Women Living with HIV: Cognitive Impact of Estrogen Receptors, Inflammation, and Aging

项目摘要/摘要 认知障碍在老年人中普遍存在，女性患认知障碍的风险更大。 认知缺陷，如痴呆症和阿尔茨海默病。虽然雌激素缺乏与 认知功能下降的风险增加，但其机制尚不清楚。有证据表明，女性 艾滋病毒携带者更有可能经历更早的更年期，从而减少 循环中的雌激素水平。此外，在艾滋病毒携带者(PLWH)人群中，妇女处于 发生认知功能衰退的风险更高，这与普通人群中的数据相一致 在没有艾滋病毒的情况下生活。由于艾滋病毒治疗的进步，PLWH的寿命延长了，增加了 迫切需要找出认知衰退加速的潜在机制。这项提议的目标是 确定雌激素受体的表达和功能在多大程度上预测WLH患者的认知能力下降。 利用亚特兰大妇女机构间艾滋病毒研究(WIHS)队列和Emory的框架 得分U54，该项目将检验艾滋病毒血清状态与更年期相互作用改变的假设 雌激素受体亚型表达和雌激素受体β的改变预示炎症 和认知结果。目标1将重点介绍雌激素受体亚型蛋白的特性 为了解两种主要雌激素在PBMC中的表达建立一种指标 受体亚型(α和β)以及它们在更年期和艾滋病毒方面的不同。目标2将建立 研究参与者的炎症和认知概况，使用纵向时间点来阐明变化 在炎症和认知状态下，都可以随着时间的推移进行跟踪。评估所产生的数据 雌激素受体亚型在绝经状态和艾滋病毒状态下的表达，加上 通过WIHS获得的认知数据将丰富我们对雌激素受体在 预测认知能力下降，并潜在地为筛选处于较高水平的女性选择生物标志物提供信息 发生认知障碍的风险，尤其是白血球过多症。这项研究和培训将与Dr一起进行。 格雷琴·N·尼尔，弗吉尼亚联邦大学博士。所提供的培训将建立在 申请者的技术、计算和分子技能，除了提供有针对性的专业技能外 发展机会，以及在假设驱动的项目设计方面的进一步培训。最终，这一培训将 为申请人将来成为一名独立的内科科学家做好准备，调查影响因素 认知随着年龄的增长而变化。

Project Summary/Abstract Cognitive impairment is prevalent in older adults and females carry a disproportionately greater risk for cognitive deficits like dementia and Alzheimer's disease. While estrogen deficiencies have been linked to an increased risk of cognitive decline, the mechanism for this remains unclear. Evidence suggests that women living with HIV (WLH) are more likely to experience an earlier onset of menopause, thereby reducing the circulating estrogen levels. Additionally, within the population of people living with HIV (PLWH), women are at a higher risk for developing cognitive decline which tracks with data seen in the general population of people living without HIV. Thanks to the advancement of HIV treatments, PLWH are living longer, adding to the urgency to identify mechanisms underlying the acceleration of cognitive decline. The goal of this proposal is to determine the extent to which estrogen receptor expression and function predict cognitive decline in WLH. Leveraging the framework of the Atlanta Women's Interagency HIV Study (WIHS) cohort and the Emory SCORE U54, this project will test the hypothesis that HIV serostatus interacts with menopause to alter estrogen receptor subtype expression and that changes to estrogen receptor β are predictive of inflammatory and cognitive outcomes. Aim 1 will focus on the characterization of estrogen receptor subtype protein expression in PBMCs to establish a metric for understanding the expression of the two prominent estrogen receptor subtypes (α and β) and how they differ in the context of menopause and HIV. Aim 2 will establish inflammatory and cognitive profiles for the study participants using longitudinal timepoints to illuminate changes in both inflammatory and cognitive states that can be tracked over time. Data resulting from the evaluation of estrogen receptor subtype expression in the context of menopausal status and HIV status, coupled with the cognitive data available through WIHS will enrich our understanding of the role of estrogen receptors in predicting cognitive decline, and potentially inform biomarker selection for screening women who are at higher risk of developing cognitive impairment, especially WLH. This research and training will be performed with Dr. Gretchen N. Neigh, Ph.D., at Virginia Commonwealth University. The training provided will build upon the applicant's technical, computational, and molecular skills, in addition to providing targeted professional development opportunities, and further training in hypothesis-driven project design. Ultimately, this training will prepare the applicant for a future as an independent physician-scientist, investigating factors that impact cognition with aging.