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

• 批准号: 10417054
• 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
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10417054
• 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

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

项目摘要/摘要 在新完成的NIA- 资助的随机对照试验，与雌二醇（Elite）的早期与晚期干预试验，该试验显示 HT施用了<6年的培训，显着降低了亚临床动脉粥样硬化的进展 相对于安慰剂，而接受HT> 10年的女性的进展没有影响 绝经。因此，尽管文献支持和精英将HT验证为特定于治疗的潜在治疗和 与年龄相关的机会减少女性心血管疾病和全因死亡率趋势的机会， 提早给药的生物学机制与年龄相关的动脉保护作用 在更年期后的晚期尚不清楚。该建议旨在解决这些基本差距 通过利用精英的设计和丰富的数据集来调查临床生物标志物和 颈动脉内膜膜厚度（CIMT）进展的分子机制 相对于更年期的HT启动。基于我们先前的研究和文献证据，我们的总体 假设是，HT启动<6年的年份对生物利用度和 循环中性激素和动脉粥样硬化相关的炎症生物标志物的信号传导，导致 减少CIMT进展。我们还假设发散的分子机制 可以通过mRNA基因表达的纵向分析来鉴定精英的动脉粥样硬化结果 血细胞中选定候选基因的DNA甲基化状态，它们可能随着年龄的影响而变化 相关过程。在AIM 1中，我们将确定性激素生物利用度的生物标志物和 可能受HT调节的炎症途径可以解释HT对亚临床的差异作用 动脉粥样硬化的进展，根据时间份概率。使用已经存在的临床数据， 这将从精英参与者使用存储的样本开发，我们将确定纵向 性激素结合球蛋白，性激素和动脉粥样硬化有关的血液水平之间的关系 在基线，6、12、24和48个月时测量的炎症生物标志物，CIMT进展为功能 早期与晚期干预的早期。在AIM 2中，我们将确定mRNA的纵向变化 编码雌激素受体和炎症的基因的表达水平和甲基化状态 血细胞中的分子是用于修饰动脉粥样硬化的解释性分子机制 启动HT时，由时间中逐渐逐渐发展的进展。了解这种性别特定的机制 与年龄相关的机会减少CVD和全因死亡率是优化HT和工具的关键 用于新药发现。雌激素缺乏对CVD率的含义是巨大的公众 健康重要性。因此，该建议具有很高的临床和

项目成果

Factors Associated With Serum Estradiol Levels Among Postmenopausal Women Using Hormone Therapy.

• DOI: 10.1097/aog.0000000000004006
• 发表时间: 2020-10
• 期刊: Obstetrics and gynecology
• 影响因子: 7.2
• 作者: Sriprasert I;Kono N;Karim R;Hodis HN;Stanczyk FZ;Shoupe D;Mack WJ
• 通讯作者: Mack WJ

Hierarchical measurement structure in the Women's Health Questionnaire: a confirmatory factor analysis.

• DOI: 10.1080/13697137.2018.1564270
• 发表时间: 2019-10
• 期刊: Climacteric : the journal of the International Menopause Society
• 作者: Shen BJ;Fan Q;Huang JS;Ho MHR;Mack WJ;Hodis HN
• 通讯作者: Hodis HN

Genetics unravels protein-metabolite relationships.

遗传学揭示了蛋白质与代谢物的关系。

• DOI: 10.1016/j.tem.2024.01.008
• 发表时间: 2024
• 期刊: Trends in endocrinology and metabolism: TEM
• 作者: Hilser,JamesR;Lusis,AldonsJ;Allayee,Hooman
• 通讯作者: Allayee,Hooman

Comparison of Cardiovascular Disease Risk Factors Between 2 Subclinical Atherosclerosis Measures in Healthy Postmenopausal Women: Carotid Artery Wall Thickness and Echogenicity: Carotid Artery Wall Thickness and Echogenicity.

健康绝经后妇女两种亚临床动脉粥样硬化措施之间心血管疾病危险因素的比较：颈动脉壁厚度和回声性：颈动脉壁厚度和回声性。

• DOI: 10.1002/jum.15985
• 发表时间: 2023
• 期刊: Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine
• 作者: Karim,Roksana;Xu,Wenrui;Kono,Naoko;Li,Yanjie;Yan,Mingzhu;Stanczyk,FrankZ;Hodis,HowardN;Mack,WendyJ
• 通讯作者: Mack,WendyJ

Subclinical carotid artery atherosclerosis and cognitive function in older adults.

• DOI: 10.1186/s13195-022-00997-7
• 发表时间: 2022-05-07
• 期刊: ALZHEIMERS RESEARCH & THERAPY
• 影响因子: 9
• 作者: Lin, Felice;Pa, Judy;Karim, Roksana;Hodis, Howard N.;Han, S. Duke;Henderson, Victor W.;St John, Jan A.;Mack, Wendy J.
• 通讯作者: Mack, Wendy J.