Development of New Treatment Strategies of Cardiovascular Pathologies by Using Epigenetic Regulation

心血管疾病等生活方式疾病的发病机制与环境因素的关系比遗传因素更密切。换句话说，基因功能和细胞表型的变化，缺乏基因组序列的任何变化，称为表观遗传调控，被认为是发病机制的原因。然而，心血管系统中的表观遗传调控尚未得到充分理解。我们期望染色质结构的变化将引导我们对真核生物转录调控机制有更深入的了解，并发现DNA结合蛋白与染色质结构变化之间的相互作用及其功能意义。我们假设，通过专注于心血管表观遗传调控，这项研究将解释如何在染色质和DNA修复转录调节心血管疾病，并将有助于药物发现。为了解决心血管中的表观遗传调控， ...更多信息 我们研究了这种疾病的关键因子KLF 5，并发现了与KLF 5相互作用的分子，如ANP 32 B。除了这些相互作用的因素，我们分析了ATM和H2 AX的功能，我们认为是重要的DNA修复的关键因素，通过使用分子生物学和基因工程技术（如敲除小鼠的产生）和疾病动物模型（如血管衰老模型）。结果，（i）通过检查组蛋白伴侣蛋白家族的调节，我们发现了一种新的组蛋白伴侣蛋白ANP 32 B，其结构分析表明，ANP 32 B调节KLF 5下游基因启动子区域中组蛋白的量（Munemasa et al.2008）。我们还解决了（Tochio等人，2010）的晶体结构。(ii)对ATM调控血管衰老新机制的分析表明，ATM通过Akt/p53/p21通路在氧化应激诱导的内皮功能障碍和血管早衰中发挥重要作用。我们的研究揭示了人类病理学中表观遗传调控的分子机制。重要的是，这些机制可能会导致新的治疗方法，以及基于我们结果的新研究。少

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 … More 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