Longitudinal Evaluation of Ovarian Aging and Cardiovascular Risk

卵巢衰老和心血管风险的纵向评估

基本信息

批准号：
9310311
负责人：
MARCELLE Ivonne CEDARS
金额：
$ 137.89万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-30 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9310311
关键词：
Address Affect Age Aging Appearance Area Awareness Behavioral Biological Markers C-reactive protein Cardiac Cardiovascular Diseases Cell Aging Chronology Communities Diagnosis Disease Early identification Emotional Estrogens Ethnic Origin Evaluation F2-Isoprostanes Functional disorder Genetic Risk Health Infertility Inflammation Intercellular adhesion molecule 1 Interleukin-6 Isoprostanes Lead Length Leukocytes Measures Mediating Mediation Menopause Menstrual cycle Methods Microvascular Dysfunction Mitochondria Mitochondrial DNA Modeling Oocytes Ovarian Ovary Oxidative Stress Pattern Peripheral Plasma Population Population Heterogeneity Predisposition Pregnancy Premature Menopause Prevention Process Public Health Race Reproductive History Risk Risk Factors Risk Marker Risk Reduction Socioeconomic Status Somatic Cell System Telomere Shortening Testing Time Woman Women&apos s Health aged aging population base cardiovascular disorder risk cardiovascular risk factor cohort ethnic disparity ethnic diversity high risk population improved indexing mitochondrial dysfunction novel novel strategies psychosocial reproductive reproductive function telomere

项目摘要

ABSTRACT Despite significant improvements in prevention and treatment of cardiovascular disease (CVD), the growing aging population suggests CVD will continue to pose a significant public health burden. Women are a special group where microvascular disease is more common and traditional risk factors may not fully identify risk. Women's reproductive history (e.g. menarcheal age, menstrual cycles, infertility, pregnancy, menopause) may pose unique risk and suggests an opportunity for new approaches. We propose a women-centered approach for early identification of women at risk that investigates the unique loss of reproductive function at an age long before other vital systems fail. Despite the importance of this process, little is known about the determinants or correlates of ovarian aging, or the health implications, especially in diverse populations. With reliable bio-markers of the remaining oocyte pool available, we have a unique opportunity to characterize the association between “ovarian age” and the health implications of accelerated oocyte loss. We hypothesize a risk independent of the well-known impact of early menopause and estrogen deficiency. Rather, we propose that common underlying cellular aging mechanisms, first evident in the ovary due to its sensitivity and earlier demise, make the ovary a window on underlying somatic health. Confirming an association between a decline in markers of ovarian age and CVD risk would allow a potentially high-risk population to be identified decades before traditional risk factors develop. The Ovarian Aging (OVA) cohort is the largest and most ethnically diverse, community-based cohort available that can be used to determine the race/ethnic and behavioral determinants of ovarian aging and its association with CVD risk in a young cycling population. To assess the relationship between markers of ovarian age (reflecting past exposures and genetic risk), the rate of ovarian aging (representing current exposures) and CVD risk, we propose to: 1. Determine whether markers of ovarian age/aging are associated with increased CVD risk by testing if ovarian age/aging is independently associated with increased CVD risk, as measured by peripheral endothelial function testing; 2. Determine whether ovarian aging may moderate or mediate established associations between race/ethnicity and/or socio/emotional health and CVD risk by examining whether observed race/ethnic disparities, or effects of socio/emotional health, on CVD risk, may vary by (moderation model) or be partially attributable to (mediation model) ovarian aging; and 3. Determine whether ovarian aging, CVD risk, and the temporal pattern of appearance correlate with markers of cellular aging: telomere length and mtDNA in peripheral leukocytes, oxidative stress (plasma F2α-isoprostanes), and indices of inflammation (C-reactive protein, interleukin- 6, and soluble intercellular adhesion molecule-1). Overall Impact: Our novel longitudinal approach to evaluating markers of ovarian and cellular aging as predictors of CVD could lead to a new way to identify women at earlier and/or increased CVD risk and be used to develop new risk-reduction strategies.

抽象的尽管心血管疾病 (CVD) 的预防和治疗取得了显着进展，但人口老龄化表明心血管疾病将继续构成重大的公共健康负担。微血管疾病更常见的群体，传统的危险因素可能无法完全识别风险。女性的生育史（例如初潮年龄、月经周期、不孕、怀孕、更年期）可能带来了独特的风险，并为采取新方法提供了机会。我们提出了一种以女性为中心的方法。用于早期识别处于危险中的妇女，调查某个年龄时独特的生殖功能丧失情况早在其他重要系统发生故障之前，尽管这个过程很重要，但人们对它知之甚少。卵巢衰老的决定因素或相关因素，或对健康的影响，尤其是在不同人群中。剩余卵母细胞库的可靠生物标记物，我们有一个独特的机会来表征 “卵巢年龄”与卵母细胞加速丢失对健康的影响之间的关联。相反，我们认为风险与早期绝经和雌激素缺乏的众所周知的影响无关。提出常见的潜在细胞衰老机制，由于其敏感性首先在卵巢中明显显现和早期死亡，使卵巢成为了解潜在躯体健康状况的窗口。卵巢年龄标志物下降与心血管疾病风险之间的关系将使潜在的高危人群卵巢衰老（OVA）队列是最大的。以及最具种族多样性、以社区为基础的队列，可用于确定卵巢衰老的种族/民族和行为决定因素及其与年轻自行车运动员心血管疾病风险的关系评估卵巢年龄标志物之间的关系（反映过去的暴露情况和遗传因素）。风险）、卵巢老化率（代表当前暴露）和 CVD 风险，我们建议： 1. 确定通过测试卵巢年龄/老化标志物是否与 CVD 风险增加相关通过外周内皮细胞测量，年龄/衰老与 CVD 风险增加独立相关功能测试；2.确定卵巢衰老是否可以缓和或介导已建立的关联通过检查观察到的种族/民族是否存在种族/民族和/或社会/情感健康与心血管疾病风险之间的关系差异或社会/情绪健康对 CVD 风险的影响可能因（调节模型）或部分而异归因于（中介模型）卵巢衰老；以及 3. 确定卵巢衰老是否与 CVD 风险以及外观的时间模式与细胞衰老的标志相关：端粒长度和 mtDNA 外周白细胞、氧化应激（血浆 F2α-异前列腺素）和炎症指数（C 反应性蛋白质、白细胞介素 6 和可溶性细胞间粘附分子 1)。评估卵巢和细胞衰老标志物作为 CVD 预测因子的方法可能会带来一种新方法识别处于早期和/或增加的 CVD 风险的女性，并用于制定新的风险降低策略。