Establishment of knoch-in mouse with genetic mutation causing severe cardiomyopathy
| Project/Area Number |
17H04061
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Experimental pathology
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| Research Institution | The University of Tokyo |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
中山 敦子 東京大学, 医学部附属病院, 助教 (60529147)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥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)
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| 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 |
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| 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.
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| 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。
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Report
(4 results)
Research Products
(16 results)
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[Journal Article] Alteration of Cardiac Performance and Serum B-Type Natriuretic Peptide Level in Healthy Aging2019
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
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Journal Title
Journal of the American College of Cardiology
Volume: 74
Issue: 14
Pages: 1789-1800
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[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.
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Journal Title
JACC Basic Transl Sci.
Volume: 4
Issue: 6
Pages: 670-680
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Impact of Pathogenic FBN1 Variant Types on the Progression of Aortic Disease in Patients With Marfan Syndrome2018
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.
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Journal Title
Circulation: Genomic and Precision Medicine
Volume: 11
Issue: 6
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[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.
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Journal Title
Nat Commun.
Volume: 9
Issue: 1
Pages: 4435-4435
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Genetic basis of cardiomyopathy and the genotypes involved in prognosis and left ventricular reverse remodeling2018
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.
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Journal Title
Sci Rep
Volume: 8
Issue: 1
Pages: 20114-20119
DOI
Related Report
Peer Reviewed / Open Access
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