Elucidation of pathomecanism for Fukuyama muscular dystrophy and dystroglycanopathy and their drug developmen
| Project/Area Number |
17H01563
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Neurology
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| Research Institution | The University of Tokyo (2018-2019)
Kobe University (2017) |
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Principal Investigator |
Toda Tatsushi 東京大学, 医学部附属病院, 教授 (30262025)
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| Co-Investigator(Kenkyū-buntansha) |
小林 千浩 神戸大学, 医学研究科, 准教授 (90324780)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥42,900,000 (Direct Cost: ¥33,000,000、Indirect Cost: ¥9,900,000)
Fiscal Year 2019: ¥12,350,000 (Direct Cost: ¥9,500,000、Indirect Cost: ¥2,850,000)
Fiscal Year 2018: ¥14,040,000 (Direct Cost: ¥10,800,000、Indirect Cost: ¥3,240,000)
Fiscal Year 2017: ¥16,510,000 (Direct Cost: ¥12,700,000、Indirect Cost: ¥3,810,000)
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| Keywords | 福山型筋ジストロフィー / アンチセンス核酸 / ジストログリカン / リビトールリン酸異常症 / ジストログリカノパチー |
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| Outline of Final Research Achievements |
As a therapeutic agent for Fukuyama muscular dystrophy, a single candidate sequence showing high activity was found by comprehensive screening of antisense nucleic acids, and toxicity and pharmacokinetics were investigated in GLP grade. The presence or absence of DG sugar chains in the radial glial contributes to the severity of subsequent brain lesions during brain formation in four DG disorder mice. The fukutin gene was introduced into the 12.5 day-old brain by in utero electroporation to prevent the onset of cerebral cortical dysplasia. DG sugar chain deficiency contributes to the pathophysiology of cardiomyopathy due to a reduction in myocardial hypertrophic response to hemodynamic stress and a reduction in contractile force of individual cardiomyocytes. As we found Golgi-microtubule structural abnormalities, reducing microtubule structural abnormalities with microtubule polymerization inhibitors leads to treatment.
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| Academic Significance and Societal Importance of the Research Achievements |
日本固有のFCMDの治療法開発は、我が国の筋ジストロフィー研究における重要課題とされているが、FCMDの治療法確立がかなり進む。また他のαジストログリカノパチー各疾患にも応用可能で、社会的・学術的な意義は非常に大きい。我々が発見したリビトールリン酸糖鎖と、その修飾に関わるフクチン、FKRP、ISPDの機能は、DG異常症研究のブレイクスルーである。CDP-リビトールが哺乳類細胞で生理機能を担っていることは想定すらされておらず、その医薬品としての応用は画期的である。治療法のない不治の病にむかって、今はじめて分子標的治療ができつつあるのは、患者、家族、国民にとって福音である。
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Report
(4 results)
Research Products
(66 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] National registry of patients with Fukuyama congenital muscular dystrophy in Japan.2018
Author(s)
Ishigaki K, Ihara C, Nakamura H, Mori-Yoshimura M, Maruo K, Taniguchi-Ikeda M, Kimura E, Murakami T, Sato T, Toda T, Kaiya H, Osawa M.
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Journal Title
Neuromuscul Disord.
Volume: 10
Issue: 10
Pages: 885-893
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Cardiac involvement in Fukuyama muscular dystrophy is less severe than in Duchenne muscular dystrophy.2017
Author(s)
Yamamoto T, Taniguchi-Ikeda M, Awano H, Matsumoto M, Lee T, Harada R, Imanishi T, Hayashi N, Sakai Y, Morioka I, Takeshima Y, Iijima K, Saegusa J, Toda T.
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Journal Title
Brain and Development
Volume: 39
Issue: 10
Pages: 861-868
DOI
Related Report
Peer Reviewed / Open Access
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