Small molecule therapies targeting chromatin architecture in heart failure

针对心力衰竭染色质结构的小分子疗法

基本信息

批准号：
10312765
负责人：
Timothy McKinsey
金额：
$ 72.05万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-12-15 至 2023-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10312765
关键词：
ATAC-seq Acetates Acute Adult Agonist Animal Model Architecture Atherosclerosis Biomechanics Bromodomain Cardiac Cardiac Myocytes Cardiovascular Diseases Cardiovascular system Cells ChIP-seq Chromatin Chromatin Modeling Chromatin Structure Clinical Complex Computer Analysis DNA Methylation DNA analysis Deoxycorticosterone Designer Drugs Disease Disease model Drug Tolerance EFRAC Environment Environmental Risk Factor Epigenetic Process Family Fibroblasts Functional disorder Gene Expression Gene Expression Regulation Genes Genetic Genome Genomics Goals Heart Heart Hypertrophy Heart failure Histologic Histone Deacetylase Histone Deacetylase Inhibitor Hormone imbalance Human Investigation Knockout Mice Measures Mediating Modeling Molecular Mus Muscle Cells Nuclear Pathogenicity Pathologic Pharmaceutical Preparations Pharmacology Phase III Clinical Trials Phenotype Physiological Play Proteins Reader Regulation Regulator Genes Regulatory Element Role Sodium Chloride Stable Disease Stimulus Stress Structure Symptoms Technology Therapeutic Treatment Failure cell type chromosome conformation capture constriction coronary fibrosis epigenetic drug epigenetic therapy epigenome epigenomics experimental study genetic manipulation genomic locus heart function inhibitor kidney dysfunction novel preclinical study preservation pressure prevent programs response small molecule targeted treatment transcriptome transcriptome sequencing

项目摘要

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.

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建立了核微环境。对于这种定制的基因调控，在细胞类型特异性和然而，表观基因组重塑支持心脏的方式。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的进一步证据表明。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我们分别捕获了针对中间体的表观遗传疗法。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我们的实验将表征染色质。我们将最终确定收缩和舒张功能障碍模型中不同细胞类型的结构变化。研究小分子表观遗传抑制剂逆转疾病相关表型和最后，我们将确定动物模型中染色质结构变化的机制。 HDAC 的染色质擦除器家族和染色质读取器 BRD4 相互作用来调节表观基因组结构以及心肌细胞或成纤维细胞表型，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。