| Budget Amount *help |
¥18,460,000 (Direct Cost: ¥14,200,000、Indirect Cost: ¥4,260,000)
Fiscal Year 2010: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2009: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2008: ¥7,670,000 (Direct Cost: ¥5,900,000、Indirect Cost: ¥1,770,000)
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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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