Development of strategy for treatment of cardiavc failure based on the nderstanding of pathogenesis and gene abnormalities

• Project/Area Number: 25293181
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Kimura Akinori 東京医科歯科大学, 難治疾患研究所, 教授 (60161551)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥18,460,000 (Direct Cost: ¥14,200,000、Indirect Cost: ¥4,260,000); Fiscal Year 2015: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2014: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2013: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000)
• Keywords: 遺伝子 / 遺伝学 / ゲノム / 循環器・高血圧 / 生体分子

Outline of Final Research Achievements

In this study, identification of gene abnormalities in hereditary cardiomyopathy and their pathogenesis were invesigated. It was revealed that the increased calcium sensitivity could directly cause hypertrophic cardiomyopathy in a mouse model and its pathogenesis was inhibited by a ROCK2 inhibirtor. In addition, molecular mechanisms for gender differences in dilated cardiomyopathy caused by lamin A/C gene mutations was found to involve transport of androgen receptor with FHL2 resulting in SRF-mediated expression of genes for cardiac remodeling. Moreover, several novel disease genes for hereditary cardiomyopathy were identified by a linkage study in a large multiplex family with hypertrophic cardiomyaopathy and by candidate gene approaches for hypertrophic cardiomyopathy and dilated cardiomyopathy. Functional abnormalities caused by the mutations in these novel disease genes were also investigated to reveal the molecular pathogenesis of cardiomyopathies.

Research Products

• [Int'l Joint Research] Institut Myologie(フランス)
• [Journal Article] Molecular genetics and pathogenesis of cardiomyopathy (2016)
  • Author(s): Kimura A
  • Journal Title: J Hum Genet Volume: 61 Issue: 1 Pages: 40-51
  • DOI: 10.1038/jhg.2015.83
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Genetic defects in a His-Purkinje system transcription factor, IRX3, cause lethal cardiac arrhythmias. (2016)
  • Author(s): Koizumi A, Sasano T, Kimura W, Miyamoto Y, Aiba T, Ishikawa T, Nogami A, Fukamizu S, Sakurada H, Takahashi Y, Nakamura H, Ishikura T, Koseki H, Arimura T, Kimura A, Hirao K, Isobe M, Shimizu W, Miura N, Furukawa T.
  • Journal Title: European Heart Journal. Volume: 37 (18) Issue: 18 Pages: 1469-1475
  • DOI: 10.1093/eurheartj/ehv449
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Hypertrophic cardiomyopathy accompanied by spinocerebellar atrophy with a novel mutation in troponin I gene (2016)
  • Author(s): Kawai H, Morimoto S, Takakuwa Y, Ueda A, Inada K, Sarai M, Arimura T, Mutoh T, Kimura A, Ozaki Y
  • Journal Title: Int Heart J Volume: -
  • NAID: 130006895905
  • Peer Reviewed
• [Journal Article] Familial hypertrophic obstructive cardiomyopathy with the GLA E66Q mutation and Zebra body (2016)
  • Author(s): Oikawa M, Sakamoto N, Kobayashi A, Suzuki A, Yoshihisa A. Yamaki T, Nakazato K, Suzuki H, Saitoh S, Kiko Y, Nakano H, Hayashi T, Kimura A, Takeishi Y
  • Journal Title: BMC Cardiovasc Dis Volume: -
  • Peer Reviewed
• [Journal Article] A novel mutation in alpha-myosin heavy chain gene is associated with sick sinus syndrome (2015)
  • Author(s): Ishikawa T, Jou CJ, Nogami A, Kowase S, Arrington CB, Barnett SM, Harrell DT, Arimura T, Tsuji Y, Kimura A, Makita N
  • Journal Title: Circ Arrhythm Electrophysiol Volume: 8 Issue: 2 Pages: 400-108
  • DOI: 10.1161/circep.114.002534
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Screening of sarcomere gene mutations in young athletes with abnormal findings in electrocardiography: identification of a MYH7 mutation and MYBPC3 mutations. (2015)
  • Author(s): Kadota C, Arimura T, Hayashi T, Naruse TK, Kawai S, Kimura A
  • Journal Title: Journal of human genetics Volume: 60 Issue: 10 Pages: 641-645
  • DOI: 10.1038/jhg.2015.81
  • NAID: 40020621514
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] A novel de novo mutation of beta-cardiac myosin heavy chain gene found in a 12-year-old boy with hypertrophic cardiomyopathy (2014)
  • Author(s): Okada S, Suzuki Y, Arimura T, Kimura A, Narumi H, Hasegawa S
  • Journal Title: J Genet Volume: 93 Issue: 2 Pages: 557-560
  • DOI: 10.1007/s12041-014-0414-8
  • Peer Reviewed
• [Journal Article] Novel calmodulin mutations associated with congenital arrhythmia susceptibility. (2014)
  • Author(s): Makita N, Tsuji Y（39人中21番目）et al
  • Journal Title: Circ Cardiovasc Genet. Volume: 7 Issue: 4 Pages: 466-474
  • DOI: 10.1161/circgenetics.113.000459
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] ET-1 induces myofibrillar disarray and contractile vector in hypertrophic cardiomyopathy-iPS cell-derived cardiomyocytes (2014)
  • Author(s): Tanaka A, Yuasa S, Mearini G, Egashira T, Seki T, Kodaira M, Kusumoto D, Kuroda Y, Okata S, Suzuki T, Arimura T, Makino S, Kimura K, Kimura A, Furukawa T, Carrier L, Nobe K, Fukuda K
  • Journal Title: J Am Heart Assoc Volume: 3 Issue: 6 Pages: 1-25
  • DOI: 10.1161/jaha.114.001263
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Impact of ANKRD1 mutations associated with hypertrophic cardiomyopathy on contraction parameters of engineered heart tissue (2013)
  • Author(s): Crocini C, Arimura T, Reischmann S, Eder A, Braren I, Hansen A, Eschenhagen T, Kimura A, Carrier L
  • Journal Title: Basic Res Cardiol Volume: (in press) Issue: 3 Pages: 349-349
  • DOI: 10.1007/s00395-013-0349-x
  • Peer Reviewed
• [Journal Article] Nuclear accumulation of androgen receptor in gender difference of dilated cardiomyopathy due to lamin A/C mutations (2013)
  • Author(s): Arimura T, Onoue K, Takahashi-Tanaka Y, Ishikawa T, Kuwahara M, Setou M, Shigenbu S, Yamaguchi K, Bertrand AT, Machida N, Takayama K, Fukusato M, Tanaka R, Somekawa T, Nakano T, Yamane Y, Kuba K, Imai Y, Saito N, Bonne G, Kimura A
  • Journal Title: Cardiovasc Res Volume: (in press) Issue: 3 Pages: 382-394
  • DOI: 10.1093/cvr/cvt106
  • Peer Reviewed
• [Journal Article] Dilated Cardiomyopathy-Associated <i>FHOD3</i> Variant Impairs the Ability to Induce Activation of Transcription Factor Serum Response Factor (2013)
  • Author(s): Arimura T, Takeya R, Ishikawa T, Yamano T, Matsuo A, Tatsumi T, Nomura T, Sumimoto H, Kimura A.
  • Journal Title: Circulation Journal Volume: 77 Issue: 12 Pages: 2990-2996
  • DOI: 10.1253/circj.CJ-13-0255
  • NAID: 10031203585
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed
• [Presentation] 心筋症の遺伝学 (2015)
  • Author(s): 木村彰方
  • Organizer: 日本人類遺伝学会第60回大会
  • Place of Presentation: 京王プラザホテル（東京）
  • Year and Date: 2015-10-17
• [Presentation] 若年及び小児の肥大型、拘束型心筋症の遺伝子変異解析 (2015)
  • Author(s): 林丈晴、谷本幸介、木村彰方
  • Organizer: 日本人類遺伝学会第60回大会
  • Place of Presentation: 京王プラザホテル（東京）
  • Year and Date: 2015-10-15
• [Presentation] 心室中部閉塞型肥大型心筋症の病因変異探索 (2015)
  • Author(s): 稲垣夏子、林丈晴、武井康悦、近森大志郎、山科章、木村彰方
  • Organizer: 日本人類遺伝学会第60回大会
  • Place of Presentation: 京王プラザホテル（東京）
  • Year and Date: 2015-10-15
• [Presentation] 心室中部閉塞型肥大型心筋症の 病因変異探索. (2014)
  • Author(s): 稲垣夏子、林丈晴、武井康悦、近森大志郎、谷本幸介、山科章、木村彰方
  • Organizer: 日本人類遺伝学会第59 回 大会
  • Place of Presentation: タワーホール船堀（東京都江戸川区）
  • Year and Date: 2014-11-20
• [Presentation] 遺伝性心筋症変異スクリーニングシステムの構築 (2014)
  • Author(s): 林丈晴、谷本幸介、木村彰方
  • Organizer: 日本人類遺伝学会第59 回 大会
  • Place of Presentation: タワーホール船堀（東京都江戸川区）
  • Year and Date: 2014-11-20