Small molecule therapies targeting chromatin architecture in heart failure

项目摘要/摘要 心脏不同细胞类型的不同转录本使适应对健康的反应 生理需求和病理应激。表观基因组学机制建立核微环境 对于这种量身定做的基因调控，在特定类型的细胞中，关闭一些基因并打开其他基因 刺激反应方式。然而，表观基因组重塑支撑心脏的方式 肥大和纤维化与临床观察的心力衰竭表型谱，包括减少 射血分数(HFrEF；收缩功能障碍)或保留EF(HFpEF；舒张期功能障碍)，尚不清楚。 新型表观遗传药物，如HDAC和BET-溴域抑制剂(即抑制 染色质读者)在心力衰竭的临床前研究中显示出巨大的希望，目前正处于III期 治疗动脉粥样硬化的临床试验，强调了这些药物在人类中的耐受性，以及 开发表观遗传疗法来治疗心血管疾病。进一步的证据表明心力衰竭是 与一种新的、半稳定的和致病的结构环境相关的结构环境来自基因组 占位研究(使用芯片序列)、染色质构象捕获研究和DNA甲基化分析。 这些发现表明，如果正确的基因组座位子集可以被设计的药物靶向，那么就会出现一个新的类别 针对心力衰竭谱系的表观基因组疗法可能会出现。 这种多PI应用集中于染色质的药理操作以识别新的靶点 心力衰竭的谱系。为了揭示不同细胞类型的作用，我们将研究表观基因组控制 心肌细胞和成纤维细胞，检查不同的心力衰竭模型，包括盐、肾脏引起的模型 功能障碍和激素失衡(单侧肾切除小鼠，DOCA颗粒和高盐)和 小鼠腹主动脉缩窄致压力超负荷心力衰竭模型的建立 分别降低射血分数。我们假设针对中间体的表观遗传疗法 染色质结构的表型和可及性为调控整个基因提供了一个强大的机会 以治疗心力衰竭的方式表达计划。我们的实验将描述染色质 收缩和舒张期功能障碍模型中不同细胞类型的结构变化。我们将最终确定 研究小分子表观遗传抑制物逆转疾病相关表型和 动物模型中染色质结构的变化。最后，我们将确定 HDAC染色质擦除器家族和染色质读取器BRD4相互作用调节表观基因组结构 肌细胞或成纤维细胞表型。总而言之，这些研究将证实心脏的一个互补类别 针对细胞类型的失败治疗，揭示染色质可及性和结构的变化 这是临床上不同形式的心力衰竭的病理基因表达的基础。

PROJECT SUMMARY/ABSTRACT Distinct transcriptomes in the heart’s different cell types enable adaptation in response to healthy physiological demand and pathologic stress. Epigenomic machinery establishes the nuclear microenvironment for such tailored gene regulation, shutting some genes off and turning others on, in a cell type-specific and stimulus-responsive manner. However, the manner in which epigenomic remodeling underpins cardiac hypertrophy and fibrosis and the spectrum of heart failure phenotypes observed clinically, including with reduced ejection fraction (HFrEF; systolic dysfunction) or preserved EF (HFpEF; diastolic dysfunction), is unknown. Novel classes of epigenetic drugs like HDAC and BET-bromodomain inhibitor (i.e. agents that inhibit chromatin readers) have shown great promise in preclinical studies of heart failure, and are now in a phase III clinical trial to treat atherosclerosis, underscoring the tolerance of these drugs in humans and the potential of developing epigenetic therapies to treat cardiovascular diseases. Further evidence that heart failure is associated with a new, semi-stable and disease-promoting structural environment has come from genome occupancy studies (using ChIP-seq), chromatin conformation capture studies, and analysis of DNA methylation. These findings suggest that if the right subset of genomic loci could be targeted with designer drugs, a new class of epigenomic therapies for the spectrum of heart failure might emerge. This multi-PI application is focused on pharmacologic manipulation of chromatin to identify novel targets for the spectrum of heart failure. To unpack the role of different cell types, we will study epigenomic control in myocytes and fibroblasts, examining distinct models of heart failure, including that resulting from salt, renal dysfunction and hormonal imbalance (unilateral nephrectomized mice with a DOCA pellet and high salt) and mice subjected to pressure overload by transverse aortic constriction, models of heart failure with preserved and reduced ejection fraction, respectively. We hypothesize that epigenetic therapies targeting the intermediate phenotypes of chromatin structure and accessibility afford a powerful opportunity to regulate entire gene expression programs in a therapeutic manner to treat heart failure. Our experiments will characterize chromatin structural changes in different cell types in models of systolic and diastolic dysfunction. We will conclusively investigate the ability of small molecule epigenetic inhibitors to reverse disease-associated phenotypic and chromatin architectural changes in animal models. Lastly, we will determine the mechanisms by which the chromatin eraser family of HDACs and the chromatin reader BRD4 interact to regulate epigenomic architecture and myocyte or fibroblast phenotype. Together, these investigations will validate a complementary class of heart failure therapies in a cell type-specific manner, revealing the changes in chromatin accessibility and structure that underpin pathologic gene expression in clinically distinct forms of heart failure.