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: 10454785
• 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/10454785
• 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; 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.

项目摘要/摘要 通过这一K23指导的以患者为导向的研究职业发展奖，我将发展技能 成为独立的临床科学家所必需的，专注于最终器官疾病的发病机理 与艾滋病毒的妇女（WLWH）。我在临床传染病方面的背景和科学硕士 临床研究为这项工作提供了基础，这将利用亚特兰大的资源 妇女妇女间艾滋病毒研究（WIHS）和埃默里专业研究中心卓越研究中心（得分） 性别差异。在此奖项期间，艾滋病毒翻译研究员Igho Ofotokun博士将我称我为 和亚特兰大的PI和得分，Gretchen Neigh博士，一位具有性恐怖经验的基础科学家 生物学和心脏病专家和研究人员Arshed Quyyumi博士拥有丰富的翻译经验 血管研究。我将完成纵向数据分析，动手培训的高级课程 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，并在女性中获得了CVD发病机理的指导性指导性 生物学和HIV临床研究。艾滋病毒是CVD的危险因素，艾滋病毒（WLWH）的年轻妇女 与其艾滋病毒未感染的对应物相比，CVD的风险特别高。背后的机制 这种现象知之甚少，但我们假设雌激素活性的差异可能起作用。 我们先前的工作表明，CRP是一般人群中与CVD相关的生物标志物，并未预测 WLWH中的亚临床CVD进展，就像在艾滋病毒未感染的妇女中一样，表明存在不同 驱动CVD在WLWH中的发病机理的机制，可能与雌激素活性有关。雌激素会影响 通过与雌激素受体（ER）和ER相互作用的炎症途径，这些途径由 基因ESR1和ESR2。我们发现ESR1和ESR2在 pBMC和颈动脉内膜媒体厚度差异划分为年龄和艾滋病毒状况。我们假设 在WLWH中，ESR1和ESR2的表达以及转化为ERα和ERβ低于HIV阴性 妇女以及降低的ESR1和ESR2表达和翻译与较大的亚临床CVD有关 患病率和进展。我们提出了一项对病毒学抑制的WLWH和高危HIV的队列研究 具有以下目的的负面女性：1）确定HIV感染在ESR1和ESR2中的影响 随着时间的推移，PBMC上的表达和翻译，2）确定ESR1和ESR2表达以及是否表达 翻译预测通过颈动脉壁厚，内皮测量的普遍亚临床CVD 功能障碍和动脉刚度，以及3）确定ESR1和ESR2表达之间的关联 并翻译和亚临床CVD进展。利用正在进行的队列研究 招聘将大大提高这些目标的可行性。这些目标的完成将使我分开 从我的导师科学上讲，将我定位为过渡到独立性，成为临床科学家。