, Furukawa K, Tashima Y, Okajima T, Kondo H, Sato T, Miyazawa K, Goto S, Togari A. Contribution of Glucosylceramide Synthase to the Proliferation of Mouse Osteoblasts. In Vivo. 2021 Nov-Dec;35(6):3111-3123. doi: 10.21873/invivo.12606. PMID: 34697142.
  7. Wang W, Okajima T, Takeuchi H. Significant Roles of Notch O-Glycosylation in Cancer. Molecules. 2022 Mar 9;27(6):1783. doi: 10.3390/molecules27061783. PMID: 35335147.
  8. Hoover C, Kondo Y, Shao B, McDaniel MJ, Lee R, McGee S, Whiteheart S, Bergmeier W, McEver RP, Xia L. Heightened activation of embryonic megakaryocytes causes aneurysms in the developing brain of mice lacking podoplanin. Blood. 2021 May 20;137(20):2756-2769. doi: 10.1182/blood.2020010310. PMID: 33619517.
  9. Jiang Y, Tang Y, Hoover C, Kondo Y, Huang D, Restagno D, Shao B, Gao L, Michael McDaniel J, Zhou M, Silasi-Mansat R, McGee S, Jiang M, Bai X, Lupu F, Ruan C, Marth JD, Wu D, Han Y, Xia L. Kupffer cell receptor CLEC4F is important for the destruction of desialylated platelets in mice. Cell Death Differ. 2021 Nov;28(11):3009-3021. doi: 10.1038/s41418-021-00797-w. Epub 2021 May 15. PMID: 33993195.
  10. Kondo Y, Larabee JL, Gao L, Shi H, Shao B, Hoover CM, McDaniel JM, Ho Y, Silasi-Mansat R, Archer-Hartmann SA, Azadi P, Srinivasan RS, Rezaie AR, Borczuk A, Laurence JC, Lupu F, Ahamed J, McEver RP, Papin JF, Yu Z, Xia L. L-SIGN is a receptor on liver sinusoidal endothelial cells for SARS-CoV-2 virus. JCI Insight. 2021 Jul 22;6(14):e148999. doi: 10.1172/jci.insight.148999.
  11. Ma X*, Li Y*, Kondo Y*, Shi H, Han J, Jiang Y, Bai X, Archer-Hartmann SA, Azadi P, Ruan C, Fu J, Xia L (*co-first). Slc35a1 deficiency causes thrombocytopenia due to impaired megakaryocytopoiesis and excessive platelet clearance in the liver. Haematologica. 2021 Mar 1;106(3):759-769. doi: 10.3324/haematol.2019.225987. PubMed PMID: 32303557; PubMed Central PMCID: PMC7927894.
2020
  1. Yesmin F, Bhuiyan RH, Ohmi Y, Ohkawa Y, Tajima O, Okajima T, Furukawa K, Furukawa K. Aminoglycosides are efficient reagents to induce readthrough of premature termination codon in mutant B4GALNT1 genes found in families of hereditary spastic paraplegia. J Biochem. in press Alam SM, Tsukamoto Y, Ogawa M, Senoo Y, Ikeda K, Tashima Y, Hideyuki Takeuchi H and Okajima T. N-glycans on EGF domain-specific O-GlcNAc transferase (EOGT) facilitate EOGT maturation and peripheral endoplasmic reticulum localization. J Biol Chem. 295(25) 8560–8574
  2. Urata Y, Saiki W,Tsukamoto Y, Sago H,Hibi H, Okajima T, Takeuchi H. Xylosyl Extension of O-Glucose Glycans on the Extracellular Domain of NOTCH1 and NOTCH2 Regulates Notch Cell Surface Trafficking. Cells (2020) 9(5), 1220; https://doi.org/10.3390/cells9051220
  3. Ogawa M, Tashima Y, Sakaguchi Y, Takeuchi H, Okajima T. Contribution of extracellular O-GlcNAc to the stability of folded epidermal growth factor-like domains and Notch1 trafficking. Biochem Biophys Res Commun. 526:184-190. (2020)
  4. Servián-Morilla E, Cabrera-Serrano M, Johnson K, Pandey A, Ito A, Rivas E, Chamova T, Muelas N, Mongini T, Nafissi S, Claeys KG, Grewal RP, Takeuchi M, Hao H, Bönnemann C, Lopes Abath Neto O, Medne L, Brandsema J, Töpf A, Taneva A, Vilchez JJ, Tournev I, Haltiwanger RS, Takeuchi H, Jafar-Nejad H, Straub V, and Paradas C. POGLUT1 biallelic mutations cause myopathy with reduced satellite cells, α-dystroglycan hypoglycosylation and a distinctive radiological pattern. Acta Neuropathol. 2020 Mar; 139 (3): 565-82.
  5. Urata Y and Takeuchi H. Effects of Notch glycosylation on health and diseases. Dev Growth Differ 2020 Jan; 62 (1): 35-48.
2019
  1. Ralser DJ, Takeuchi H, Fritz G, Basmanav FB, Effern M, Sivalingam S, El-Shabrawi-Caelen L, Degirmentepe EN, Kocatürk E, Singh M, Booken N, Spierings NMK, Schnabel V, Heineke A, Knuever J, Wolf S, Wehner M, Tronnier M, Leverkus M, Tantcheva-Poór I, Wenzel J, Oji V, Has C, Hölzel M, Frank J, Haltiwanger RS, and Betz RC. Altered Notch signaling in Dowling-Degos disease: Additional mutations in POGLUT1 and further insights into disease pathogenesis. J Invest Dermatol 2019 139: 960-964.
  2. Takeuchi H. Notch-Modifying Protein O-Glucosyltransferase 1 (POGLUT1): Specificities, Structures, and Human Disease Implications. Trends in Glycoscience and Glycotechnology 2019; 31: E49-E52.
  3. Hashimoto N, Ito S, Tsuchida A, Bhuiyan RH, Okajima T, Yamamoto A, Furukawa K, Ohmi Y, Furukawa K. The ceramide moiety of disialoganglioside (GD3) is essential for GD3 recognition by the sialic acid-binding lectin SIGLEC7 on the cell surface. J Biol Chem. 294(28):10833-10845. (2019)
  4. Bhuiyan RH, Ohmi Y, Ohkawa Y, Zhang P, Takano M, Hashimoto N, Okajima T, Furukawa K, Furukawa K. Loss of Enzyme Activity in Mutated B4GALNT1 Gene Products in Patients with Hereditary Spastic Paraplegia Results in Relatively Mild Neurological Disorders: Similarity with Phenotypes of B4galnt1 Knockout Mice. Neuroscience. 397:94-106. (2019)
  5. Yu H and Takeuchi H. Protein O-glucosylation: another essential role of glucose in biology. Curr Opin Struct Biol 2019 Jan; 56: 64-71.\t

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糖鎖研究に興味のある方は、ぜひ気軽にお問い合わせください。基礎から応用まで幅広いテーマに一緒に取り組みましょう。

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