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

绝经过渡期间压力刺激的免疫特征和心脏代谢风险

• 批准号: 10510682
• 负责人: David R. Rubinow
• 金额: $ 27.21万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10510682
• 关键词: Address; Age; Aging; Animal Model; Anti-Inflammatory Agents; Biocompatible Materials; Biological Availability; Biological Markers; Biological Response Modifiers; Blood Vessels; Cardiometabolic Disease; Coagulation Process; Collection; Data; Disease; Early Intervention; Early identification; Elderly woman; Endothelium; Estradiol; Exposure to; Goals; High Risk Woman; Hormonal Change; Human; Immune; Immune response; Immunologic Markers; Individual; Inflammation; Insulin Resistance; Interleukin-6; Intervention; Knowledge; Laboratories; Leptin; Link; Measures; Menopausal Symptom; Menopause; Metabolic; Metabolic syndrome; Metadata; Mission; Modeling; Molecular; Molecular Target; Moods; Outcome; Participant; Pathway interactions; Perimenopause; Placebos; Plasma; Positioning Attribute; Prevalence; Prevention; Process; Psychosocial Stress; Public Health; RANTES; Race; Regulation; Research; Rest; Risk; Risk Assessment; Risk Marker; Smoking; Stress; Testing; Thrombopoietin; Time; Trier Social Stress Test; Woman; aging population; base; cardiometabolic risk; cardiometabolism; cardioprotection; circulating biomarkers; cohort; cytokine; experience; immune function; innovation; insight; macrophage-derived chemokine; men; mortality; novel; predictive marker; randomized placebo controlled trial; response; stressor; systemic inflammatory response; trait; trial design

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.

项目总结 免疫功能的改变，特别是全身性炎症，一再与 暴露在心理社会压力下，并增加与衰老有关的疾病的风险，但其机制 这些联系背后的原因尚不清楚。这项研究的长期目标是帮助阐明免疫 心理社会压力与衰老相关的机制，特别是心脏代谢性疾病。这个 这项应用的总体目标是确定多种免疫介质水平在多大程度上 围绝经期妇女应激反应的协调变化和心脏代谢风险的预测 人群的特点是压力负担高，雌二醇水平下降，并急剧增加 心脏代谢风险。中心假说是围绝经期的压力会触发全身变化。 在多种细胞因子和其他循环分子的水平上，这些系统变化协同作用 雌激素水平下降会增加心脏代谢风险。因此，这一应用程序的基本原理 是确定多种循环标志物的水平及其对应激的协调反应 围绝经期可以产生新的、复合的(多标记物)老年心脏代谢性疾病预测指标 女人。核心假设将通过追求两个具体目标来检验：1)确定压力如何 调节老年围绝经期妇女的免疫介质和免疫途径；2)识别多标记物 绝经过渡期间心脏代谢恶化的预测指标。为了实现这些目标， 拟议的研究将使用之前收集的血浆-无论是在基线休息时还是在实验室后 压力-在151名围绝经期妇女中特征良好的队列中，已经有记录表明 血管和代谢功能的测量。两个采集时间点的血浆将使用以下方法进行分析 定量细胞因子阵列分析参与心脏代谢相关过程的80个循环标志物 疾病，如炎症、代谢调节和凝血。这项研究中提出的 应用程序具有创新性，因为它将首次执行广泛的、应激刺激的细胞因子分析 在更年期过渡期间，以高压力负担、荷尔蒙变化和 免疫环境和增加的心脏代谢风险，因此处于独特的位置来解决这些关键的 知识中的关系鸿沟。这项拟议的研究意义重大，因为它利用了已有的研究成果 生物材料和广泛的元数据，以识别新的分子靶标和风险标记，并最终 加强老年妇女心脏代谢性疾病的早期干预。