Epigenetic mechanisms linking psychosocial stress with coronary heart disease

项目总结 心理社会压力的增加--现代快节奏社会的一个标志--一再与 免疫功能改变和冠心病(CHD)风险增加，但潜在的机制 这些关联尚不清楚。DNA甲基化，关键的和研究最多的表观遗传过程之一 人类，已经成为环境暴露和人类健康之间的关键纽带。我们的长期合作 目的是阐明表观遗传学和其他分子机制通过心理社会应激 导致动脉粥样硬化性疾病。本申请的总体目标是定义甲基组 在全血和不同免疫细胞类型中与应激相关的差异以及确定如何 这些差异可以塑造免疫功能并预测冠心病风险。中心假说是压力 驱动甲基组模式，在表观遗传水平上上调促炎症介质和其他免疫介质 不同的血细胞类型，从而导致冠心病的发生。这个应用程序的基本原理是确定 外周血液免疫细胞的应激相关表观基因组模式及其功能后遗症 可用于加强CHD预防和治疗的新型复合预测因子和分子靶点 治疗。中心假设将通过结合人类队列中的大规模分析和 细胞模型中的力学研究。将追求三个不同但相辅相成的具体目标：1) 确定全血中与压力相关的甲基组特征，预测冠心病的发生；2)确定细胞类型- 与应激和预测冠心病相关的特定甲基组模式；以及3)机械解剖 应激在培养中如何表观调控单核细胞功能。目标1和目标2将利用多个大型队列 参加NHLBI精密医学(TOPMed)计划的研究，并有合适的 心理社会压力、全血DNA甲基化和/或冠心病事件数据。细胞类型特异性甲基组 图案将使用该研究最近开发的尖端计算方法进行解卷 一队。关键的表观遗传信号将使用单核细胞和单核细胞的细胞模型进行机械解剖。 来源的巨噬细胞暴露于生理水平的应激激素和靶向DNA 培养中的甲基化编辑。这一跨学科的提议是创新的，因为它将整合大规模的 将新的计算方法应用于具有尖端技术的多项TOPMed研究 免疫细胞模型中的机械性工作。这项拟议的研究意义重大，因为它有望产生创新的 表观遗传预测因子和可操作的分子靶点，可用于加强预防和 应激性冠心病的治疗。

PROJECT SUMMARY Elevated psychosocial stress – a hallmark of modern, fast-paced societies – has been repeatedly associated with altered immune function and increased coronary heart disease (CHD) risk, but the mechanisms underlying these associations are unclear. DNA methylation, one of the critical and most studied epigenetic processes in humans, has emerged as a key link between environmental exposures and human health. Our long-term goal is to elucidate the epigenetic and other molecular mechanisms through which psychosocial stress contributes to atherosclerotic disease. The overall objective of this application is to define the methylomic differences associated with stress both in whole blood and in distinct immune cell types and to determine how these differences can shape immune function and predict CHD risk. The central hypothesis is that stress drives methylomic patterns that epigenetically upregulate proinflammatory and other immune mediators across distinct blood cell types, thereby contributing to incident CHD. The rationale for this application is that determining stress-associated epigenomic patterns and their functional sequelae in peripheral blood immune cells can yield novel composite predictors and molecular targets that can be leveraged to enhance CHD prevention and treatment. The central hypothesis will be tested by combining large-scale analyses in human cohorts and mechanistic investigations in cell models. Three distinct but complementary specific aims will be pursued: 1) Identify stress-associated methylomic profiles in whole blood that predict incident CHD; 2) Define cell type- specific methylomic patterns that are associated with stress and predict CHD; and 3) Mechanistically dissect how stress epigenetically regulates monocyte function in culture. Aims 1 and 2 will leverage multiple large cohort studies that participate in the NHLBI Trans-Omics for Precision Medicine (TOPMed) program and have suitable psychosocial stress, whole-blood DNA methylation, and/or incident CHD data. Cell type-specific methylomic patterns will be deconvoluted using cutting-edge computational methods recently developed by the research team. Key epigenetic signals will be mechanistically dissected using cell models of monocytes and monocyte- derived macrophages undergoing exposure to physiological levels of stress hormones and targeted DNA methylation editing in culture. This interdisciplinary proposal is innovative as it will integrate large-scale association efforts that apply novel computational methods across multiple TOPMed studies with cutting-edge mechanistic work in immune cell models. The proposed research is significant as it is expected to yield innovative epigenetic predictors and actionable molecular targets that can be leveraged to enhance prevention and treatment of stress-associated CHD.