Understanding the role of estrogen receptor expression in CVD risk in women with and without HIV

项目摘要/摘要 有了这个K23导师以患者为导向的研究职业发展奖，我将发展技能 成为一名独立的临床医生兼科学家，专注于终末器官疾病的发病机制 艾滋病毒携带者妇女(WLWH)。我的临床传染病背景和 临床研究为这项工作提供了基础，这将利用亚特兰大医院的资源 妇女机构间艾滋病毒研究(WIHS)和埃默里卓越专门研究中心(SCORE)关于 性别差异。在这个奖项中，我将得到艾滋病毒翻译研究员Igho Ofotokun博士的指导 亚特兰大WIHS和SCORE的PI，Gretchen Neigh博士，一位在性激素方面有经验的基础科学家 生物学，和阿尔谢德·奎尤米博士，他是一名心脏病专家和研究人员，在翻译方面有丰富的经验 血管研究。我将完成纵向数据分析方面的高级课程，实践培训 测量雌激素受体基因表达和翻译、血管功能和 颈动脉壁厚度和接受指导在女性CVD发病机制中的性激素 生物学和艾滋病毒临床研究。艾滋病毒是心血管疾病的危险因素，年轻女性感染艾滋病毒(WLWH) 与未感染艾滋病毒的同龄人相比，患心血管疾病的风险特别高。背后的机制 人们对这一现象知之甚少，但我们推测雌激素活性的差异可能起到了一定作用。 我们先前的工作表明，在普通人群中与心血管疾病相关的生物标记物CRP不能预测 WLWH中的亚临床心血管疾病进展，就像在未感染艾滋病毒的女性中一样，表明存在不同的 WLWH CVD发病机制可能与雌激素活性有关。雌激素影响 通过其与雌激素受体(ER)和ER的相互作用，炎症通路由 基因ESR1和ESR2。我们发现ESR1和ESR2的表达之间存在关联 WIHS患者的PBMC和颈动脉内膜-中层厚度因年龄和HIV状况而不同。我们假设 WLWH患者ESR1和ESR2的表达及向ERα和ERβ的转化均低于HIV阴性患者 女性，以及ESR1和ESR2表达和翻译减少与更多的亚临床心血管疾病相关 流行和进展。我们建议对病毒学上抑制的WLWH和高危HIV进行一项队列研究。 阴性妇女的目标如下：1)确定艾滋病毒感染对ESR1和ESR2的影响 外周血单核细胞随时间的表达和翻译，2)确定ESR1和ESR2的表达和 根据颈动脉壁厚度、血管内皮细胞厚度预测流行的亚临床心血管疾病 功能障碍和动脉僵硬，3)确定ESR1和ESR2表达之间的关联 以及转化为和亚临床CVD进展。利用正在进行的队列研究，这些研究 招聘将极大地增强这些目标的可行性。完成这些目标将把我分开 从我的导师那里学到科学，并让我过渡到作为一名临床医生-科学家的独立。

PROJECT SUMMARY/ABSTRACT With this K23 Mentored Patient-Oriented Research Career Development Award, I will develop the skills necessary to become an independent clinician-scientist focused on the pathogenesis of end-organ disease in women living with HIV (WLWH). My background in clinical Infectious Diseases and a Master of Science in Clinical Research have provided a foundation for this work, which will leverage the resources of the Atlanta Women’s Interagency HIV Study (WIHS) and Emory Specialized Center of Research Excellence (SCORE) on Sex Differences. During this Award, I will be mentored by Dr. Igho Ofotokun, an HIV translational researcher and PI of the Atlanta WIHS and SCORE, Dr. Gretchen Neigh, a basic scientist with experience in sex hormone biology, and Dr. Arshed Quyyumi, a cardiologist and researcher with extensive experience in translational vascular studies. I will complete advanced coursework in longitudinal data analysis, hands-on training in laboratory methods to measure estrogen receptor gene expression and translation, vascular function, and carotid artery wall thickness, and receive directed mentorship in CVD pathogenesis in women, sex hormone biology, and HIV clinical research. HIV is a risk factor for CVD, and young women living with HIV (WLWH) have an especially high risk for CVD compared to their HIV-uninfected counterparts. The mechanisms behind this phenomenon are poorly understood, but we postulate that differences in estrogen activity may play a role. Our prior work showed that CRP, a biomarker associated with CVD in the general population, does not predict subclinical CVD progression in WLWH, as it does in HIV-uninfected women, suggesting that there is a different mechanism driving the pathogenesis of CVD in WLWH, possibly related to estrogen activity. Estrogen affects inflammatory pathways via its interactions with estrogen receptor (ER) and ER, which are encoded by the genes ESR1 and ESR2, respectively. We found that the association between ESR1 and ESR2 expression on PBMCs and carotid intima-media thickness differs by age and HIV status in women in WIHS. We hypothesize that ESR1 and ESR2 expression and translation into ERα and ERβ is lower in WLWH than in HIV-negative women, and reduced ESR1 and ESR2 expression and translation are associated with greater subclinical CVD prevalence and progression. We propose a cohort study of virologically suppressed WLWH and at-risk HIV- negative women with the following aims: 1) To determine the effect of HIV infection in ESR1 and ESR2 expression and translation on PBMCs over time, 2) To determine if ESR1 and ESR2 expression and translation predicts prevalent subclinical CVD as measured by carotid artery wall thickness, endothelial dysfunction and arterial stiffness, and 3) To determine the association between ESR1 and ESR2 expression and translation in and subclinical CVD progression. Leveraging ongoing cohort studies that are actively recruiting will greatly enhance the feasibility of these aims. Completion of these aims will separate me scientifically from my mentors and position me to transition to independence as a clinician-scientist.