| Project/Area Number |
25461469
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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 |
Collagenous pathology/Allergology
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| Research Institution | The University of Tokyo |
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Principal Investigator |
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| Co-Investigator(Renkei-kenkyūsha) |
Tanaka Hirotoshi 東京大学, 医科学研究所, 教授 (00171794)
Shimizu Noriaki 東京大学, 医科学研究所, 特任研究員 (30396890)
Sano Motoaki 慶應義塾大学, 医学部, 准教授 (30265798)
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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 |
¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
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| Keywords | 膠原病 / 肺高血圧症 / 右心肥大 / 右心不全 / 心臓リモデリング / HEXIM1 / P-TEFb / HIF-1 / 低酸素 / 肺線維症 / HIF / 膠原病性肺高血圧症 / HIF1 / VEGF |
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| Outline of Final Research Achievements |
To develop novel therapeutic strategies for connective tissue disease (CTD)-associated pulmonary hypertension (PH), we hypothesized that direct interruption of fatal right ventricular hypertrophy (RVH)/RV remodeling improves their prognosis.
We investigated that overexpression of HEXIM1, which suppresses positive transcription elongation factor b-dependent transcription, prevents cardiomyocyte hypertrophy and hypertrophic genes expression, and that cardiomyocyte-specific HEXIM1 transgenic mice (HEXcTg) ameliorates RVH in hypoxia-induced PH model. Moreover, we revealed that overexpression of HEXIM1 prevented hypoxia-induced expression of hypoxia inducible factor 1α (HIF-1α) protein and its target genes in cardiomyocytes, and that HEXcTg repressed RV myocardial angiogenesis in hypoxia-induced PH model. We further investigated that HEXcTg could prevent RVH of bleomycin-induced PH/RVH model. Thus, HEXIM1 would be a molecular target for mitigating CTD-associated PH and RVH/RV remodeling.
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