新たな分子病因の解明に基づく心筋症と心不全病態の治療戦略に関する研究

2009 年度 研究成果報告書

• 研究課題/領域番号: 19390208
• 研究種目: 基盤研究(B)
• 配分区分: 補助金
• 応募区分: 一般
• 研究分野: 循環器内科学
• 研究機関: 東京医科歯科大学
• 研究代表者: 木村 彰方 東京医科歯科大学, 難治疾患研究所, 教授 (60161551)
• 研究期間 (年度): 2007 – 2009
• キーワード: 心筋症 / 遺伝子変異 / サルコメア / 筋収縮 / カルシウム感受性 / Z帯

研究概要

新規の心筋症原因遺伝子としてCARP変異を同定し、その機能異常を解明した。また、拡張型心筋症の原因となるZASP変異は、糖代謝に関わる酵素PGM1の局在心筋異常を生じることを見出した。一方、心筋ミオシンフォスファターゼの抑制サブユニットM21は心筋におけるM110のリン酸化を制御することを明らかにした。また、拡張型心筋症モデルマウスを用いて、心筋収縮のカルシウム感受性制御による心不全病態抑制を示した。

研究成果

• [雑誌論文] A global in vivo Drosophila RNAi screen identifies NOT3 as a conserved regulator of heart function (2010)
  • 著者名/発表者名: Neelyl GG, Kuba K, Cammarato A, Isobe K, Amann S, Zhang L, Murata M, Elmen L, Gupta V, Arora S, Sarangi R, Dan D, Fujisawa S, Usami T, Xia CP, Keene AC, Alayari NA, Yamakawa H, Elling U, Berger C, Novatchkova M, Koglgruber R, Fukuda K, Nishina H, Isobe M, Pospisilik JA, Imai Y, Pfeufer A, Hicks A, Pramstaller PP, Subramaniam S, Kimura A, Ocorr K, Bodmer R, Penninger JM.
  • 雑誌名: Cell 141(1) ページ: 142-153
• [雑誌論文] Molecular basis of hereditary cardiomyopathy : abnormalities in calcium sensitivity, stretch response, stress response and beyond (2010)
  • 著者名/発表者名: Kimura A.
  • 雑誌名: J Hum Genet 55(2) ページ: 81-90
• [雑誌論文] Improvement of left ventricular dysfunction and of survival prognosis of dilated cardiomyopathy by administration of calcium sensitizer SCH00013 in a mouse model (2010)
  • 著者名/発表者名: Arimura T, Sato R, Machida N, Bando H, Zhang DY, Morimoto S, Tanaka R, Yamane Y, Bonne G, Kimura A.
  • 雑誌名: J Am Coll Cardiol 55(14) ページ: 1503-1505
• [雑誌論文] A novel protein found in the I bands of myofibrils is produced by alternative splicing of the DLST gene (2010)
  • 著者名/発表者名: Matuda S, Arimura T, Kimura A, Takekura H, Ohta S, Nakano K.
  • 雑誌名: Biochim Biophys Acta 1800(1) ページ: 31-39
• [雑誌論文] Novel mechanisms of trafficking defect caused by KCNQ1 mutations found in long QT syndrome (2009)
  • 著者名/発表者名: Sato A, Arimura T, Makita N, Ishikawa T, Aizawa Y, Ushinohama H, Aizawa Y, Kimura A.
  • 雑誌名: J Biol Chem 284(50) ページ: 35122-35133
• [雑誌論文] Validation of eight genetic risk factors in East Asian populations replicated the association of BRAP with coronary artery disease (2009)
  • 著者名/発表者名: Hinohara K, Ohtani H, Nakajima T, Sasaoka T, Sawabe M, Lee BS, Ban J, Park JE, Izumi T, Kimura A.
  • 雑誌名: J Hum Genet 54(11) ページ: 642-646
• [雑誌論文] Validation of the association between AGTRL1 polymorphism and coronary artery disease in Japanese and Korean populations (2009)
  • 著者名/発表者名: Hinohara K, Nakajima T, Sasaoka T, Sawabe M, Lee BS, Ban J, Park JE, Izumi T, Kimura A.
  • 雑誌名: J Hum Genet 54(9) ページ: 554-556
• [雑誌論文] Megakaryoblastic leukemia factor-1gene in the susceptibility to coronary artery disease (2009)
  • 著者名/発表者名: Hinohara K, Nakajima T, Yasunami M, Houda S, Sasaoka T, Yamamoto K, Lee BS, Shibata H, Takahashi TY, Arimura T, Sato A, Naruse T, Ban J, Inoko H, Yamada Y, Sawabe M, Park JE,, Izumi T, Kimura A.
  • 雑誌名: Hum Genet 126(4) ページ: 539-547
• [雑誌論文] Cardiac ankyrin repeat protein gene (ANKRD1) mutations in hypertrophic cardiomyopathy (2009)
  • 著者名/発表者名: Arimura T, Bos MJ, Sato A, Kubo T, Okamoto H, Nishi H, Harada H, Koga Y, Moulik M, Doi YL, Towbin JA, Ackerman MJ, Kimura A.
  • 雑誌名: J Am Coll Cardiol 54(4) ページ: 334-342
• [雑誌論文] ANKRD-the gene encoding cardiac ankyrin repeat protein-is a novel dilated cardiomyopathy gene (2009)
  • 著者名/発表者名: Moulik M, Vatta M, Witt SH, Alora AM, Murphy RT, McKenna WJ, Boriek A, Oka K, Labeit S, Bowles NE, Arimura T, Kimura A, Towbin JA.
  • 雑誌名: J Am Coll Cardiol 54(4) ページ: 325-333
• [雑誌論文] Does a gene polymorphism predisposing to the intermediate phenotype predict the risk of disease? (2009)
  • 著者名/発表者名: Kimura A.
  • 雑誌名: Circ J. 73(6) ページ: 1016-1017
• [雑誌論文] Impaired binding of ZASP/Cypher with phosphoglucomutase 1 is associated with dilated cardiomyopathy (2009)
  • 著者名/発表者名: Arimura T, Inagaki N, Hayashi T, Shichi D, Sato A, Hinohara K, Vatta M, Towbin JA, Chikamori T, Yamashina A, Kimura A.
  • 雑誌名: Cardiovasc Res. 83(1) ページ: 80-88
• [雑誌論文] Replication studies for the association of PSMA6 polymorphism with coronary artery disease in East Asian populations (2009)
  • 著者名/発表者名: Hinohara K, Nakajima T, Sasaoka T, Sawabe M, Lee BS, Ban J, Park JE, Izumi T, Kimura A.
  • 雑誌名: J Hum Genet 54(4) ページ: 248-251
• [雑誌論文] Role of HCN4 channel in preventing ventricular arrhythmia (2009)
  • 著者名/発表者名: Ueda K, Hirano Y, Higashiuesato Y, Aizawa Y, Hayashi T, Inagaki N, Tana T, Ohya Y, Takishita S, Muratani H, Hiraoka M, Kimura A.
  • 雑誌名: J Hum Genet 54(2) ページ: 115-121
• [雑誌論文] HLA-DPB1 and NFKBIL1 may confer the susceptibility to chronic thromboembolic pulmonary hypertension in the absence of deep vein thrombosis (2009)
  • 著者名/発表者名: Kominami S, Tanabe N, Ota M, Naruse T, Katsuyama Y, Nakanishi N, Tomoike H, Sakuma M, Shirato K, Takahashi M, Shibata H, Yasunami M, Chen Z, Kasahara Y, Tatsumi K, Kuriyama T, Kimura A.
  • 雑誌名: J Hum Genet 54(2) ページ: 108-114
• [雑誌論文] Mutational analysis of fukutin gene in dilated cardiomyopathy and hypertrophic cardiomyopathy (2009)
  • 著者名/発表者名: Arimura T, Hayashi YK, Murakami T, Oya Y, Funabe S, Hirasawa EA, Hattori N, Nishino I, Kimura A.
  • 雑誌名: Circ J. 73(1) ページ: 158-161
• [雑誌論文] Molecular etiology and pathogenesis of hereditary cardiomyopathy (2008)
  • 著者名/発表者名: Kimura A.
  • 雑誌名: Circ J. 72(Suppl A) ページ: A38-48
• [雑誌論文] Replication of association between a chromosome 9p21 polymorphism with coronary artery disease in Japanese and Korean populations (2008)
  • 著者名/発表者名: Hinohara K, Nakajima T, Takahashi M, Hohda S, Sasaoka T, Nakahara K, Chida K, Sawabe M, Arimura T, Sato A, Lee BS, Ban J, Yasunami M, Park JE, Izumi T, Kimura A.
  • 雑誌名: J Hum Genet 53(4) ページ: 357-359
• [雑誌論文] High-density association study and nomination of susceptibility genes for hypertension in the Japanese national project (2008)
  • 著者名/発表者名: Kato N, Miyata T, Tabara Y, Katsuya T, Yanai K, Hanada H, Kamide K, Nakura J, Hohara K, Takeuchi F, Mano H, Yasunami M, Kimura A, Kita Y, Ueshima H, Nakamura T, Soma M, Hata A, Fujioka A, Kawano Y, Nakao K, Sekine A, Yoshida T, Nakamura Y, Saruta T, Ogihara T, Sugano S, Miki T, Tomoike H.
  • 雑誌名: Hum Mol Genet 17(4) ページ: 617-627
• [雑誌論文] Molecular etiology of idiopathic cardiomyopathy (2007)
  • 著者名/発表者名: Arimura T, Hayashi T, Kimura A.
  • 雑誌名: Acta Myologica 26(3) ページ: 153-158
• [雑誌論文] Interaction of BMP10 with Tcap may modulate the course of hypertensive cardiac hypertrophy (2007)
  • 著者名/発表者名: Nakano N, Hori H, Abe M, Shibata H, Arimura T, Sasaoka T, Sawabe M, Chida K, Arai T, Nakahara K, Kubo T, Sugimoto K, Katsuya T, Ogihara T, Doi Y, Izumi T, Kimura A.
  • 雑誌名: Am J Physiol Heart Card Physiol 293(6) ページ: H3396-H3403
• [雑誌論文] Impaired heart contractility in Apelin gene-deficient mice associated with aging and pressure overload (2007)
  • 著者名/発表者名: Kuba K, Zhang L, Imai Y, Arab S, Chen M, Maekawa Y, Leschnik M, Leibbrabdt A, Makovic M, Schwaighofer J, Beetz N, Musialek R, Neely GG, Komnenoviv V, Kolm U, Metzler B, Ricci R, Hara H, Meixner A, Nghiem M, Chen X, Dawood F, Wong KM, Sarao R, Cukerman E, Kimura A, Hein L, Thalhammer J, Liu PP, Penninger JM.
  • 雑誌名: Circ Res. 101(4) ページ: e32-e42
• [雑誌論文] Structural analysis of obscurin gene in hypertrophic cardiomyopathy (2007)
  • 著者名/発表者名: Arimura T, Matsumoto Y, Okazaki O, Hayashi T, Takahashi M, Inagaki N, Hinohara K, Ashizawa N, Yano K, Kimura A.
  • 雑誌名: Biochem Biophys Res Commun 362(2) ページ: 281-287
• [雑誌論文] Synergistic contribution of CD14 and HLA loci to the susceptibility to Buerger disease (2007)
  • 著者名/発表者名: Chen Z, Takahashi M, Naruse T, Nakajima T, Chen YW, Inoue Y, Ishilkawa I, Iwai T, Kimura A.
  • 雑誌名: Hum Genet 122(3-4) ページ: 367-372
• [雑誌論文] Laminin alpha 4 and integrin-linked kinase mutations cause human cardiomyopathy via simultaneous defects in cardiomyocytes and in endothelial cells (2007)
  • 著者名/発表者名: Knoll R, Postel R, Wang J, Kraetzner R, Hennecke G, Vacaru AM, Vakeel P, Schubert C, Murthy K, Rana BK, Dieter K, Gudrun K, Schaefer K, Hayashi T, Holm T, Kimura A, Schork N, Toliat MR, Nuemberg P, Schultheiss P, Schaper W, Schaper J, Bos E, Hertog JD, van Eeden F, Peters P, Hasenfuss G, Chien KR, Bakkers J.
  • 雑誌名: Circulation 116(5) ページ: 515-525
• [雑誌論文] A novel mutation in KCNQ1 associated with a potent dominant negative effect as the basis for the LQT1 form of the long QT syndrome (2007)
  • 著者名/発表者名: Aizawa Y, Ueda K, Scornik F, Cordeiro JM, Wu Y, Desai M, Guerchicoff A, Pollevick GD, Sicouri S, Sato A, Nagata Y, Iesaka Y, Aizawa Y, Kimura A, Hiraoka M, Anzelevitch C.
  • 雑誌名: J Cardiovasc Electrophysiol 18(9) ページ: 972-977
• [雑誌論文] Structural analysis of four and half LIM protein-2 in dilated cardiomyopathy (2007)
  • 著者名/発表者名: Arimura T, Hayashi T, Matsumoto Y, Shibata H, Hiroi S, Nakamura T, Inagaki N, Hinohara K, Takahashi M, Itoh-Satoh M, Bonne G, Schwartz K, Kimura A.
  • 雑誌名: Biochem Biophys Res Commun 357(1) ページ: 162-167
• [雑誌論文] Long-term outcome of four Korean families with hypertrophic cardiomyopathy caused by four different mutations
  • 著者名/発表者名: Choi JO, You CW, Nah JC, Park JR, Lee BS, Choi BY, Cho BY, Lee SC, Park SW, Kimura A, Park JE.
  • 雑誌名: Clin Cardiol (In Press)
• [雑誌論文] Losartan inhibits LPS-induced inflammatory signaling by PPAR-gamma-dependent mechanism in human THP-1 macrophage
  • 著者名/発表者名: An J, Nakajima T, Kuba K, Kimura A.
  • 雑誌名: Hypertension Res. (In Press)
• [学会発表] Molecular analysis of arrhythmia associated with HCN4 mutations (2009)
  • 著者名/発表者名: Kimura A, Ueda K, Aizawa Y, Sato A, Arimura T, Makita N, Ishikawa T, Aizawa Y
  • 学会等名: 12th Cardiovascular Genomics and Atherosclerosis Symposium
  • 発表場所: Seoul
  • 年月日: 2009-10-17
• [学会発表] テストステロンはラミンA/C遺伝子変異LmnaH222P/H222Pマウスにおける拡張型心筋症を増悪させる (2009)
  • 著者名/発表者名: 有村卓朗, 木村彰方
  • 学会等名: 第54回日本人類遺伝学会
  • 発表場所: 東京
  • 年月日: 2009-09-24
• [学会発表] Identification of a novel gene for hypertrophic cardiomyopathy (2009)
  • 著者名/発表者名: Arimura T, Bos JM, Sato A, Kubo T, Okamoto H, Nishi H, Harada H, Koga Y, Doi YL, Ackerman MJ, Kimura A
  • 学会等名: 第73回日本循環器学会学術集会
  • 発表場所: 大阪
  • 年月日: 2009-03-22
• [学会発表] Overview : Molecular pathogenesis of hereditary cardiomyopathy (2008)
  • 著者名/発表者名: Kimura A
  • 学会等名: 11th Cardiovascular Genomics and Atherosclerosis Symposium
  • 発表場所: Seoul
  • 年月日: 2008-11-01
• [学会発表] Genome-wide association study to identify the disease-associated genes for coronary artery disease (2008)
  • 著者名/発表者名: Kimura A
  • 学会等名: 11th Cardiovascular Genomics and Atherosclerosis Symposium
  • 発表場所: Seoul
  • 年月日: 2008-10-31
• [学会発表] CARPおよびタイチンN2A領域内変異は肥大型心筋症を引き起こす (2008)
  • 著者名/発表者名: 有村卓朗, 佐藤光希, 久保亨, 岡本洋, 西宏文, 原田晴仁, 古賀義則, 土居義典, 木村彰方
  • 学会等名: 第53回日本人類遺伝学会
  • 発表場所: 横浜
  • 年月日: 2008-09-28
• [学会発表] Testicular hormone accelerates the development and progress of dilated cardiomyopathy in an animal model (2008)
  • 著者名/発表者名: Arimura T, Kimura A
  • 学会等名: 第73回日本循環器学会学術集会
  • 発表場所: 福岡
  • 年月日: 2008-03-29
• [学会発表] 難治性循環器疾患の病因と病態形成機構の解明に向けて (2007)
  • 著者名/発表者名: 木村彰方
  • 学会等名: 第16回日本組織適合性学会大会
  • 発表場所: 京都
  • 年月日: 2007-09-10
• [学会発表] Molecular pathogenesis of hereditary cardiomyopathy (2007)
  • 著者名/発表者名: Kimura A
  • 学会等名: The 41st Lake Kawaguchi Conference of Cardiology
  • 発表場所: Fukuoka
  • 年月日: 2007-07-29
• [学会発表] Genome-wide microsatellite association study to identify the disease-related loci for myocardial infarction (2007)
  • 著者名/発表者名: Kimura A
  • 学会等名: The 10th Cardiovascular Genomics and Atherosclerosis Symposium
  • 発表場所: Seoul
  • 年月日: 2007-04-10
• [学会発表] Molecular etiology of hypertrophic cardiomyopathy (2007)
  • 著者名/発表者名: Kimura A
  • 学会等名: The 1st International Congress of Cardiomyopathies and Heart Failure
  • 発表場所: Kyoto
  • 年月日: 2007-03-12