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

与遗传因素相比，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更为密切。换句话说，基因功能和细胞表型的改变缺乏基因组序列的任何变化，即所谓的表观遗传调节，被认为是导致发病的原因。然而，心血管系统中的表观遗传调控还没有被充分了解。我们期望染色质结构的变化将使我们更好地理解真核生物转录调控的机制，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，通过关注心血管的表观遗传调控，这项研究将解释染色质转录和DNA修复如何在心血管疾病中受到调控，并将有助于药物的发现。为了解决心脏…的表观遗传调控对于更常见的疾病，我们研究了KLF5，KLF5是这种疾病的关键因素，并发现了与KLF5相互作用的分子，如ANP32B。除了这些相互作用的因素外，我们还利用分子生物学和基因工程技术(如基因敲除小鼠的产生)和疾病动物模型(如血管衰老模型)，分析了ATM和H2 AX的功能，这是我们认为对DNA修复至关重要的关键因素。因此，(1)通过研究组蛋白伴侣蛋白家族的调控，我们发现了一个新的组蛋白伴侣蛋白ANP32B，其结构分析表明ANP32B调控KLF5下游基因启动子区域的组蛋白含量(Munemasa等人，2008)。我们还解决了(Tochio等人，2010)的晶体结构。(2)ATM对血管衰老新的调控机制的分析表明，ATM通过Akt/p53/p21途径在氧化应激诱导的内皮功能障碍和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和基于我们结果的新研究。较少

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