Determination of the molecular mechanisms underlying heart development based on genome-wide analysis for congenital heart disease
| Project/Area Number |
16K10059
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Pediatrics
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| Research Institution | The University of Tokyo |
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Principal Investigator |
Inuzuka Ryo 東京大学, 医学部附属病院, 講師 (00597560)
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| Co-Investigator(Kenkyū-buntansha) |
平田 陽一郎 東京大学, 医学部附属病院, 講師 (40447397)
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| Research Collaborator |
Nakagama Yu
Nakanishi Toshio
Takeuchi Jun
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2017: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | 先天性心疾患 / RAS/MAPK症候群関連心臓病 / 心臓発生 / ゼブラフィッシュ / マウス / 遺伝子改変疾患動物モデリング / RAS/MAP症候群関連心臓病 / 網羅的遺伝子解析 / 発生 / 心筋症 / 内臓錯位 / 線毛機能 / 内臓錯位症候群 / 左右軸 / 心房心室不一致 / 遺伝子改変ノックアウト変異体 / ゲノム編集 / 機能解析 |
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| Outline of Final Research Achievements |
Based on genome-wide analysis and bioinformatic analysis, LZTR1 was selected as a candidate gene for a pedigree with conotruncal anomaly and hypertrophic cardiomyopathy. We performed in-vivo functional analysis for LZTR1 based on zebra fish model using the CRISPR-Cas9 system. A chimeric F0 mutant harboring a 7bp deletion germline allele was identified and backcrossed to wild-type fish to obtain F1 heterozygotes (lztr1del/+). F1 heterozygotes were crossed to generate F2 homozygous mutants (lztr1del/del), which recapitulated hypertrophic cardiomyopathy. Further, immunohistochemical analysis using anti-phospho-ERK antibody indicated active RAS/MAPK signaling, the deleterious signature of NS-associated hypertrophic cardiomyopathy.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究では、RAS/MAPK症候群関連心臓病におけるLZTR1の重要性が明らかになった。本研究で作出された、疾患モデルゼブラフィッシュは今後RAS/MAPK症候群関連心臓病の病態生理の解明に役立つことが期待される。特に、ゼブラフィッシュから得られる単離心筋細胞は、哺乳動物のそれと異なり、中長期培養、薬剤刺激、RNA阻害実験に適しており、RAS/MAPK症候群関連心臓病の細胞レベルの病態生理を解析する上で、最適なプラットフォームを提供してくれると考えられる。
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Report
(4 results)
Research Products
(17 results)
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[Journal Article] Accelerated Cardiomyocyte Proliferation in the Heart of a Neonate With LEOPARD Syndrome-Associated Fatal Cardiomyopathy.2018
Author(s)
Nakagama Y, Inuzuka R, Ichimura K, Hinata M, Takehara H, Takeda N, Kakiuchi S, Shiraga K, Asakai H, Shindo T, Hirata Y, Saitoh M, Oka A.
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Journal Title
Circulation: Heart Failure
Volume: 11(4)
Issue: 4
DOI
Related Report
Peer Reviewed
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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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