2019 Fiscal Year Final Research Report
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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| Keywords | 心不全 / 心筋症 |
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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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| Free Research Field |
循環器内科学
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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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