2010 Fiscal Year Final Research Report
Development of New Treatment Strategies of Cardiovascular Pathologies by Using Epigenetic Regulation
| Project/Area Number |
20390219
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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 |
Circulatory organs internal medicine
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| Research Institution | The University of Tokyo |
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Principal Investigator |
SUZUKI Toru The University of Tokyo, 医学部附属病院, 特任准教授 (90359620)
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| Project Period (FY) |
2008 – 2010
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| Keywords | 循環器・高血圧 / ストレス / 蛋白質 / トランスレーショナル・リサーチ / プロテオーム |
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| Research Abstract |
The pathogenesis of lifestyle diseases such as cardiovascular disease is more closely related to environmental factors than genetic factors. In other words, the changes in gene function and cellular phenotype lacking any changes in genomic sequence, known as epigenetic regulation, is considered to be responsible for the pathogenesis. Epigenetic regulation in the cardiovascular system, however, has not been sufficiently understood. We expected that the changes in chromatin structure would lead us towards a greater understanding of the mechanism of regulation of transcription in eukaryotes and discovered the interactions between DNA binding proteins and chromatin structural changes and their functional significance. We hypothesized that by focusing on cardiovascular epigenetic regulation, this study will explain how transcription in chromatin and DNA repair is regulated in cardiovascular disease and will contribute to drug discovery. In order to address epigenetic regulation in cardiovas
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cular disease, we studied KLF5, a key factor of this disease, and discovered molecules, such as ANP32B, which interact with KLF5. In addition to these interactive factors, we analyzed the function of ATM and H2AX, the key factors for DNA repair that we considered were important, by employing molecular biological and genetic engineering techniques (e.g. the generation of knockout mice) and disease animal models (e.g. vascular senescence models). As a result, (i) by examining the regulation of the histone chaperone family, we found a novel histone chaperone ANP32B, and its structural analysis revealed that ANP32B regulates the amount of histone in the promoter region of KLF5 downstream genes (Munemasa et al.2008). We also solved the crystal structure of (Tochio et al.2010). (ii) The analysis of the new regulative mechanism of vascular senescence by ATM showed that ATM plays an important role in oxidative stress-induced endothelial dysfunction and premature senescence through the Akt/p53/p21 pathway. Our research revealed the molecular mechanisms of epigenetic regulation in human pathology. Importantly, it is possible that these mechanisms may lead to new treatments, and new studies based on our results. Less
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[Journal Article] Response to letter regarding article, "Diagnosis of acute aortic dissection by D-dimer ; the IRAD-Bio experience".2010
Author(s)
Suzuki T, Distante A, Zizza A, Trimarchi S, Villani M, Antonio J, Salerno Uriarte JA, de Luca Tupputi Schinosa L, Renzulli A, Sabino F, Nowak R, Birkhahn R, Hollander J, Counselman F, Vijayendran R, Bossone E, Eagle K.
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Journal Title
Circulation 121
Pages: e24
Peer Reviewed
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[Journal Article] for the IRAD-Bio Investigators. Diagnosis of acute aortic dissection by D-Dimer. The International Registry of Acute Aortic Dissection substudy on biomarkers (IRAD-Bio) experience.2009
Author(s)
Suzuki T, Distante A, Zizza A, Trimarchi S, Villani M, Salerno Uriarte JA, de Luca Tupputi Schinosa L, Renzulli A, Sabino F, Nowak R, Birkhahn R, Hollander JE, Counselman F, Vijayendran R, Bossone E, Eagle K
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Journal Title
Circulation 119(20)
Pages: 2702-2707
Peer Reviewed
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[Journal Article] International Registry of Acute Aortic Dissection Substudy on Biomarkers (IRAD-Bio) Investigators. Preliminary experience with the smooth muscle troponin-like protein, calponin, as a novel biomarker for diagnosing acute aortic dissection.2008
Author(s)
Suzuki T, Distante A, Zizza A, Trimarchi S, Villani M, Salerno Uriarte JA, de Luca Tupputi Schinosa L, Renzulli A, Sabino F, Nowak R, Birkhahn R, Hollander JE, Counselman F, Bossone E, Eagle K
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Journal Title
Eur Heart J 29(11)
Pages: 1439-1445
Peer Reviewed
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[Remarks] ホームページ等
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