心筋イオンチャネル病のリスク層別化と臨床管理におけるシミュレーションの応用
Publicly Offered Research
Project Area | Establishment of Integrative Multi-level Systems Biology and its Applications |
Project/Area Number |
25136705
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Research Category |
Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
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Allocation Type | Single-year Grants |
Review Section |
Complex systems
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Research Institution | Shiga University of Medical Science |
Principal Investigator |
伊藤 英樹 滋賀医科大学, 医学部, 助教 (30402738)
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Project Period (FY) |
2013-04-01 – 2015-03-31
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Project Status |
Completed (Fiscal Year 2014)
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Budget Amount *help |
¥9,230,000 (Direct Cost: ¥7,100,000、Indirect Cost: ¥2,130,000)
Fiscal Year 2014: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2013: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
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Keywords | QT延長症候群 / 筋緊張性ジストロフィー / イオンチャネル / シミュレーション / チャネル / ブルガダ症候群 / SCN5A |
Outline of Annual Research Achievements |
大阪大学神経内科の高橋正紀先生とフランスの研究施設と共同で筋緊張性ジストロフィー症の発症病態に関して研究に行い、特にコンピューター・シミュレーションを利用してイオンチャネルの動態変化にともなう心電図変化を検討した。筋緊張性ジストロフィー症患者においては、心筋ナトリウムチャネルの胎児型から成人型への切り替えが障害されていた。正常状態では、成人になるとともにナトリウムチャネルの選択的スプライシングの変化が起こることで成人型ナトリウムチャネルへの発現に変化するが、スプライシングの調節蛋白であるMBNLにCTGリピートが結合することで、MBNLがナトリウムチャネルのスプライシングを阻害していた。この現象はトランスジェニックマウスにおいても観察された。電気生理学的実験において胎児型と成人型のナトリウムチャネルの特性が異なることを明らかにし、胎児型ではloss of function(機能喪失型)であった。ヒト心筋モデル(O'Haraモデル)を利用し、ナトリウムチャネルの変化特性を組み込んだ心筋細胞を連結させ仮想心電図を構築すると、筋緊張性ジストロフィー症ではQRS幅の延長を確認でき、臨床像と一致する所見であった。筋緊張性ジストロフィー症例で認められるCTGリピートの延長が心筋ナトリウムチャネルの選択的スプライシングに関与するMBNLの作用を阻害し、loss of function型の機能を有する胎児型のナトリウムチャネルが発現し続ける事で心伝導障害が発症することが明らかとなった。
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Research Progress Status |
26年度が最終年度であるため、記入しない。
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Strategy for Future Research Activity |
26年度が最終年度であるため、記入しない。
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Report
(2 results)
Research Products
(48 results)
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[Journal Article] Gain-of-function KCNH2 mutations in patients with Brugada syndrome.2014
Author(s)
Wang Q, Ohno S, Ding WG, Fukuyama M, Miyamoto A, Itoh H, Makiyama T, Wu J, Bai J, Hasegawa K, Shinohara T, Takahashi N, Shimizu A, Matsuura H, Horie M.
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Journal Title
J Cardiovasc Electrophysiol.
Volume: 25
Issue: 5
Pages: 522533-522533
DOI
Related Report
Peer Reviewed / Open Access / Acknowledgement Compliant
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[Journal Article] Long QT Syndrome Type8: Novel CACNA1C Mutations Causing QT Prolongation and Variant Phenotypes.2014
Author(s)
Fukuyama M, Wang Q, Kato K, Ohno S, Ding WG, Toyoda F, Itoh H, Kimura H, Makiyama T, Ito M, Matsuura H, Horie M.
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Journal Title
Europace.
Volume: in press
Issue: 12
Pages: 1828-37
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] A Kir3.4 mutation causes Andersen-Tawil syndrome by an inhibitory effect on Kir2.1.2014
Author(s)
Kokunai Y, Nakata T, Furuta M, Sakata S, Kimura H, Aiba T, Yoshinaga M, Osaki Y, Nakamori M, Itoh H, Sato T, Kubota T, Kadota K, Shindo K, Mochizuki H, Shimizu W, Horie M, Okamura Y, Ohno K, Takahashi MP.
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Journal Title
Neurology
Volume: 82
Pages: 1058-64
Related Report
Peer Reviewed
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[Journal Article] Cardiac channelopathies associated with infantile fatal ventricular arrhythmias: from the cradle to the bench.2014
Author(s)
Kato K, Makiyama T, Wu J, Ding WG, Kimura H, Naiki N, Ohno S, Itoh H, Nakanishi T, Matsuura H, Horie M.
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Journal Title
J Cardiovasc Electrophysiol
Volume: 25
Issue: 1
Pages: 66-73
DOI
Related Report
Peer Reviewed
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[Journal Article] A novel KCNQ1 missense mutation identified in a patient with juvenile-onset atrial fibrillation causes constitutively open IKs channels.2014
Author(s)
Hasegawa K, Ohno S, Ashihara T, Itoh H, Ding WG, Toyoda F, Makiyama T, Aoki H, Nakamura Y, Delisle BP, Matsuura H, Horie M.
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Journal Title
Heart Rhythm
Volume: 11
Issue: 1
Pages: 67-75
DOI
Related Report
Peer Reviewed
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[Journal Article] Genetic background of catecholaminergic polymorphic ventricular tachycardia in Japan.2013
Author(s)
Kawamura M, Ohno S, Naiki N, Nagaoka I, Dochi K, Wang Q, Hasegawa K, Kimura H, Miyamoto A, Mizusawa Y, Itoh H, Makiyama T, Sumitomo N, Ushinohama H, Oyama K, Murakoshi N, Aonuma K, Horigome H, Honda T, Yoshinaga M, Ito M, Horie M.
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Journal Title
Circ J
Volume: 77
Pages: 1705-13
NAID
Related Report
Peer Reviewed
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[Presentation] The genetics underlying the acquired long QT syndrome. Impact on management2015
Author(s)
Itoh H, Spazzolini C, Crotti L, Aiba T, Denjoy I, Fressart V, Hayashi K, Nakajima T, Ohno S, Makiyama T, Wu J, Hasegawa K, Mastantuono E, Dagradi F, Pedrazzini M, Yamagishi M, Berthet M, Murakami Y, Shimizu W, Guicheney P, Schwartz PJ, Horie M
Organizer
Heart Rhythm Society’s 36th Annual Scientific Sessions
Place of Presentation
Boston,アメリカ合衆国
Year and Date
2015-05-13 – 2015-05-15
Related Report
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[Presentation] Pregnancy in the Congenital Long-QT Syndrome: Efficacy and Safety of Beta-Blocker Therapy for Prevention of Lethal Ventricular Arrhythmias2015
Author(s)
Ishibashi K, Aiba T, Sakaguchi H, Miyazaki A, Kamiya C, Yamauchi T, Ito H, Ohno S, Motomura H, Ogawa T, Goto H, Watanabe H, Yoshimatsu J, Kamakura S, Miyamoto Y, Shiraishi I, Yasuda S, Ogawa H, Horie M, Shimizu W, Kusano K
Organizer
The 79th Annual Scientific Meeting of the Japanese Circulation Society
Place of Presentation
Osaka
Year and Date
2015-04-24 – 2015-04-26
Related Report
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[Presentation] Electrophysiological Properties of L-type Calcium Channels in Human Induced Pluripotent Stem Cells-Derived Cardiomyocytes2015
Author(s)
Harita T, Makiyama T, Sasaki K, Hayano M, Nishiuchi S, Yamamoto Y, Kohjitani H, Chen J, Wuriyanghai Y, Ohno S, Ito H, Yoshida Y, Horie M, Kimura T
Organizer
The 79th Annual Scientific Meeting of the Japanese Circulation Society
Place of Presentation
Osaka
Year and Date
2015-04-24 – 2015-04-26
Related Report
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[Presentation] Genetics in acquired long QT syndrome2014
Author(s)
Pedrazzini M, Itoh H, Crotti L, Aiba T, Denjoy I, Fressart V, Hayashi K, Nakajima T, Ohno S, Makiyama T, Wu J, Hasegawa K, Mastantuono E, Dagradi F, Yamagishi M, Berthet M, Shimizu W, Guicheney P, Schwartz PJ, Horie M
Organizer
ESHG 2014
Place of Presentation
Milano,イタリア共和国
Year and Date
2014-05-31 – 2014-06-03
Related Report
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[Presentation] Asymmetry of parental origin in Long QT syndrome.2013
Author(s)
Itoh H, Berthet M, Fressart V, Denjoy I , Maugenre S, Klug D, Mizusawa Y, Makiyama T, Hofman N, Husemann A, Shimizu W, Wilde AA , Schulze-Bahr E, Horie M, du Montcel ST, Guicheney P.
Organizer
European Human Genetics Conference
Place of Presentation
Paris, France
Related Report
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[Presentation] Novel CACNA1C mutations in Long QT syndrome patients- The subtype of Long QT syndrome type 8.2013
Author(s)
Fukuyama M, Wang Q, Kato K, Ohno S, Kimura H, Makiyama T, Itoh H, Ito M, Matsuura H, Horie M.
Organizer
Denis Escande Symposium
Place of Presentation
Amsterdam, the Netherlands
Related Report
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[Presentation] Altered splicing of cardiac sodium channel might be responsible for cardiac conduction defects in myotonic dystrophy.2013
Author(s)
Kokunai Y, Kino Y, Li M, Itoh H, Nakamori M, Kimura T, Matsumura T, Fujimura H, Nukina N, Sakoda S, Horie M, Imoto K, Ishiura S, Swanson MS, Charlet-Berguerand N, Takahashi MP.
Organizer
the 9th International Myotonic Dystrophy Consortium
Place of Presentation
Basque, Spain
Related Report
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