Small molecule therapies targeting chromatin architecture in heart failure

项目概要/摘要 心脏不同细胞类型中不同的转录组能够适应健康的环境 生理需求和病理应激。表观基因组机制建立核微环境 对于这种定制的基因调控，在细胞类型特异性和 刺激反应方式。然而，表观基因组重塑支撑心脏的方式 肥厚和纤维化以及临床观察到的心力衰竭表型谱，包括减少 射血分数（HFrEF；收缩功能障碍）或保留 EF（HFpEF；舒张功能障碍）尚不清楚。 新型表观遗传药物，如 HDAC 和 BET-溴结构域抑制剂（即抑制 染色质读取器）在心力衰竭的临床前研究中显示出巨大的前景，目前正处于 III 期研究 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。进一步证据表明心力衰竭 与新的、半稳定的、促进疾病的结构环境相关的来自基因组 占用研究（使用 ChIP-seq）、染色质构象捕获研究和 DNA 甲基化分析。 这些发现表明，如果可以用设计药物靶向基因组位点的正确子集，那么一类新药物 针对心力衰竭谱系的表观基因组疗法可能会出现。 该多 PI 应用专注于染色质的药理学操作，以识别新靶标 对于心力衰竭谱系。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，包括由盐、肾病引起的心力衰竭模型 功能障碍和荷尔蒙失衡（单侧肾切除小鼠使用 DOCA 颗粒和高盐）和 小鼠因横向主动脉缩窄而承受压力超负荷，并保留了心力衰竭模型 分别降低射血分数。我们假设表观遗传疗法针对中间体 染色质结构和可及性的表型为调节整个基因提供了强大的机会 以治疗方式表达程序来治疗心力衰竭。我们的实验将表征染色质 收缩和舒张功能障碍模型中不同细胞类型的结构变化。我们将最终 研究小分子表观遗传抑制剂逆转疾病相关表型和 动物模型中染色质结构的变化。最后，我们将确定机制 HDAC 的染色质擦除家族和染色质读取器 BRD4 相互作用来调节表观基因组结构 和肌细胞或成纤维细胞表型。总之，这些研究将验证心脏的互补类别 以细胞类型特异性方式进行失败治疗，揭示染色质可及性和结构的变化 支撑临床不同形式的心力衰竭的病理基因表达。

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.