MECHANISMS UNDERLYING THE AGE-RELATED ATHEROPROTECTIVE EFFECTS OF HORMONE THERAPY

激素治疗与年龄相关的动脉粥样硬化保护作用的机制

基本信息

批准号：
9752440
负责人：
Howard Neil Hodis
金额：
$ 72.4万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9752440
关键词：
Address Adverse effects Affect Age Aging Archives Atherosclerosis Belief Benefits and Risks Biological Biological Availability Biological Markers Blood Blood Cells Blood Circulation CCL2 gene Candidate Disease Gene Cardiovascular Diseases Carotid Arteries Cause of Death Cell Adhesion Molecules Clinical Clinical Data Country CpG Islands DNA Methylation Data Data Set Distant E-Selectin ESR1 gene ESR2 gene Estradiol Estrogen Receptor alpha Estrogens Funding Gene Expression Gene Expression Profiling Genes Gonadal Steroid Hormones Health IL8 gene Inflammatory Interleukin-1 alpha Interleukin-1 beta Interleukin-10 Interleukin-6 Intervention Trial Knowledge Life Expectancy Literature Measures Menopause Messenger RNA Methylation Modification Molecular Outcome P-Selectin Participant Pathway interactions Placebos Postmenopause Prevention therapy Primary Prevention Process Public Health Publishing Randomized Controlled Trials Risk Sampling Sex Hormone-Binding Globulin Signal Transduction TNF gene Testing Testosterone Therapeutic Therapeutic Intervention Time Tissues Vascular Endothelial Growth Factors Vascular Endothelium Woman age related atheroprotective base cardiovascular disorder prevention chemokine clinical biomarkers cytokine design drug discovery hormone therapy intimal medial thickening longitudinal analysis mRNA Expression men mortality novel therapeutics older women promoter sex time interval trend

项目摘要

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

项目概要/摘要绝经期激素治疗（HT）时机假说最近在一项新完成的 NIA- 资助的随机对照试验，雌二醇早期与晚期干预试验（ELITE）显示绝经后 6 年以内服用 HT 可显着减少亚临床动脉粥样硬化进展相对于安慰剂，而接受 HT > 10 年以来的女性的进展没有影响绝经。因此，虽然文献支持并且 ELITE 验证了 HT 作为一种潜在的治疗特异性和减少女性心血管疾病和全因死亡率趋势的与年龄相关的机会，早期施用 HT 时与年龄相关的动脉粥样硬化保护作用的生物学机制与绝经后晚期的情况尚不清楚。该提案旨在解决这些根本性差距通过利用 ELITE 的设计和丰富的数据集来研究临床生物标志物和颈动脉内膜中层厚度（CIMT）进展随时间变化的分子机制 HT 起始相对于更年期的影响。根据我们之前的研究和文献证据，我们的总体假设是绝经后 6 年内开始 HT 对生物利用度和循环中性激素和动脉粥样硬化相关炎症生物标志物的信号传导，导致减少 CIMT 进展。我们还假设不同的分子机制 ELITE 中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，该状态会随着年龄的变化而变化相关流程。在目标 1 中，我们将确定性激素生物利用度和生物标志物是否 HT 可能调节的炎症通路可以解释 HT 对亚临床症状的不同影响根据绝经后的时间，动脉粥样硬化进展。使用已经存在的临床数据将由精英参与者使用存储的样本开发，我们将确定纵向血液中性激素结合球蛋白水平、性激素与动脉粥样硬化的关系以 CIMT 进展为函数，在基线、6、12、24 和 48 个月时测量炎症生物标志物早期与晚期 HT 干预的比较。在目标 2 中，我们将确定 mRNA 是否发生纵向变化编码雌激素受体和一组炎症的基因的表达水平和甲基化状态血细胞中的分子是改变动脉粥样硬化的分子机制的解释当 HT 开始时，按绝经后时间进行进展。了解这种性别特异性的机制减少 CVD 和全因死亡率的与年龄相关的机会是优化 HT 和仪器治疗的关键用于新药发现。雌激素缺乏对心血管疾病发病率的影响受到广大公众的关注健康的重要性。因此，该方案具有较高的临床和应用价值。