Establishment of precision medicine for cardiomyopathy using genome analysis and single cell analysis

• Project/Area Number: 17H06566
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Cardiovascular medicine
• Research Institution: Chiba University
• Principal Investigator: Satoh Masahiro 千葉大学, 医学部附属病院, 医員 (10802564)
• Project Period (FY): 2017-08-25 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000); Fiscal Year 2018: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 循環器内科学 / 精密医療 / 循環器 / 遺伝子 / 臨床

Outline of Final Research Achievements

In this study, we performed targeted sequencing on dilated cardiomyopathy and hypertrophic cardiomyopathy in Japan. Dilated cardiomyopathy patients harboring TTN truncating variants had better prognosis than those with LMNA variants. Most patients with TTN truncating variants achieved left ventricular reverse remodeling, unlike most patients with LMNA variants. We performed single cardiomyocyte RNA sequencing and single molecule fluorescence in situ hybridization and elucidated heart failure patients with a high proportion of failing cardiomyocytes have treatment resistance. To achieve the mechanism about the whole heart tissue of cardiomyopathy patients, we are integrating the genome analysis and single cell analysis.

Academic Significance and Societal Importance of the Research Achievements

現在心筋症の治療法は心不全や致死性不整脈などの臨床症状のみに依存する形で画一的に選択されている。しかし、本研究により治療反応性の予測可能な遺伝子変異を同定することに成功し、さらに1細胞解析をヒトサンプルに応用することにも成功した。予後を含めた詳細な臨床情報、心筋症ゲノム解析、single cell RNA sequencing, 心筋生検を用いた1分子RNAI FISHなどの1細胞解析を統合し心筋症予後予測確立へむけて解析を進めている。

Research Products

• [Journal Article] High-throughput single-molecule RNA imaging analysis reveals heterogeneous responses of cardiomyocytes to hemodynamic overload (2019)
  • Author(s): Satoh M、Nomura S、Harada M、Yamaguchi T、Ko T、Sumida T、Toko H、Naito AT.、Takeda N、Tobita T、Fujita T、Ito M、Fujita K、Ishizuka M、Kariya T、Akazawa H、Kobayashi Y、Morita H、Takimoto E、Aburatani H、Komuro I
  • Journal Title: Journal of Molecular and Cellular Cardiology Volume: 128 Pages: 77-89
  • DOI: 10.1016/j.yjmcc.2018.12.018
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cardiomyocyte gene programs encoding morphological and functional signatures in cardiac hypertrophy and failure. (2018)
  • Author(s): Nomura S, Satoh M, Fujita T, Higo T, Sumida T, Ko T, Yamaguchi T, Tobita T, Naito AT, Ito M, Fujita K, Harada M, Toko H, Kobayashi Y, Ito K, Takimoto E, Akazawa H, Morita H, Aburatani H, Komuro I.
  • Journal Title: Nat Commun. Volume: 9 Issue: 1 Pages: 4435-4435
  • DOI: 10.1038/s41467-018-06639-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genetic basis of cardiomyopathy and the genotypes involved in prognosis and left ventricular reverse remodeling (2018)
  • Author(s): Tobita T, Nomura S, Fujita T, Morita H, Asano Y, Onoue K, Ito M, Imai Y, Suzuki A, Ko T, Satoh M, Fujita K, Naito AT, Furutani Y, Toko H, Harada M, Amiya E, Hatano M, Takimoto E, Shiga T, Nakanishi T, Sakata Y, Ono M, Saito Y, Takashima S, Hagiwara N, Aburatani H, Komuro I.
  • Journal Title: Sci Rep Volume: 8 Issue: 1 Pages: 20114-20119
  • DOI: 10.1038/s41598-018-20114-9
  • Peer Reviewed / Open Access
• [Presentation] Single cell analysis of cardiomyocyte reveals spatial and temporal heterogeneity in heart failure (2018)
  • Author(s): Masahiro Satoh, Seitaro Nomura, Takanori Fujita, Toshiyuki Ko, Takashige Tobita, Kanna Fujita, Masamichi Ito, Hirotaka Ieki, Shintaro Yamada, Bo Zhang, Xiaohui Tian, Yoshio Kobayashi, Hiroyuki Aburatani, Issei Komuro
  • Organizer: 第2回日本循環器学会基礎研究フォーラム
• [Presentation] High-throughput single-molecule RNA imaging analysis reveals spatial heterogeneity in heart failure (2018)
  • Author(s): Masahiro Satoh, Seitaro Nomura, Takanori Fujita, Toshiyuki Ko, Takashige Tobita, Masamichi Ito, Kanna Fujita, Hiroyuki Aburatani, Yoshio Kobayashi, Issei Komuro
  • Organizer: The 32nd European Society of Cardiology (ESC) Congress, Munich, Germany
  • Int'l Joint Research
• [Presentation] Marked Decreased Myocardial Washout Rate of 123I-BMIPP is a Crucial Index in Diagnosing Triglyceride Deposit Cardiomyovasculopathy. (2018)
  • Author(s): Satoh M, Miyauchi H, Mori N, Iimori T, Sawada K, Kuwabawa Y, Hirano K, Kobayashi Y.
  • Organizer: The 91st American Heart Association (AHA) Scientific Sessions in Chicago
  • Int'l Joint Research
• [Presentation] Single cell analysis of cardiomyocyte reveals spatial and temporal heterogeneity in heart failure (2018)
  • Author(s): Masahiro Satoh, Seitaro Nomura, Takanori Fujita, Toshiyuki Ko, Takashige Tobita, Masamichi Ito, Kanna Fujita, Hiroyuki Aburatani, Yoshio Kobayashi, Issei Komuro
  • Organizer: 第22回日本心不全学会
• [Presentation] High-throughput single-RNA molecule imaging analysis reveals spatial heterogeneity in heart failure (2018)
  • Author(s): Masahiro Satoh, Seitaro Nomura, Takanori Fujita, Toshiyuki Ko, Takashige Tobita, Kanna Fujita, Masamichi Ito, Yoshio Kobayashi, Hiroyuki Aburatani, Issei Komuro
  • Organizer: 第1回日本循環器学会基礎研究フォーラム
• [Presentation] High-throughput single molecule RNA imaging analysis reveals spatial heterogeneity in heart failure (2018)
  • Author(s): Masahiro Satoh, Seitaro Nomura, Takanori Fujita, Toshiyuki Ko, Takashige Tobita, Kanna Fujita, Masamichi Ito, Yoshio Kobayashi, Hiroyuki Aburatani, Issei Komuro
  • Organizer: Keystone Symposia, Keystone, Colorado
  • Int'l Joint Research
• [Presentation] High-throughput Single molecule RNA-Imaging Analysis Reveals Spatial Heterogeneity of Cardiomyocytes In Stress Response. (2018)
  • Author(s): Masahiro Satoh, Seitaro Nomura, Toshiyuki Ko, Takashige Tobita, Masamichi Ito, Kanna Fujita, Yoshio Kobayashi, Issei Komuro
  • Organizer: The 82nd Annual Scientific Meeting of the Japanese Circulation Society, Osaka,
• [Presentation] High-throughput Single molecule RNA-Imaging Analysis Reveals Spatial Heterogeneity of Cardiomyocytes In Stress Response. (2017)
  • Author(s): Masahiro Satoh, Seitaro Nomura, Takanori Fujita, Toshiyuki Ko, Takashige Tobita, Masamichi Ito, Kanna Fujita, Hiroyuki Aburatani, Yoshio Kobayashi, Issei Komuro
  • Organizer: The 90th American Heart Association (AHA) Scientific Sessions in Anaheim, California
  • Int'l Joint Research
• [Presentation] SPECT-Guided Myocardial Perfusion and Metabolic Fatty Acid Planar Imaging Reflects the Severity of the Pulmonary Hypertension in Patients with Chronic Thromboembolic Pulmonary Hypertension. (2017)
  • Author(s): Masahiro Satoh, Hideyuki Miyauchi, Seiichiro Sakao,Takashi Iimori, Koichi Sawada,Yoichi Kuwabara,Koichiro Tatsumi, Yoshio Kobayashi
  • Organizer: The 90th American Heart Association (AHA) Scientific Sessions in Anaheim, California
  • Int'l Joint Research
• [Remarks] シングルセル解析と機械学習により心不全発症のメカニズムを解明
  • URL: https://www.genome.rcast.u-tokyo.ac.jp/3939
• [Remarks] シングルセル解析と1分子RNA FISHにより心不全進展過程の空間情報を解明
  • URL: https://www.genome.rcast.u-tokyo.ac.jp/3995
• [Remarks] シングルセル解析と機械学習により心不全において心筋細胞が 肥大化・不全化するメカニズムを解明
  • URL: https://www.rcast.u-tokyo.ac.jp/ja/news/release/181030.html
• [Remarks] シングルセル解析と機械学習により心不全において心筋細胞が肥大化・不全化するメカニズムを解明
  • URL: http://www.h.u-tokyo.ac.jp/press/press_archives/20181030.html
• [Remarks] シングルセル解析と AI により心不全発症のメカニズムを解明
  • URL: http://www.j-circ.or.jp/topics/pr20181031.pdf
• [Remarks] 日本人における拡張型心筋症・肥大型心筋症のゲノム解析
  • URL: https://www.genome.rcast.u-tokyo.ac.jp/3807
• [Remarks] Keystone Symposia Heart Failure 見聞記
  • URL: https://www.genome.rcast.u-tokyo.ac.jp/3798