Stress and Atherosclerotic Plaque Macrophages - A Systems Biology Approach

摘要 长期的社会压力是我们繁忙的当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，也是心脏病的预测因子。 脑梗塞和中风。压力导致更高的心血管事件发生率的机制是 主要归因于对行为的次要影响，包括吸烟或食物摄入量。压力对人的影响 大脑可以直接影响心血管疾病是一个未知领域。 来自该项目研究人员的临床前初步数据描述了 社会压力、神经信号和动脉粥样硬化，这是一种由脂质驱动的慢性炎症性疾病 心肌梗死和中风的根本原因。关键的连接组件是巨噬细胞，一种 起源于骨髓并聚集在动脉粥样硬化病变中的大的吞噬细胞。 根据大量已发表和未发表的数据，我们假设慢性可变压力会加剧 通过干扰巨噬细胞的动力学导致心血管疾病。 具体地说，我们希望(I)了解应激在生物学上如何影响巨噬细胞的动力学。 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。我们的高度创新 方案项目由在心血管领域具有互补专业知识的不同研究人员团队组成 免疫学(Swirski、Fisher、Moore)；临床前心血管成像(Mulder、Nahrendorf、Calcagno)； 翻译成像(Fayad，Tawakol，Mani，Fuster)；神经科学(Murough，Shin，Pitman，Charney)。 在结构上，我们有3个主要项目，辅之以一个行政/统计核心和一个成像核心。 我们将从有利的角度，从三个具体目标来解决计划项目的中心假设 生物、技术和医学。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研究。在目标2(技术)中，我们将开发和翻译非 动脉粥样硬化中监测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，我们将阐明创伤后应激障碍导致动脉粥样硬化的机制。 我们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，如压力和心血管之间的联系 疾病可以被最好地接近并整合到病人护理中。

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 Informed by abundant published and unpublished data, we hypothesize that chronic variable stress aggravates cardiovascular disease by interfering with macrophage dynamics.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.