Investigation of molecular pathogenesis and development of therapeutic methods for Fukuyama muscular dystrophy and related diseases
Project/Area Number |
16H05353
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Research Category |
Grant-in-Aid for Scientific Research (B)
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Allocation Type | Single-year Grants |
Section | 一般 |
Research Field |
Pediatrics
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Research Institution | Kobe University |
Principal Investigator |
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Project Period (FY) |
2016-04-01 – 2020-03-31
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Project Status |
Completed (Fiscal Year 2019)
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Budget Amount *help |
¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000)
Fiscal Year 2019: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
Fiscal Year 2018: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
Fiscal Year 2017: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2016: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
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Keywords | 糖鎖 / 筋ジストロフィー / 脳神経疾患 / 酵素 / 遺伝子 / ジストログリカノパチー / fukutin / α-dystroglycan |
Outline of Final Research Achievements |
In this study, we aimed to delineate the full O-Man glycan structure of a-dystroglycan (a-DG) whose abnormalities cause muscular dystrophy, to clarify the biosynthesis pathway of the glycan, to understand the pathogenesis of neuronal dysfunction of the disease, and to explore its therapeutic possibility. We determined the unknown glycan structure that contained ribitol phosphate. We also identified the functions of four gene proteins such as fukutin that are responsible for muscular dystrophy, and determined the biosynthesis pathway for ribitol phosphate of the glycan. We could not find novel proteins modified with the O-Man glycan or a-DG ligands. Some therapeutic strategies were found to be effective for the disease model cells and mice. Further investigations are required.
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Academic Significance and Societal Importance of the Research Achievements |
α-DGのO-Man型糖鎖の完全構造と生合成機構を明らかにしたことで、重篤なα-DGpathyの発症機序を理解でき、新たな治療標的発見、有効な治療法開発につながる。新たな翻訳後修飾の発見であり、医学的のみならず生物学的にも学術的な意義がある。また、O-Man型糖鎖と脳奇形・神経機能との関連を示し、神経機能障害の治療の有効性が示されれば、問題の多い胎児治療ではなく、生後の治療が可能になり、実現可能な脳の治療法の構築につながることが期待でき、社会的意義が大きい。
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Report
(5 results)
Research Products
(31 results)
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[Journal Article] Crystal structures of fukutin-related protein (FKRP), a ribitol-phosphate transferase related to muscular dystrophy.2020
Author(s)
Kuwabara N, Imae R, Manya H, Tanaka T, Mizuno M, Tsumoto H, Kanagawa M, Kobayashi K, Toda T, Senda T, Endo T, Kato R.
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Journal Title
Nat Commun.
Volume: 11
Issue: 1
Pages: 303-303
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Cell endogenous activities of fukutin and FKRP coexist with the ribitol xylosyltransferase, TMEM5.2018
Author(s)
Nishihara, R., Kobayashi, K., Imae, R., Tsumoto, H., Manya, H., Mizuno, M., Kanagawa, M., Endo, T., and Toda, T.
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Journal Title
Biochemical and Biophysical Research Communications
Volume: 497
Issue: 4
Pages: 1025-1030
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Identification of a post-translational modification with ribitol-phosphate and its defect in muscular dystrophy2016
Author(s)
Kanagawa M, Kobayashi K, Tajiri M, Manya H, Kuga A, Yamaguchi Y, Akasaka-Manya K, Furukawa J, Mizuno M, Kawakami H, Shinohara Y, Wada Y, Endo T, Toda T.
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Journal Title
Cell Reports
Volume: 14
Issue: 9
Pages: 2209-2223
DOI
NAID
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
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[Journal Article] Analysis of phenotype, enzyme activity, and genotype of Chinese patients with POMT1 mutation2016
Author(s)
Haipo Yang, Hiroshi Manya, Kazuhiro Kobayashi, HUI JIAO, Xiaona Fu, Jiangxi Xiao, Xiaoqing Li, Jingmin wang, Yuwu Jiang, TATSUSHI TODA, Tamao Endo, Xiru Wu,Hui Xiong,
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Journal Title
J. Hum. Genet
Volume: 印刷中
Issue: 8
Pages: 753-759
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
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[Journal Article] Carbohydrate-binding domain of the POMGnT1 stem region modulates O-mannosylation sites of α-dystroglycan.2016
Author(s)
Kuwabara N, Manya H, Yamada T, Tateno H, Kanagawa M, Kobayashi K, Akasaka-Manya K, Hirose Y, Mizuno M, Ikeguchi M, Toda T, Hirabayashi J, Senda T, Endo T, Kato R.
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Journal Title
Proc Natl Acad Sci U S A.
Volume: 113
Issue: 33
Pages: 9280-9285
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] The muscular dystrophy gene TMEM5encodes a ribitol β1-4 Xylosyltransferase required for the functional glycosylation of dystroglycan.2016
Author(s)
Manya, H., Yamaguchi, Y., Kanagawa, M., Kobayashi, K., Tajiri, M., Akasaka-Manya, K., Kawakami, H., Mizuno, M., Wada, Y., Toda, T., and Endo, T.
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Journal Title
J. Biol. Chem
Volume: 291
Issue: 47
Pages: 24618-24627
DOI
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
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[Presentation] Wide distribution of alpha-synuclein oligomers in MSA brain detected by proximity ligation2019
Author(s)
関谷博顕, 古和久朋, 古閑日奈子, 髙田真利子, 佐竹渉, 二村直伸, 舟川格, 陣内研二, 高橋玄倫, 近藤武史, 上野易弘, 金川基, 小林千浩, 戸田達史
Organizer
第60回日本神経学会学術大会
Related Report
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[Presentation] αジストログリカン糖鎖のリビトールリン酸タンデム構造とその生合成経路2016
Author(s)
Kazuhiro Kobayashi, Motoi Kanagawa, Michiko Tajiri, Hiroshi Manya, Atsushi Kuga, Yoshiki Yamaguchi, Keiko Akasaka-Manya, Jun-ichi Furukawa, Mamoru Mizuno, Hiroko Kawakami, Yasuro Shinohara, Yoshinao Wada, Tamao Endo, Tatsushi Toda
Organizer
第2回日本筋学会学術集会
Related Report
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[Presentation] αジストログリカン糖鎖のリビトールリン酸タンデム構造とその生合成機構2016
Author(s)
Kazuhiro Kobayashi, Motoi Kanagawa, Michiko Tajiri, Hiroshi Manya, Atsushi Kuga, Yoshiki Yamaguchi, Keiko Akasaka-Manya, Jun-ichi Furukawa, Mamoru Mizuno, Hiroko Kawakami, Yasuro Shinohara, Yoshinao Wada, Tamao Endo, Tatsushi Toda
Organizer
第39回日本分子生物学会年会
Related Report
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