Troponin T replacement can be a new therapy for dilated cardiomyopathy

• Project/Area Number: 16K15184
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: General physiology
• Research Institution: Jikei University School of Medicine
• Principal Investigator: Minamisawa Susumu 東京慈恵会医科大学, 医学部, 教授 (40257332)
• Co-Investigator(Kenkyū-buntansha): 赤池 徹 東京慈恵会医科大学, 医学部, 講師 (20647101)
• Research Collaborator: 久我 和寛 ; 藤本 義隆
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 心筋症 / 遺伝子治療 / 遺伝子異常 / 筋原線維 / トロポニン / 突然死 / 乳幼児 / 心不全

Outline of Final Research Achievements

The goal of this study is to develop a radical treatment for juvenile-onset dilated cardiomyopathy (DCM) with extremely poor prognosis. We hypothesized that "mutant troponin T can be replaced by overexpression of normal troponin T" and examined it using a juvenile onset DCM model mouse. We aimed to identify signaling molecules and regulatory mechanisms that act in progressive pathogenesis in children. In addition, structural and functional abnormalities of the myocardium in the very early stage of juvenile DCM mice were investigated, We found that the ΔK210-KI mouse is useful as a model for juvenile-onset DCM and is a good model for developing therapy for DCM. This study provided the fundamental basis for development of new DCM therapy.

Academic Significance and Societal Importance of the Research Achievements

本研究はトロポニン複合体を筋膜を温存した心筋細胞・組織においても置換可能であるという仮説を、実際の拡張型心筋症モデルを用いて検証する点に学術的特色がある。その検証の結果、ΔK210に由来する心筋細胞のカルシウム感受性低下を是正することが出来、心筋症の構造的・機能的異常を改善し得る可能性がある。また、若年型拡張型心筋症の極めて初期段階での異常を調べることによって、病態悪化に働くシグナル分子や調節機構を同定し、心移植に代わる新たな治療法の開発に繋がる。本研究は心移植が難しく、極めて予後不良である若年型拡張型心筋症への根本的治療法の開発につながり、臨床医学的にも意義深いと考える。

Research Products

• [Int'l Joint Research] University of California, Los Angels(米国)
• [Journal Article] The serine/threonine-protein kinase/endoribonuclease IRE1α protects the heart against pressure overload?induced heart failure (2018)
  • Author(s): Steiger DeAnna、Yokota Tomohiro、Li Jin、Ren Shuxun、Minamisawa Susumu、Wang Yibin
  • Journal Title: Journal of Biological Chemistry Volume: 293 Issue: 25 Pages: 9652-9661
  • DOI: 10.1074/jbc.ra118.003448
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Truncated dystrophin ameliorates the dystrophic phenotype of mdx mice by reducing sarcolipin-mediated SERCA inhibition (2018)
  • Author(s): Tanihata Jun、Nagata Tetsuya、Ito Naoki、Saito Takashi、Nakamura Akinori、Minamisawa Susumu、Aoki Yoshitsugu、Ruegg Urs T.、Takeda Shin'ichi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 505 Issue: 1 Pages: 51-59
  • DOI: 10.1016/j.bbrc.2018.09.039
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pyruvate dehydrogenase activation precedes the down-regulation of fatty acid oxidation in monocrotaline-induced myocardial toxicity in mice (2018)
  • Author(s): Nakai Gaku、Shimura Daisuke、Uesugi Ken、Kajimura Ichige、Jiao Qibin、Kusakari Yoichiro、Soga Tomoyoshi、Goda Nobuhito、Minamisawa Susumu
  • Journal Title: Heart and Vessels Volume: 34 Issue: 3 Pages: 545-555
  • DOI: 10.1007/s00380-018-1293-3
  • Peer Reviewed / Open Access
• [Journal Article] A Sarcoplasmic Reticulum Localized Protein Phosphatase Regulates Phospholamban Phosphorylation and?Promotes Ischemia Reperfusion Injury?in?the Heart (2017)
  • Author(s): Akaike Toru、Du Na、Lu Gang、Minamisawa Susumu、Wang Yibin、Ruan Hongmei
  • Journal Title: J Am Coll Cardiol Basic Trans Science Volume: 2 Issue: 2 Pages: 160-180
  • DOI: 10.1016/j.jacbts.2016.12.002
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The effects of heat stress on morphological properties and intracellular signaling of denervated and intact soleus muscles in rats (2017)
  • Author(s): Ohira Takashi、Higashibata Akira、Seki Masaya、Kurata Yoichi、Kimura Yayoi、Hirano Hisashi、Kusakari Yoichiro、Minamisawa Susumu、Kudo Takashi、Takahashi Satoru、Ohira Yoshinobu、Furukawa Satoshi
  • Journal Title: Physiol Rep Volume: 5 Issue: 15 Pages: e13350-e13350
  • DOI: 10.14814/phy2.13350
  • NAID: 120007134851
  • Peer Reviewed / Open Access
• [Journal Article] Time-dependent effects of ipragliflozin on behaviour and energy homeostasis in normal and type 2 diabetic rats: continuous glucose telemetry analysis. (2017)
  • Author(s): Iuchi H, Sakamoto M, Matsutani D, Suzuki H, Kayama Y, Takeda N, Minamisawa S, Utsunomiya K.
  • Journal Title: Sci Rep Volume: 22 Issue: 1 Pages: 351-354
  • DOI: 10.1038/s41598-017-12106-y
  • Peer Reviewed / Open Access
• [Journal Article] Tissue thrombin is associated with the pathogenesis of dilated cardiomyopathy. (2016)
  • Author(s): Ito K, Hongo K, Date T, Ikegami M, Hano H, Owada M, Morimoto S, Kashiwagi Y, Katoh D, Yoshino T, Yoshii A, Kimura H, Nagoshi T, Kajimura I, Kusakari Y, Akaike T, Minamisawa S, Ogawa K, Minai K, Ogawa T, Kawai M, Yajima J, Matsuo S, Yamane T, Taniguchi I, Morimoto S, Yoshimura M.
  • Journal Title: Int J Cardiol. Volume: 228 Pages: 821-827
  • DOI: 10.1016/j.ijcard.2016.11.176
  • Peer Reviewed / Open Access
• [Journal Article] Impairment of excitation-contraction coupling in right ventricular hypertrophied muscle with fibrosis induced by pulmonary artery banding. (2016)
  • Author(s): Kusakari Y, Urashima T, Shimura D, Amemiya E, Miyasaka G, Yokota S, Fujimoto Y, Akaike T, Inoue T, Minamisawa S．
  • Journal Title: PLoS One. Volume: 12 Issue: 1 Pages: e0169564-e0169564
  • DOI: 10.1371/journal.pone.0169564
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Nano-imaging of the beating mouse heart in vivo: Importance of sarcomere dynamics, as opposed to sarcomere length per se, in the regulation of cardiac function. (2016)
  • Author(s): Kobirumaki-Shimozawa F, Oyama K, Shimozawa T, Mizuno A, Ohki T, Terui T, Minamisawa S, Ishiwata S, Fukuda N
  • Journal Title: Journal of General Physiology Volume: 147 Issue: 1 Pages: 53-62
  • DOI: 10.1085/jgp.201511484
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Low Cardiac Output Leads Hepatic Fibrosis in Right Heart Failure Model Rats. (2016)
  • Author(s): Fujimoto Y, Urashima T, Shimura D, Ito R, Kawachi S, Kajimura I, Akaike T, Kusakari Y, Fujiwara M, Ogawa K, Goda N, Ida H, Minamisawa S
  • Journal Title: PLoS One Volume: 11(2) Issue: 2 Pages: e0148666-e0148666
  • DOI: 10.1371/journal.pone.0148666
  • Peer Reviewed / Open Access
• [Journal Article] New mouse model of skeletal muscle atrophy using spiral wire immobilization (2016)
  • Author(s): Onda A, Kono H, Jiao Q, Akimoto T, Miyamoto T, Sawada Y, Suzuki K, Kusakari Y, Minamisawa S, Fukubayashi T
  • Journal Title: Muscle Nerve Volume: 54 Issue: 4 Pages: 788
  • DOI: 10.1002/mus.25202
  • Peer Reviewed / Open Access
• [Journal Article] Sarcolipin in atrium-specific gene targeting (2016)
  • Author(s): Shimura D, Nakano A, Minamisawa S
  • Journal Title: Cardiovasc Regen Med Volume: 3
  • DOI: 10.14800/crm.1297
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Heterozygous deletion of sarcolipin maintains normal cardiac function. (2015)
  • Author(s): Shimura D, Kusakari Y, Sasano T, Nakashima Y, Nakai G, Jiao Q, Jin M, Yokota T, Ishikawa Y, Nakano A, Goda N, Minamisawa S.
  • Journal Title: Am J Physiol Heart Circ Physiol. Volume: 310(1) Issue: 1 Pages: 92-103
  • DOI: 10.1152/ajpheart.00411.2015
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Urine Connectin/Titin Is Increased in Patients After Heart Surgery with Cardiopulmonary Bypass. (2018)
  • Author(s): Tanihata J, Nishioka N, Inoue T, Bando K, Minamisawa S.
  • Organizer: Experimental Biology 2018
  • Int'l Joint Research
• [Presentation] Acute Diastolic Overstretch Causes Abrupt Inner Mitochondrial Collapsing of Isolated Rat Papillary Muscle. (2018)
  • Author(s): Nishioka N, Kusakari Y, Tanihata J, Minamisawa S.
  • Organizer: AHA Scientific Sessions 2018
  • Int'l Joint Research
• [Presentation] 心筋筋小胞体でのカルシウム再取り込み機構 (2017)
  • Author(s): 南沢 享
  • Organizer: 第94回日本生理学会大会
• [Presentation] 心筋過伸展による線維化関連因子発現変化 (2017)
  • Author(s): 碓井文雄, 山田祐揮，草刈洋一郎，南沢 享．
  • Organizer: 第94回日本生理学会大会
• [Presentation] 幼児期発症拡張型心筋症モデルとしてのトロポニンＴアミノ酸変異（ΔK210）ノックインマウス (2017)
  • Author(s): 南沢 享, 谷端 淳, 藤本義隆, 赤池 徹, 草刈洋一郎, 森本幸生．
  • Organizer: 第3回日本筋学会学術集会
• [Presentation] トロポニンＴアミノ酸変異（ΔK210）ノックインマウスは幼児期発症拡張型心筋症モデルとなり得る (2017)
  • Author(s): 南沢 享．
  • Organizer: 第65回日本心臓病学会学術集会
• [Presentation] Diastolic overstretch of isolated rat papillary muscle reduced force development and increased gene expression of fibrosis-related factors. (2017)
  • Author(s): Usui F, Yamada Y, Kusakari Y, Minamisawa S.
  • Organizer: 第134回成医会総会
• [Presentation] 乳頭筋過伸展による線維化関連因子の発現変化. (2017)
  • Author(s): 草刈洋一郎, 碓井文雄, 南沢 享.
  • Organizer: 第247回東京談話会
• [Presentation] 乳頭筋過伸展による線維化関連因子の発現変化とミトコンドリア内部の崩壊 (2017)
  • Author(s): 碓井文雄, 草刈洋一郎, 南沢 享.
  • Organizer: 筋生理の集い
• [Presentation] 筋ジストロフィー病態における細胞内Ca2+動態の解明と新たな治療法の開発 (2017)
  • Author(s): 谷端 淳，永田哲也，伊藤尚基，齊藤 崇，中村昭則，南沢 享，青木吉嗣，武田伸一.
  • Organizer: 第5回骨格筋生物学研究会
• [Presentation] 乳児期発症拡張型心筋症モデルとしてのトロポニンTアミノ酸変異 (ΔK210) ノックインマウス (2017)
  • Author(s): 南沢 享，谷端 淳，藤本義隆，赤池 徹，草刈洋一郎，森本幸生
  • Organizer: 日本筋学会第3回学術集会
• [Presentation] 筋ジストロフィー病態における細胞内Ca2+動態の解明と新たな治療法の開発 (2017)
  • Author(s): 谷端 淳，永田哲也，伊藤尚基，齊藤 崇，中村昭則，南沢 享，青木吉嗣，武田伸一
  • Organizer: 日本筋学会第3回学術集会
• [Presentation] Cytosolic Ca2+ dynamics through the SR is associated with pathology of muscular dystrophy. (2017)
  • Author(s): Tanihata J, Nagata T, Ito N, Saito T, Nakamura A, Minamisawa S, Aoki Y, Takeda S.
  • Organizer: 第3回Neo Vitamin D Workshop学術集会
  • Int'l Joint Research
• [Presentation] Troponin T amino acid mutation (ΔK210) knock-in mice as an infant-onset dilated cardiomyopathy model. (2017)
  • Author(s): Tanihata J, Fujimoto Y, Akaike T, Kusakari Y, Morimoto S, Minamisawa S.
  • Organizer: The 8th TAKAO International Symposium on Molecular Mechanisms of Cardioplumonary Disease
  • Int'l Joint Research
• [Presentation] 筋ジストロフィー病態における細胞内 Ca2+ 動態の解明と新規治療法の開発 (2017)
  • Author(s): 谷端 淳、永田哲也、青木吉嗣、南沢 享、武田伸一.
  • Organizer: 第247回生理学東京談話会
• [Presentation] GF23 promote cardiac fibrosis by activating FGFR1 in presence of TGF- stimulation (2016)
  • Author(s): Kuga K, Kusakari Y, Akaike T, Minamisawa S
  • Organizer: 第33回国際心臓研究学会日本部会(ISHR2016)
  • Place of Presentation: 東京
  • Year and Date: 2016-12-16
• [Presentation] FGF23によるTGF-を介した心臓線維化促進効果 (2016)
  • Author(s): 久我和寛、草刈洋一郎、南沢享
  • Organizer: 心血管膜輸送研究会2016 「心血管膜輸送分子の構造・機能・病態の統合的研究戦略」
  • Place of Presentation: 福岡
  • Year and Date: 2016-10-24