Stress and Atherosclerotic Plaque Macrophages - A Systems Biology Approach

总结 长期的社会压力是我们忙碌的现代生活中不可或缺的一部分。大量数据表明， 严重的慢性心理社会应激是心血管疾病的危险因素，也是心肌梗死的预测因子。 梗塞和中风。压力导致心血管事件发生率升高的机制有 主要归因于对行为的次级影响，包括吸烟或食物摄入。压力如何影响 大脑可以直接影响心血管疾病是未知领域。 来自该项目研究者的临床前初步数据描述了 社会压力，神经信号，动脉粥样硬化，脂质驱动的慢性炎症性疾病， 心肌梗死和中风的根本原因。关键的连接成分是巨噬细胞， 起源于骨髓并在动脉粥样硬化损伤处聚集的大的吞噬性白细胞。 根据大量已发表和未发表的数据，我们假设慢性可变压力 心血管疾病通过干扰巨噬细胞动力学。 具体来说，我们希望（i）了解压力如何在生物学上影响巨噬细胞动力学， 动脉粥样硬化;（ii）开发非侵入性监测巨噬细胞动力学的技术;以及（iii）阐明 创伤后应激障碍（PTSD）导致动脉粥样硬化的机制。我们高度创新的 计划项目由具有心血管领域互补专业知识的多元化研究者团队组成 免疫学（Swirski，Fisher，摩尔）;临床前心血管成像（Mulder，Nazodorf，Calcagno）; 平移成像（Fayad，Tawakol，Mani，Fuster）;和神经科学（Murrough，Shin，皮特曼，Charney）。 在结构上，我们有3个主要项目，由行政/统计核心和成像核心补充。 我们将从以下三个Vantage的角度来解决该计划项目的三个具体目标的中心假设 of biology生物，technology技术，and medicine医学.在目标1（生物学）中，我们将研究压力如何控制巨噬细胞 动脉粥样硬化小鼠模型的动力学。在目标2（技术）中，我们将开发和翻译非 监测动脉粥样硬化中巨噬细胞动力学的侵入性成像方法和纳米技术 在压力下。在目标3（医学）中，我们将阐明PTSD导致动脉粥样硬化的机制。 我们的计划项目的总体和长期目标是共同建立一个健全的科学 生物医学和临床社区的基础，如压力和心血管疾病之间的联系， 疾病可以最好地接近和整合在病人护理中。

SUMMARY Chronic social stress is an integral part of our busy contemporary lives. Abundant data show that severe chronic psychosocial stress is a risk factor for cardiovascular disease and a predictor of myocardial infarction and stroke. The mechanisms by which stress contributes to the higher cardiovascular event rates are primarily attributed to secondary effects on behavior, including smoking or food intake. How stress' effect on the brain can directly impact cardiovascular disease is uncharted territory. Preclinical preliminary data from this Program's investigators describe a direct causal link between social stress, neural signals, and atherosclerosis, the lipid-driven chronic inflammatory disease that is the underlying cause of myocardial infarction and stroke. The key connecting component is the macrophage, a large phagocytic leukocyte that originates in the bone marrow and accumulates in atherosclerotic lesions. Informed by abundant published and unpublished data, we hypothesize that chronic variable stress aggravates cardiovascular disease by interfering with macrophage dynamics. Specifically, we wish to (i) understand how stress biologically affects macrophage dynamics in atherosclerosis; (ii) develop technology that monitors macrophage dynamics non-invasively; and (iii) elucidate the mechanism by which post-traumatic stress disorder (PTSD) leads to atherosclerosis. Our highly innovative Program Project comprises a diverse team of investigators with complementary expertise in cardiovascular immunology (Swirski, Fisher, Moore); preclinical cardiovascular imaging (Mulder, Nahrendorf, Calcagno); translational imaging (Fayad, Tawakol, Mani, Fuster); and neuroscience (Murrough, Shin, Pitman, Charney). Structurally, we have 3 main Projects complemented by an Administrative/Statistical Core and Imaging Core. We will tackle the Program Project's central hypothesis in three Specific Aims from the vantage points of biology, technology, and medicine. In Aim 1 (Biology) we will investigate how stress controls macrophage dynamics in mouse models of atherosclerosis. In Aim 2 (Technology), we will develop and translate non- invasive imaging approaches and nanotechnologies that monitor macrophage dynamics in atherosclerosis during stress. In Aim 3 (Medicine), we will elucidate the mechanism by which PTSD leads to atherosclerosis. Our Program Project's overarching and long-term goal is to collectively institute a sound scientific foundation for the biomedical and clinical community as how the link between stress and cardiovascular disease can be best approached and integrated in patient care.