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

了解雌激素受体表达在感染和未感染 HIV 的女性 CVD 风险中的作用

• 批准号: 10155590
• 负责人: Caitlin Moran
• 金额: $ 17.94万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10155590
• 关键词: AIDS/HIV problem; Affect; Age; Antiinflammatory Effect; Antioxidants; Automobile Driving; Award; Binding; Biological Markers; Biology; Blood Vessels; Cardiac; Cardiovascular Diseases; Carotid Arteries; Cells; Centers of Research Excellence; Clinical; Clinical Research; Cohort Studies; Communicable Diseases; Data; Data Analyses; Disease; Disease Progression; ESR1 gene; ESR2 gene; Estradiol; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogen Receptors; Estrogens; Fibrosis; Foundations; Gene Expression; General Population; Gonadal Steroid Hormones; HIV; HIV Infections; HIV Seronegativity; Immune; Immune system; Inflammation; Inflammatory; Ischemic Stroke; Laboratories; Light; Link; Macrophage Activation; Master of Science; Measures; Menopausal Status; Menopause; Mentored Patient-Oriented Research Career Development Award; Mentors; Mentorship; Methods; Myocardial Infarction; Organ; Participant; Pathogenesis; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Persons; Play; Positioning Attribute; Premenopause; Prevalence; Process; Recruitment Activity; Relative Risks; Research; Research Personnel; Research Proposals; Research Training; Resources; Risk; Risk Factors; Role; Sampling; Scientist; Serum; Sex Differences; Specialized Center; Testing; Thick; Time; Training; Translations; Viral; Visit; Woman; Women' s Interagency HIV Study; Work; antiretroviral therapy; arterial stiffness; cardioprotection; cardiovascular disorder risk; cardiovascular risk factor; career; carotid intima-media thickness; cohort; design; early experience; endothelial dysfunction; experience; high risk; innovation; longitudinal analysis; men; primary outcome; prospective; protein expression; receptor; receptor expression; receptor function; recruit; secondary outcome; skills; training opportunity; translational scientist; trend; virology; young woman

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.

项目总结/摘要 有了这个K23指导的以患者为导向的研究职业发展奖，我将发展技能 有必要成为一个独立的临床医生，科学家专注于终末器官疾病的发病机制， 感染艾滋病毒的妇女（WLWH）。我的背景是临床传染病， 临床研究为这项工作提供了基础，这项工作将利用亚特兰大的资源 妇女机构间艾滋病毒研究（WIHS）和埃默里专业研究卓越中心（SCORE） 性别差异。在此期间，我将由Igho Ofotokun博士指导，他是一位艾滋病毒转化研究人员 亚特兰大WIHS和SCORE的PI，Gretchen Neigh博士，在性激素方面有经验的基础科学家 Arshed Quyyumi博士是一位心脏病专家和研究人员，在转化生物学方面拥有丰富的经验。 血管研究。我将完成纵向数据分析的高级课程， 实验室方法测量雌激素受体基因表达和翻译，血管功能， 颈动脉壁厚度，并接受指导指导，在女性CVD发病机制，性激素 生物学和艾滋病临床研究。艾滋病毒是心血管疾病的危险因素，年轻女性艾滋病毒感染者（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 这种现象还不太清楚，但我们推测雌激素活性的差异可能起作用。 我们之前的研究表明，CRP，一种与普通人群中CVD相关的生物标志物， WLWH中的亚临床CVD进展，与未感染HIV的女性一样，表明存在不同的 在WLWH中驱动CVD发病机制的机制，可能与雌激素活性有关。雌激素影响 通过与雌激素受体（ER）β和ER β的相互作用，通过炎症途径，这是由 基因ESR 1和ESR 2。我们发现，ESR 1和ESR 2表达之间的关联， WIHS中女性的PBMC和颈动脉内膜中层厚度因年龄和HIV状态而异。我们假设 在WLWH中ESR 1和ESR 2的表达和翻译成ERα和ERβ的表达低于HIV阴性的 ESR 1和ESR 2表达和翻译的减少与亚临床CVD的发生有关 流行和进展。我们提出了一项病毒学抑制的WLWH和高危HIV的队列研究， 目的：1）确定ESR 1和ESR 2中HIV感染的影响 2）为了确定ESR 1和ESR 2的表达和翻译是否随时间变化， 通过颈动脉壁厚度、内皮细胞厚度、血管内皮细胞厚度、 功能障碍和动脉僵硬度，以及3）确定ESR 1和ESR 2表达之间的关联 和亚临床CVD进展中的转化。利用正在进行的队列研究， 招聘人员将大大提高这些目标的可行性。完成这些目标将使我 从我的导师那里学到科学知识，让我成为一名独立的临床科学家。