Role of Monocyte Oxidative Stress and Mineralocorticoid Receptor Signaling on Cardiovascular Disease and Persistent Inflammation in Antiretroviral-Treated HIV+ Persons

单核细胞氧化应激和盐皮质激素受体信号传导对接受抗逆转录病毒治疗的艾滋病毒患者心血管疾病和持续性炎症的作用

• 批准号: 8920373
• 负责人: JEFFREY MILUSH
• 金额: $ 23.78万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8920373
• 关键词: Acquired Immunodeficiency Syndrome; Adrenal Cortex Hormones; Aldosterone; Anti-Inflammatory Agents; Anti-Retroviral Agents; Anti-inflammatory; Antioxidants; Area; Atherosclerosis; Attenuated; Automobile Driving; Binding; Biological Assay; Cardiac Myocytes; Cardiovascular Diseases; Carotid Arteries; Cause of Death; Cells; Chronic; Clinical; Clinical Research; Corticosteroid Receptors; Data; Development; Epithelial Cells; Evaluation; Event; Flow Cytometry; Genes; Glucocorticoid Receptor; HIV; HIV Infections; HIV-1; Heart Diseases; Hormone Receptor; Human; Hydrocortisone; Hyperglycemia; Hyperlipidemia; Immune; Immune system; Individual; Inflammation; Inflammatory; Intervention; Kidney; Laboratories; Link; Lipodystrophy; Longevity; Measures; Messenger RNA; Metabolic; Methods; Mineralocorticoid Receptor; Mineralocorticoids; Modeling; Molecular; Morbidity - disease rate; Mus; Myeloid Cells; NADPH Oxidase; Natural Immunity; Nuclear Hormone Receptors; Oxidases; Oxidation-Reduction; Oxidative Stress; Participant; Pathogenesis; Pathway interactions; Patients; Persons; Phenotype; Physiological; Play; Production; Property; Protein-Serine-Threonine Kinases; Quality of life; Rattus; Receptor Signaling; Research; Risk; Role; Signal Pathway; Signal Transduction; Specimen; Stress; System; Transcript; Translating; United States; abstracting; antiretroviral therapy; base; cardiovascular disorder risk; cytokine; high throughput screening; immune activation; inflammatory marker; inhibitor/antagonist; innovation; insight; intimal medial thickening; kinase inhibitor; macrophage; monocyte; mortality; new therapeutic target; novel; prevent; public health relevance; receptor expression; receptor function; response

 DESCRIPTION (provided by applicant): Worldwide, heart disease remains the leading cause of death for more than a decade and a leading cause of death in the United States. Combination antiretroviral therapy (cART) has reduced HIV-related morbidity and mortality; however these patients are now facing new clinical issues including increased risk of cardiovascular disease (CVD). Among HIV+ individuals in the United States, CVD is the leading non-AIDS-related cause of death. Chronic inflammation and myeloid cell dysregulation are key features of both CVD and HIV infection, but how they are biologically linked remains poorly understood. We will use specimens from HIV+ participants in ongoing clinical studies of HIV and CVD as a model to understand the factors that may regulate monocyte responses that contribute to CVD. Nuclear hormone receptors play an important role in monocyte activation and differentiation. We will assess the role of two nuclear hormone receptors, the glucocorticoid and mineralocorticoid receptors, for their role in low-grade chronic inflammation and risk of CVD observed in cART- suppressed HIV+ patients. While the glucocorticoid receptor has well-defined anti-inflammatory functions in immune cells, the mineralocorticoid receptor has predominantly been studied in renal epithelial cells. In comparison, very little is known about mineralocorticoid receptor expression and function in human immune cells or its connection with physiologic and pathophysiologic conditions. The proposed studies take advantage of several innovative flow cytometry-based assays developed in our laboratory that allow simultaneous quantitative measures of the glucocorticoid and mineralocorticoid receptor expression and function with immune cell phenotype as well as a novel flow cytometry-based quantitative mRNA assay to measure gene transcripts on a per cell basis. We will use these assays to assess whether cortisol-induced activation of the mineralocorticoid receptor in monocytes results in pro-inflammatory/pro-fibrotic cytokine production and accelerated CVD in cART-suppressed HIV+ patients. We will use specimens from HIV+ participants in ongoing clinical studies of HIV and CVD to assess the relationships between oxidative stress, inflammation and corticosteroid receptor expression and signaling with carotid artery intima-media thickness measures. We will then explore the molecular pathways involved in mineralocorticoid receptor signaling during oxidative stress using specific inhibitors of oxidases, redox-sensitive serine kinases and corticosteroid receptor antagonists. This project is expected to provide novel insights into an unexplored area of corticosteroid receptor signaling in monocytes that will not only strengthen our understanding of this mechanism in CVD pathogenesis, but will also enable the development of additional mechanistic studies to characterize this important signaling pathway in immune cells. The availability of mineralocorticoid receptor antagonists, as well as the ongoing development of oxidase and kinase inhibitors, further enhance the potential clinical impact of this research, as there are clear potential pathways for translating insights from this bench research to the bedside.

 描述（由申请人提供）：在世界范围内，心脏病仍然是十多年来的主要死因，也是美国的主要死因。联合抗逆转录病毒治疗（cART）降低了HIV相关的发病率和死亡率;然而，这些患者现在面临着新的临床问题，包括心血管疾病（CVD）风险增加。在美国的HIV+个体中，CVD是主要的非艾滋病相关死亡原因。慢性炎症和骨髓细胞失调是CVD和HIV感染的关键特征，但它们在生物学上的联系仍然知之甚少。我们将使用来自正在进行的HIV和CVD临床研究中的HIV+参与者的标本作为模型，以了解可能调节导致CVD的单核细胞反应的因素。核激素受体在单核细胞活化和分化中起重要作用。我们将评估两种核激素受体（糖皮质激素和盐皮质激素受体）在cART抑制的HIV+患者中观察到的低度慢性炎症和CVD风险中的作用。虽然糖皮质激素受体在免疫细胞中具有明确的抗炎功能，但盐皮质激素受体主要在肾上皮细胞中进行研究。相比之下，很少有人知道盐皮质激素受体的表达和功能在人类免疫细胞或其与生理和病理生理条件的连接。拟议的研究利用了我们实验室开发的几种创新的基于流式细胞术的检测方法，可以同时定量测量糖皮质激素和盐皮质激素受体的表达和功能与免疫细胞表型，以及一种新的基于流式细胞术的定量mRNA检测方法，以测量每个细胞的基因转录。我们将使用这些试验来评估皮质醇诱导的单核细胞盐皮质激素受体激活是否会导致cART抑制的HIV+患者中促炎/促纤维化细胞因子产生和加速CVD。我们将使用正在进行的HIV和CVD临床研究中的HIV+参与者的标本来评估氧化应激、炎症和皮质类固醇受体表达和信号传导与颈动脉内膜中层厚度测量之间的关系。然后，我们将探讨在氧化应激过程中使用特定的氧化酶，氧化还原敏感性丝氨酸激酶和皮质类固醇受体拮抗剂抑制剂的盐皮质激素受体信号转导的分子途径。该项目有望为单核细胞中皮质类固醇受体信号传导的未探索领域提供新的见解，这不仅将加强我们对CVD发病机制的理解，而且还将使其他机制研究的发展能够表征免疫细胞中这一重要的信号传导途径。盐皮质激素受体拮抗剂的可用性，以及氧化酶和激酶抑制剂的持续开发，进一步增强了这项研究的潜在临床影响，因为有明确的潜在途径将这项实验室研究的见解转化为床边研究。