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: 10013898
• 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/10013898
• 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.

项目概要/摘要 通过这个 K23 指导的以患者为导向的研究职业发展奖，我将发展以下技能 有必要成为一名独立的临床医生科学家，专注于终末器官疾病的发病机制 感染艾滋病毒的女性 (WLWH) 我的临床传染病背景和理学硕士学位。 临床研究为这项工作奠定了基础，它将利用亚特兰大的资源 妇女机构间艾滋病毒研究 (WIHS) 和埃默里大学专业卓越研究中心 (SCORE) 性别差异。在这个奖项期间，我将受到艾滋病毒转化研究员 Igho Ofotokun 博士的指导。 亚特兰大 WIHS 和 SCORE 的 PI，Gretchen Neigh 博士，一位在性激素方面拥有丰富经验的基础科学家 生物学和 Arshed Quyyumi 博士是一位心脏病学家和研究员，在转化方面拥有丰富的经验 我将完成纵向数据分析的高级课程和实践培训。 测量雌激素受体基因表达和翻译、血管功能的实验室方法，以及 颈动脉壁厚度，并接受女性 CVD 发病机制、性激素的指导指导 生物学和 HIV 临床研究 HIV 是 CVD 的危险因素，以及感染 HIV 的年轻女性 (WLWH)。 与未感染艾滋病毒的捐赠者相比，他们患心血管疾病的风险特别高。 人们对这种现象知之甚少，但我们推测雌激素活性的差异可能发挥了作用。 我们之前的工作表明，CRP（一种与普通人群中 CVD 相关的生物标志物）并不能预测 WLWH 中的亚临床 CVD 进展与未感染 HIV 的女性一样，表明存在不同的情况 WLWH 中 CVD 发病机制的驱动机制，可能与雌激素活性的影响有关。 通过与雌激素受体 (ER)α 和 ERβ 的相互作用来调节炎症通路，雌激素受体 (ER)α 和 ERβ 是由 我们分别发现ESR1和ESR2基因表达之间的关联。 WIHS 女性的 PBMC 和颈动脉内膜中层厚度因年龄和 HIV 状况而异。 WLWH 中的 ESR1 和 ESR2 表达以及翻译成 ERα 和 ERβ 的水平低于 HIV 阴性者 女性，ESR1 和 ESR2 表达和翻译的减少与亚临床 CVD 的增加有关 我们提出了一项针对病毒学抑制的 WLWH 和高危 HIV 的队列研究。 阴性女性的目的如下： 1) 确定 HIV 感染对 ESR1 和 ESR2 的影响 随着时间的推移，PBMC 上的表达和翻译，2) 确定 ESR1 和 ESR2 表达和翻译是否 翻译可预测流行的亚临床 CVD（通过颈动脉壁厚度、内皮细胞厚度测量） 功能障碍和动脉僵硬度，以及 3) 确定 ESR1 和 ESR2 表达之间的关联 利用正在进行的队列研究积极进行亚临床CVD进展。 招募将大大提高这些目标的可行性，完成这些目标将使我分离。 科学地从我的导师那里获得帮助，使我能够过渡到作为一名临床医生科学家的独立地位。