Establishment of knoch-in mouse with genetic mutation causing severe cardiomyopathy

• Project/Area Number: 17H04061
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: The University of Tokyo
• Principal Investigator: Morita Hiroyuki 東京大学, 医学部附属病院, 講師 (60323573)
• Co-Investigator(Kenkyū-buntansha): 中山 敦子 東京大学, 医学部附属病院, 助教 (60529147)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥17,940,000 (Direct Cost: ¥13,800,000、Indirect Cost: ¥4,140,000); Fiscal Year 2019: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2018: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2017: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000)
• Keywords: 心不全 / 心筋症 / 拡張型心筋症 / 疾患モデル動物 / 循環器・高血圧

Outline of Final Research Achievements

In this study, I established knock-in mouse (C57BL/6NJcl) with one copy of HOPX Lys23Asn variant allele using CRISPR-Cas9 system. I established the new mouse model which reflected the pathological condition of human heart failure and performed the analysis on the pathophysiology of heart failure using this mouse model. Left ventricular fractional shortening fell to 30-35% at 36 weeks of age in heterozygous knock-in mouse (versus 60% in the control group). In addition, the left ventricle was significantly enlarged as compared with controls. Interestingly, in 40-50% of heterozygous knock-in mice, systolic dysfunction and dilatation were not virtually observed. Knock-in with one copy of HOPX Lys23Asn variant allele could not induce the severe heart failure as was observed in the patient with one copy of HOPX Lys23Asn variant allele.

Academic Significance and Societal Importance of the Research Achievements

患者病態を反映した新規心不全モデルマウスを確立した。HOPX変異1コピーの遺伝子導入では、HOPX変異過剰発現マウスでみられたような重度の心不全をきたさないことが明らかになった。HOPX変異が単独で重症心不全をきたすということではなく、他の原因遺伝子変異ないしは環境要因のgenetic modifierとして作用し心筋症発症を誘導・促進している可能性をも考慮しなくてはならない。HOPX変異がどのような心筋転写制御の異常をもたらすか究明するため、胎仔心筋細胞を採取しsingle-cell RNAシークエンスをおこなった。今後はそのデータ解析を続行する予定である。

Research Products

• [Journal Article] Beautiful Harmony of the Japanese Precious Healthcare Legacies for the New Imperial Era (2020)
  • Author(s): Kaneko H, Morita H, Komuro I.
  • Journal Title: Circulation Journal Volume: 84 Issue: 3 Pages: 371-373
  • DOI: 10.1253/circj.CJ-19-1059
  • NAID: 130007801797
  • ISSN: 1346-9843, 1347-4820
  • Year and Date: 2020-02-25
  • Peer Reviewed / Open Access
• [Journal Article] Effect of Treatment by Female Cardiologists on Short-Term Readmission Rates of Patients Hospitalized With Cardiovascular Diseases (2019)
  • Author(s): Nakayama A, Morita H, Fujiwara T, Komuro I
  • Journal Title: Circulation Journal Volume: 83 Issue: 9 Pages: 1937-1943
  • DOI: 10.1253/circj.CJ-19-0357
  • NAID: 130007695017
  • ISSN: 1346-9843, 1347-4820
  • Year and Date: 2019-08-23
  • Peer Reviewed / Open Access
• [Journal Article] Cost-Effectiveness of Percutaneous Coronary Intervention Compared With Medical Therapy for Ischemic Heart Disease in Japan (2019)
  • Author(s): Kodera S
  • Journal Title: Circulation Journal Volume: 83 Issue: 7 Pages: 1498-1505
  • DOI: 10.1253/circj.CJ-19-0148
  • NAID: 130007666976
  • ISSN: 1346-9843, 1347-4820
  • Year and Date: 2019-06-25
  • Peer Reviewed / Open Access
• [Journal Article] Alteration of Cardiac Performance and Serum B-Type Natriuretic Peptide Level in Healthy Aging (2019)
  • Author(s): Yoshida Y, Nakanishi K (corresponding), Daimon M, Ishiwata J, Sawada N, Hirokawa M, Kaneko H, Nakao T, Mizuno Y, Morita H, Di Tullio MR, Homma S, Komuro I
  • Journal Title: Journal of the American College of Cardiology Volume: 74 Issue: 14 Pages: 1789-1800
  • DOI: 10.1016/j.jacc.2019.07.080
  • NAID: 40022442752
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Quantification of DNA Damage in Heart Tissue as a Novel Prediction Tool for Therapeutic Prognosis of Patients With Dilated Cardiomyopathy. (2019)
  • Author(s): Ko T, Fujita K, Nomura S, Uemura Y, Yamada S, Tobita T, Katoh M, Satoh M, Ito M, Domoto Y, Hosoya Y, Amiya E, Hatano M, Morita H, Fukayama M, Aburatani H, Komuro I.
  • Journal Title: JACC Basic Transl Sci. Volume: 4 Issue: 6 Pages: 670-680
  • DOI: 10.1016/j.jacbts.2019.05.010
  • Peer Reviewed / Open Access
• [Journal Article] Cost-Effectiveness of PCSK9 Inhibitor Plus Statin in Patients With Triple-Vessel Coronary Artery Disease in Japan (2018)
  • Author(s): Kodera S, Morita H, Kiyosue A, Ando J, Takura T, Komuro I.
  • Journal Title: Circulation Journal Volume: 82 Issue: 10 Pages: 2602-2608
  • DOI: 10.1253/circj.CJ-17-1455
  • NAID: 130007489796
  • ISSN: 1346-9843, 1347-4820
  • Year and Date: 2018-09-25
  • Peer Reviewed / Open Access
• [Journal Article] Blood lipid-related low-frequency variants in LDLR and PCSK9 are associated with onset age and risk of myocardial infarction in Japanese. (2018)
  • Author(s): ２）Tajima T, Morita H, Ito K, Yamazaki T, Kubo M, Komuro I, Momozawa Y.
  • Journal Title: Scientific Reports Volume: 8 (1) Issue: 1 Pages: 8107-8107
  • DOI: 10.1038/s41598-018-26453-x
  • Peer Reviewed / Open Access
• [Journal Article] Impact of Pathogenic FBN1 Variant Types on the Progression of Aortic Disease in Patients With Marfan Syndrome (2018)
  • Author(s): Takeda N, Inuzuka R, Maemura S, Morita H, Nawata K, Fujita D, Taniguchi Y, Yamauchi H, Yagi H, Kato M, Nishimura H, Hirata Y, Ikeda Y, Kumagai H, Amiya E, Hara H, Fujiwara T, Akazawa H, Suzuki JI, Imai Y, Nagai R, Takamoto S, Hirata Y, Ono M, Komuro I.
  • Journal Title: Circulation: Genomic and Precision Medicine Volume: 11 Issue: 6
  • DOI: 10.1161/circgen.117.002058
  • 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] Outcomes of cardiac screening in adolescent soccer players. (2018)
  • Author(s): Morita H, Komuro I.
  • Journal Title: New England Journal of Medicine Volume: 379 Issue: 21 Pages: 2083-2084
  • DOI: 10.1056/nejmc1813056
• [Journal Article] Heart Failure as an Aging-Related Phenotype (2018)
  • Author(s): Morita Hiroyuki、Komuro Issei
  • Journal Title: International Heart Journal Volume: 59 Issue: 1 Pages: 6-13
  • DOI: 10.1536/ihj.17-519
  • NAID: 130006321414
  • ISSN: 1349-2365, 1349-3299
  • Peer Reviewed / Open Access
• [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
• [Journal Article] Cardiac rehabilitation protects against the expansion of abdominal aortic aneurysm (2018)
  • Author(s): Nakayama A, Morita H, Nagayama M, Hoshina K, Uemura Y, Tomoike H, Komuro I.
  • Journal Title: Journal of the American Heart Association Volume: 7 Issue: 5 Pages: 5-12
  • DOI: 10.1161/jaha.117.007959
  • Peer Reviewed / Open Access
• [Journal Article] Omega-3 Polyunsaturated Fatty Acid and Coronary Atherosclerotic Plaques (2017)
  • Author(s): Nakao Tomoko、Morita Hiroyuki
  • Journal Title: International Heart Journal Volume: 58 Issue: 6 Pages: 837-839
  • DOI: 10.1536/ihj.17-552
  • NAID: 130006251669
  • ISSN: 1349-2365, 1349-3299
  • Peer Reviewed / Open Access
• [Journal Article] Identification of MYLK3 mutations in familial dilated cardiomyopathy (2017)
  • Author(s): Tobita Takashige、Nomura Seitaro、Morita Hiroyuki、Ko Toshiyuki、Fujita Takanori、Toko Haruhiro、Uto Kenta、Hagiwara Nobuhisa、Aburatani Hiroyuki、Komuro Issei
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 17495-17495
  • DOI: 10.1038/s41598-017-17769-1
  • Peer Reviewed / Open Access
• [Presentation] 循環器領域における分子病態研究の新展開 (2017)
  • Author(s): 森田啓行
  • Organizer: 第54回日本臨床分子医学会学術集会
  • Invited