Epigenomic basis of resilience to heart failure

心力衰竭恢复能力的表观基因组基础

• 批准号: 10090629
• 负责人: Thomas M. Vondriska
• 金额: $ 19.5万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10090629
• 关键词: Adrenergic beta-Agonists; Adult; Animal Model; Atrial Fibrillation; Biological Markers; Blood; Cardiac; Cardiac Surgery procedures; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Cell physiology; Clinical; Clinical Data; Computerized Medical Record; Consent; Coronary Artery Bypass; DNA; DNA Methylation; Data; Data Set; Development; Diagnostic; Disease; Down Syndrome; Enrollment; Epidemic; Epigenetic Process; Exposure to; Future; Gene Expression; Genes; Genetic Transcription; Genetic Variation; Genome; Grant; Heart; Heart Atrium; Heart failure; Human; Inbred Strains Mice; Inbreeding; Incidence; Individual; Injury; Institutional Review Boards; Investigation; Isoproterenol; Life Style; Link; Los Angeles; Malignant Neoplasms; Maps; Measures; Methylation; Molecular Target; Morbidity - disease rate; Mouse Strains; Mus; Nature; Obesity; Operative Surgical Procedures; Organ; Pathologic; Pathology; Patients; Phenotype; Population; Postoperative Period; Predisposition; Process; Protocols documentation; Recombinants; Research; Resistance; Risk; Sampling; Schizophrenia; Severity of illness; Source; Stimulus; Stress; Symptoms; Testing; Therapeutic; Time; Translating; Work; base; biosignature; bisulfite sequencing; cardiogenesis; cardiovascular health; cell type; chromatin modification; cohort; data mining; environmental stressor; epigenome; epigenomics; heart function; innovation; member; methylation pattern; methylome; mouse model; multiple omics; novel; predictive marker; prognostic; programs; research clinical testing; resilience; response; tool; trait; valve replacement

PROJECT SUMMARY/ABSTRACT Epigenomic features centrally underpin cardiovascular health. Among these, DNA methylation has emerged as a stable, but not immutable, chromatin modification that can be associated with gene expression but yet decorates non-genic regions of the genome, influencing cellular function by means other than transcription at the locus it occurs. In this grant we seek to determine whether these epigenomic marks can serve to predict—prior to the development of severe complications—heart failure, and to explore the underlying mechanisms of epigenomic resilience to cardiovascular disease. Rather than studying the disease process, we see to understand why some individuals develop heart failure whereas others do not. Our preliminary work in mouse models shows that DNA methylation in the heart of mice correlates with the severity of disease prior to the exposure to environmental stress (e.g. isoproterenol). Following up on this initial observation, we have now characterized DNA methylomes in a panel of inbred and recombinant inbred mouse strains, allowing us to explore the basic principles of how DNA methylation interacts with genetic variation to influence cardiovascular resilience. We now seek to translate this phenomenon to humans, identifying multi- locus epigenomic risk metrics for heart failure that distinguish resilient individuals from those more susceptible to cardiovascular complications over time. These metrics will be the basis for a new class of precision prognostic and diagnostic tools in heart failure. Our research team has initiated an IRB-approved clinical program to measure epigenetic factors in the blood of patients undergoing cardiac surgery, linking these factors to clinical data through an innovative data- mining platform that interrogates electronic medical records. As of February 2019, we have enrolled ~250 patients and performed bisulfite sequencing on 110 of them (remaining patients’ samples in process). Moving forward, independent of this application, we continue to expand this cohort to include a representative sampling of the adult population in the Los Angeles region. The hypothesis we will test in this grant is that DNA methylation mechanistically underpins differential resilience to cardiac pathology and is a source of a novel class of biomarkers for human heart failure.

项目摘要/摘要 表观基因组特征主要基础心血管健康。其中，DNA甲基化具有 作为一种可以与基因表达相关的稳定但不可变的染色质修饰的出现 但是，装饰基因组的非生成区域，通过以外的其他方式影响细胞功能 它发生的基因座的转录。在这笔赠款中，我们试图确定这些表观基因组是否可以服务 预测（预测严重并发症的发展），心脏失败并探索基础 对心血管疾病的表观基因组弹性的机制。而不是研究疾病过程，我们 要了解为什么有些人会发展心力衰竭，而另一些人则没有。 我们在小鼠模型中的初步工作表明，小鼠心脏中的DNA甲基化与 暴露于环境压力之前的疾病严重程度（例如异丙肾上腺素）。跟进此 最初的观察结果，我们现在表征了一组近交和重组的近交易所中的DNA甲基组 小鼠菌株，使我们能够探索DNA甲基化与遗传变异相互作用的基本原理 影响心血管弹性。现在，我们试图将这种现象转化为人类，确定多种多样 基因座表观基因组风险的心力衰竭指标，将弹性个体与更多人区分开 随着时间的流逝，患心血管并发症。这些指标将成为新的精度的基础 心力衰竭的预后和诊断工具。 我们的研究团队启动了IRB批准的临床计划，以衡量表观遗传因素 接受心脏手术的患者的血液，通过创新数据将这些因素与临床数据联系起来 - 询问电子病历的采矿平台。截至2019年2月，我们已注册约250 患者并在其中110个（其余​​患者的样本中）进行了亚硫酸盐测序。移动 向前，独立于此应用程序，我们继续扩展此队列以包括代表性抽样 洛杉矶地区的成年人口。我们将在这笔赠款中检验的假设是DNA甲基化 机械学上是对心脏病理学的差异韧性的基础，是新型类别的来源 人类心力衰竭的生物标志物。

项目成果

Longitudinal profiling in patients undergoing cardiac surgery reveals postoperative changes in DNA methylation.

• DOI: 10.1186/s13148-022-01414-4
• 发表时间: 2022-12-30
• 期刊: Clinical epigenetics
• 影响因子: 5.7