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.

项目摘要/摘要心脏的不同细胞类型中的不同转录组可以适应健康生理需求和病理压力。表观基因组机械建立了核微环境对于这种量身定制的基因调节，在细胞类型特异性和刺激反应方式。但是，表观基因组重塑的方式基础是心脏的基础肥大和纤维化以及心力衰竭表型的光谱在临床上观察到，包括减少射血分数（HFREF；收缩功能障碍）或保留的EF（HFPEF；舒张功能障碍）是未知的。新型的表观遗传药物，例如HDAC和BET-溴ab剂抑制剂（即抑制剂的药物染色质读取器）在心力衰竭的临床前研究中表现出了巨大的希望，现在正在III期中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以治疗心血管疾病。进一步的证据表明心力衰竭是与新的半稳定和促进疾病的结构环境有关的基因组占用研究（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，如果基因组局部的正确子集可以用名牌药物来定位，则是新类可能会出现有关心力衰竭范围的表观基因组疗法。该多PI应用的重点是染色质的药理学操纵，以识别新靶标对于心力衰竭的范围。为了解开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，肾脏产生的模型功能障碍和骑马失衡（单侧肾切除型小鼠，具有DOCA颗粒和高盐）和横向主动脉收缩，心力衰竭的模型和保留和射血分数分别减少。我们假设针对中间体的表观遗传疗法染色质结构和可访问性的表型为调节整个基因提供了有力的机会以治疗方式来治疗心力衰竭的表达程序。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。我们将结束研究小分子表观遗传抑制剂反向疾病相关的表型和动物模型中的染色质结构变化。最后，我们将确定 HDACS的染色质橡胶家族和染色质读取器BRD4相互作用以调节表观基因组体系结构以及心肌细胞或成纤维细胞表型。这些调查将共同验证一类完整的心脏以特异性细胞类型的方式进行故障疗法，揭示了染色质可及性和结构的变化该病理基因表达的基础是临床上不同的心力衰竭形式。