The Psychosocial & Genetic Basis of Estrogen Metabolism & Blood Pressure in Aging

描述(申请人提供)：尽管老年人的慢性残疾患病率下降，但年龄仍然与高血压和高血压相关疾病的风险有关，包括冠状动脉疾病和中风。在这项K08应用中，PI将积极探索与年龄相关的高血压疾病的潜在机制，特别是在高危人群中。拟议研究的理论基础基于芝加哥健康、老龄化和社会关系研究(CHASRS)内的PI生成的数据。这项研究由NIA资助，约翰·卡乔波博士指导，试图解释包括孤独在内的心理社会因素对与年龄相关的收缩压(SBP)变化的影响。CHASRS的最新数据表明，孤独和敌意与尿雌激素代谢产物浓度有关，而这些浓度与SBP有关。由于饮食、运动和应激激素可以影响雌激素代谢，因此假设高血压的许多危险因素与雌激素代谢有关，血清雌激素代谢产物水平与SBP有关。具体目的是在CHASRS队列中探索这些假设，并在荷兰孪生注册中心的更大队列中验证它们。具体目标1是确定哪种血清雌激素代谢物或血清雌激素代谢物的组合最能预测中老年男性和女性的收缩压。具体目标2是确定血清雌激素代谢物浓度与尿中雌激素代谢物浓度的相关程度。具体目标3是确定编码特定雌激素代谢酶的基因的单核苷酸多态(SNP)是否预测与收缩压最密切相关的雌激素代谢物的血清浓度。具体目标4是确定雌激素代谢物在多大程度上解释了中老年男性和女性高血压危险因素与收缩压之间的关系。完成这些目标，以及卡乔波博士的指导和心理学、老年病学、内分泌学、血管生物学和遗传学方面的额外培训，将确保PI发展成为一名独立的临床研究员，拥有雌激素代谢和年龄相关血压变化的人口统计、心理社会和遗传决定因素方面的专业知识。

DESCRIPTION (provided by applicant): Despite the declining prevalence of chronic disability among older individuals, age continues to be associated with risk of hypertension and hypertension-related diseases, including coronary artery disease and stroke. In this K08 application, the PI will aggressively explore the mechanisms underlying age-related hypertensive disease, especially among those at highest risk. The theoretical underpinnings of the proposed research are based upon data generated by the PI within the Chicago Health, Aging, and Social Relations Study (CHASRS). Funded by the NIA and directed by Dr. John Cacioppo, this study seeks to explain the effect of psychosocial factors, including loneliness, on age-related changes in systolic blood pressure (SBP). Recent data from CHASRS indicate that loneliness and hostility are associated with urinary estrogen metabolite concentrations and these concentrations are associated with SBP. Because diet, exercise, and stress hormones can influence estrogen metabolism, it is hypothesized that many risk factors for hypertension are associated with estrogen metabolism and that serum levels of estrogen metabolites are associated with SBP. The specific aims are designed to explore these hypotheses in the CHASRS cohort and validate them in a larger cohort from the Netherlands Twin Registry. Specific Aim 1 is to determine which serum estrogen metabolite or combination of serum estrogen metabolites best predicts systolic blood pressure in middle aged and older men and women. Specific Aim 2 is to determine the degree to which serum estrogen metabolite concentrations are correlated with urinary estrogen metabolite concentrations. Specific Aim 3 is to determine whether single nucleotide polymorphisms (SNP's) of genes which encode specific estrogen metabolizing enzymes predict the serum concentrations of the estrogen metabolites most closely associated with systolic blood pressure. Specific Aim 4 is to determine the extent to which estrogen metabolites explain the associations between established hypertension risk factors and systolic blood pressure in middle aged and older men and women. Completion of these aims, as well as mentorship by Dr. Cacioppo and additional training in psychology, geriatrics, endocrinology, vascular biology, and genetics, will ensure the PI develops into an independent clinician investigator with expertise in the demographic, psychosocial, and genetic determinants of estrogen metabolism and age-related blood pressure changes.