Compositional and Functional Alterations of HDL Over Ovarian Aging

卵巢增龄对高密度脂蛋白成分和功能的影响 项目总结 此申请是对当前NIA FOA：PA-17-088对现有 使用来自妇女研究的数据和生物样本的队列、数据集和存储的生物样本 全国健康(SWAN)，以解决关于临床衰老的关键问题，即卵巢衰老 高密度脂蛋白(HDL)对心血管疾病(CVD)风险的影响。多个历史记录 流行病学研究报告高密度脂蛋白胆固醇(HDLC)与 和心血管疾病，这表明高密度脂蛋白-C具有直接的心脏保护作用。然而，最近的结果来自于 孟德尔随机研究和几种高密度脂蛋白胆固醇增高剂降低心血管疾病风险的失败 对高密度脂蛋白胆固醇心脏保护功能的怀疑。当女性步入更年期时，似乎出现了一个转变 在高密度脂蛋白-C与心血管疾病风险之间的关联方向上，高密度脂蛋白-C水平与 绝经前心血管风险较低，绝经后心血管风险较高。高密度脂蛋白是一族 在物理化学组成和功能上不同的不同的子类。高密度脂蛋白胆固醇只测量 高密度脂蛋白颗粒的胆固醇负荷，因此可能不能反映高密度脂蛋白组成和功能的变化 可能伴随着卵巢老化。高密度脂蛋白组成和功能的度量提供了更好的反映 高密度脂蛋白比高密度脂蛋白具有更强的抗动脉粥样硬化作用。这些新的高密度脂蛋白指标的生物学变化并没有 卵巢老化的特征导致了对更年期转变的影响的不确定性 (MT)可能对高密度脂蛋白具有抗动脉粥样硬化的能力。MT是女性经历的一个人生阶段 亚临床脑血管病的加速。充分了解高密度脂蛋白生物变化的本质是至关重要的 伴随着中年女性的卵巢老化。针对当前的NIA FOA：PA-17-088，当前 应用程序的目标是1)描述在MT过程中高密度脂蛋白组成和功能的变化，并评估如何 高密度脂蛋白组成的变化影响中年女性高密度脂蛋白功能的变化；2)评估 激素、代谢和炎症标志物的变化对高密度脂蛋白组成和功能的影响 并探讨高密度脂蛋白组成和功能改变与亚临床心血管疾病进展的关系。 在中年妇女中，并评估潜在的途径。来自妇女的冰冻标本参与了天鹅，一个 卵巢老化的纵向研究，将被用来重复测量1)核磁共振高密度脂蛋白 亚类；2)磷脂和甘油三酯的高密度脂蛋白含量；以及3)高密度脂蛋白颗粒促进 外周细胞的胆固醇转运(高密度脂蛋白-胆固醇流出能力)，这是心脏保护的关键功能 高密度脂蛋白，在MT上。无与伦比的纵向更年期队列(Swan)和 由完善的高密度脂蛋白组成和功能度量组成的全面建议小组将显著 加深我们对高密度脂蛋白在卵巢老化过程中的复杂生物学变化的理解，以及这些变化是如何 这些变化可能会影响心血管疾病的早期标志物，从而促进老年女性心血管疾病的发展。

Title: Compositional and Functional Alterations of HDL Over Ovarian Aging PROJECT SUMMARY This application is in response to the current NIA FOA: PA-17-088 Secondary Analyses of Existing Cohorts, Data Sets and Stored Biospecimens to use data and biospecimens from the Study of Women’s Health Across the Nation (SWAN) to address a critical question about clinical aging, i.e. how ovarian aging impacts the role of high-density lipoproteins (HDL) on risk for cardiovascular disease (CVD). Multiple historic epidemiologic studies reported an inverse association between high-density lipoprotein cholesterol (HDL-C) and CVD, which suggests a direct cardio-protective function of HDL-C. However, recent results from Mendelian randomization studies and the failure of several HDL-C raising agents to reduce CVD risk, cast doubt on a cardio-protective function of HDL-C . As women traverse menopause there appears to be a switch in the direction of the association between HDL-C and CVD risk, with higher HDL-C level being associated with lower CVD risk before menopause and with higher CVD risk after menopause. HDL is a family of heterogeneous subclasses that vary in physico-chemical composition and function. HDL-C only measures the cholesterol load of HDL particles and therefore may not reflect changes in HDL composition and function that could accompany ovarian aging. Metrics of HDL composition and function provide a better ability to reflect the athero-protective features of HDL than HDL-C. Biological changes in these novel metrics of HDL have not been characterized over ovarian aging leading to uncertainty about the impact that the menopausal transition (MT) may have on HDL athero-protective capacity. The MT is a phase of life when women experience an acceleration of subclinical CVD. It is critical to fully understand the nature of the biological changes in HDL that accompany ovarian aging in midlife women. In response to the current NIA FOA: PA-17-088, the current application aims to 1) characterize changes in HDL composition and function over the MT, and assess how changes in HDL composition impact changes in HDL function in women at midlife; 2) evaluate the impacts of hormonal, metabolic and inflammatory marker changes on HDL composition and function changes over the MT; and to explore associations of changes in HDL composition and function with subclinical CVD progression in midlife women and to assess potential pathways. Frozen specimens from women participated in SWAN, a longitudinal study of ovarian aging, will be used to repeatedly measure 1) nuclear magnetic resonance HDL subclasses; 2) HDL content of phospholipids and triglycerides; and 3) the ability of HDL particles to promote cholesterol transport from peripheral cells (HDL-cholesterol efflux capacity), a key cardio-protective function of HDL, over the MT. The combination of the incomparable longitudinal menopause cohort (SWAN) and the comprehensive proposed panel of well-developed HDL composition and function metrics will significantly enhance our understanding of the complex biological changes in HDL over ovarian aging and how these changes could impact early markers of CVD and thus contribute to CVD development in aging women.