| Project/Area Number |
25670130
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| Research Category |
Grant-in-Aid for Challenging Exploratory Research
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| Allocation Type | Multi-year Fund |
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| Research Field |
General pharmacology
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| Research Institution | Kyushu University |
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Principal Investigator |
Morimoto Sachio 九州大学, 医学(系)研究科(研究院), 准教授 (50202362)
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| Co-Investigator(Renkei-kenkyūsha) |
TAKAHASHI Fumi 九州大学, 大学院医学研究院, 講師 (50274436)
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| Research Collaborator |
Mohamed Rasha
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| Project Period (FY) |
2013-04-01 – 2016-03-31
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| Project Status |
Completed (Fiscal Year 2015)
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| Budget Amount *help |
¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
Fiscal Year 2015: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2014: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | 拡張型心筋症 / GSK3β / 心臓リモデリング / 心臓収縮機能 / 生命予後 / 心不全 / ノックアウトマウス / ノックインマウス / 心肥大抑制 / セレコキシブ / ジメチルセレコキシブ |
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| Outline of Final Research Achievements |
GSK3β plays a central role in both cardiac physiology and pathology. Herein ｗe generated a mouse model carrying a heterozygous knock-out mutation of GSK3β (GSK3β +/- KO) together with a ΔK210 knock-in mutation in cardiac troponin T (ΔK210 cTnT KI), which was proved to be one of the genetic causes of familial dilated cardiomyopathy (DCM). GSK3β +/- KO prevented the slow and rapid deterioration in left ventricular systolic function accompanying heart failure (HF) in DCM mice with heterozygous and homozygous ΔK210 cTnT KI mutations, respectively. GSK3β +/- KO also prevented cardiac enlargement, myocardial fibrosis and cardiomyocyte apoptosis and markedly reduced the expression of cardiac β-myosin heavy chain isoform, indicative of HF, in DCM mice with homozygous ΔK210 cTnT KI mutation. GSK3β +/- KO also extended the life-span of these DCM mice. This study suggests that the inhibition of GSK3β is cardioprotective in familial DCM associated with ΔK210 cTnT mutation.
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