MECHANISMS UNDERLYING THE AGE-RELATED ATHEROPROTECTIVE EFFECTS OF HORMONE THERAPY

项目总结/摘要 绝经期激素治疗（HT）时间假说最近在一项新完成的NIA中得到验证， 受资助的随机对照试验，早期与晚期干预试验（ELITE）显示， 绝经后<6年给予HT可显着减少亚临床动脉粥样硬化进展 相对于安慰剂，而在接受HT >10年的女性中， 绝经因此，虽然文献支持和ELITE验证HT作为一种潜在的治疗特异性， 减少妇女心血管疾病和全因死亡趋势的与年龄有关的机会， HT早期给药时年龄相关动脉粥样硬化保护作用的生物学机制 与绝经后晚期的对比尚不清楚。这项建议旨在解决这些根本性的差距， 通过利用ELITE的设计和丰富的数据集来研究临床生物标志物， 颈动脉内膜中层厚度（CIMT）进展的分子机制作为时间的函数 与绝经期相关的HT起始。根据我们先前的研究和文献证据，我们的总体 假设绝经后<6年开始HT对生物利用度有有利影响， 性激素和动脉粥样硬化相关炎症生物标志物在循环中的信号传导， 减少CIMT进展。我们还假设， ELITE的动脉粥样硬化结果可以通过mRNA基因表达的纵向分析来确定， 以及血细胞中选定候选基因的DNA甲基化状态，其可以作为年龄的函数而变化- 相关过程。在目标1中，我们将确定性激素生物利用度的生物标志物和 可能由HT调节的炎症通路可以解释HT对亚临床炎症的不同作用。 根据绝经后时间的动脉粥样硬化进展。使用已经存在的临床数据， 我们将使用存储的样本从ELITE参与者中开发， 血中性激素结合球蛋白、性激素水平与动脉粥样硬化相关性 在基线、6、12、24和48个月时测量的炎症生物标志物，CIMT进展作为函数 早期与晚期HT干预的对比。在目标2中，我们将确定mRNA的纵向变化是否 雌激素受体编码基因的表达水平和甲基化状态，以及一组炎性细胞因子， 血细胞中的分子是动脉粥样硬化修饰的解释性分子机制 当HT开始时，根据绝经后时间进行进展。了解这种性别特异性的机制 与年龄相关的降低心血管疾病和全因死亡率的机会是优化HT和仪器的关键。 用于新药研发雌激素缺乏对心血管疾病发病率的影响是巨大的公众 健康的重要性。因此，该建议具有较高的临床和

PROJECT SUMMARY/ABSTRACT The menopausal hormone therapy (HT) timing hypothesis was recently validated in a newly completed NIA- funded randomized controlled trial, the Early Versus Late Intervention Trial with Estradiol (ELITE) that showed that HT administered <6 years-since-menopause significantly reduced subclinical atherosclerosis progression relative to placebo, whereas there was no effect on progression in women who received HT >10 years-since- menopause. Thus, while the literature supports and ELITE validates HT as a potential treatment-specific and age-related opportunity for reducing cardiovascular disease and all-cause mortality trends in women, the biological mechanisms underlying the age-related atheroprotective effects of HT when administered early versus late after menopause are not known. This proposal seeks to address these fundamental gaps in knowledge by leveraging the design and rich dataset of ELITE to investigate the clinical biomarkers and molecular mechanisms of carotid artery intima-media thickness (CIMT) progression as a function of the timing of HT initiation relative to menopause. Based on our prior studies and evidence from the literature, our overall hypothesis is that HT initiation <6 years-since-menopause has favorable effects on the bioavailability and signaling of sex hormones and atherosclerosis-related inflammatory biomarkers in the circulation, which leads to reduced CIMT progression. We also hypothesize that the molecular mechanisms for the divergent atherosclerosis outcomes in ELITE can be identified through longitudinal analyses of mRNA gene expression and DNA methylation status of selected candidate genes in blood cells, which can vary as a function of age- related processes. In Aim 1, we will determine whether biomarkers of sex hormone bioavailability and inflammatory pathways potentially regulated by HT can explain the differential effect of HT on subclinical atherosclerosis progression according to time-since-menopause. Using clinical data that already exists and that will be developed from ELITE participants using stored samples, we will determine the longitudinal relationship between blood levels of sex hormone binding globulin, sex hormones and atherosclerosis-related inflammatory biomarkers measured at baseline, 6, 12, 24 and 48 months with CIMT progression as a function of early versus late HT intervention. In Aim 2, we will determine whether longitudinal changes in mRNA expression levels and methylation status of genes encoding estrogen receptors and a panel of inflammatory molecules in blood cells are explanatory molecular mechanisms for the modification of atherosclerosis progression by time-since-menopause when HT is initiated. Understanding mechanism(s) of this sex-specific and age-related opportunity for reducing CVD and all-cause mortality is key to optimizing HT and instrumental for new drug discovery. The implications of estrogen deficiency on the rates of CVD are of enormous public health importance. As such, this proposal has high clinical and