Stress-stimulated immune profiles and cardiometabolic risk during the menopausal transition

项目摘要 改变的免疫功能，特别是全身性炎症，已经反复与 暴露于心理社会压力和增加与衰老有关的疾病的风险，但机制 这些关联的基础尚不清楚。这项研究的长期目标是帮助阐明免疫 将心理社会压力与衰老相关疾病，特别是心脏代谢疾病联系起来的机制。的 本申请的总体目的是确定多种免疫介质的水平 在围绝经期妇女中，随着年龄的增长， 以高压力负担为特征的人群，雌二醇水平下降， 心脏代谢风险。核心假设是围绝经期的压力引发了系统性变化 在多种细胞因子和其他循环分子的水平上，这些系统性变化是一致的， 雌二醇水平下降会增加心脏代谢风险。因此，本申请的基本原理 确定多种循环标志物的水平及其对压力的协调反应， 围绝经期可以产生衰老心脏代谢疾病的新型复合（多标志物）预测因子 妇女中心假设将通过追求两个具体目标进行测试：1）确定压力如何 调节老年围绝经期妇女的免疫介质和途径;和2）鉴定多标记物 绝经过渡期心脏代谢恶化的预测因子。为了实现这些目标， 拟议的研究将使用先前收集的血浆--包括基线休息时和实验室后的血浆 压力-在一个特征良好的队列中，151名围绝经期妇女已经记录了纵向 测量血管和代谢功能。将使用以下方法分析两个采集时间点的血浆 定量细胞因子阵列分析涉及心脏代谢相关过程的80种循环标志物 疾病，如炎症、代谢调节和凝血。这项研究提出， 该应用是创新的，因为它将首次进行广泛的，应激刺激的细胞因子分析 在绝经过渡期，这一时期的特点是高压力负担，改变荷尔蒙， 免疫环境和增加的心脏代谢风险，从而独特地定位于解决这些关键问题。 知识上的差距。拟议的研究意义重大，因为它利用了现有的 生物材料和广泛的元数据，以确定新的分子靶标和风险标志物，并最终 加强对老年妇女心脏代谢疾病的早期干预。

PROJECT SUMMARY Altered immune function, and in particular systemic inflammation, has been repeatedly associated with exposure to psychosocial stress and with increased risk for aging-related disease, but the mechanisms underlying these associations are unclear. The long-term goal of this research is to help elucidate the immune mechanisms linking psychosocial stress with aging-related and, in particular, cardiometabolic disease. The overall objective of this application is to determine the extent to which the levels of multiple immune mediators coordinately change in response to stress and predict cardiometabolic risk in perimenopausal women, an aging population characterized by high stress burden, declining estradiol levels, and dramatically increasing cardiometabolic risk. The central hypothesis is that stress during the perimenopause triggers systemic changes in the levels of multiple cytokines and other circulating molecules, and these systemic changes act in concert with declining estradiol levels to increase cardiometabolic risk. Consequently, the rationale of this application is that determining the levels of multiple circulating markers and their coordinated responses to stress during the perimenopause can yield novel, composite (multi-marker) predictors of cardiometabolic disease in aging women. The central hypothesis will be tested by pursuing two specific aims: 1) Determine how stress modulates immune mediators and pathways in aging perimenopausal women; and 2) Identify multi-marker predictors of cardiometabolic worsening during the menopausal transition. To accomplish these aims, the proposed research will use blood plasma previously collected – both at baseline rest and post-laboratory stress – in a well-characterized cohort of 151 perimenopausal women with already documented longitudinal measures of vascular and metabolic function. Plasma at both collection timepoints will be analyzed using quantitative cytokine arrays to profile 80 circulating markers involved in processes relevant for cardiometabolic disease, such as inflammation, metabolic regulation, and coagulation. The research proposed in this application is innovative because it will for the first time perform extensive, stress-stimulated cytokine profiling during the menopausal transition, a period characterized by high stress burden, changing hormonal and immune milieu, and increasing cardiometabolic risk, thus being uniquely positioned to address these critical relational gaps in knowledge. The proposed research is significant because it leverages already available biological material and extensive metadata to identify new molecular targets and risk markers and to ultimately enhance early interventions for cardiometabolic disease in aging women.