Impact of Poor Sleep on Inflammation and the Adenosine Signaling Pathway in HIV Infection

睡眠不良对 HIV 感染中炎症和腺苷信号通路的影响

• 批准号: 10155515
• 负责人: Bernard Jonas C Macatangay
• 金额: $ 49.59万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-01 至 2023-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10155515
• 关键词: Acute; Adenosine; Adverse effects; Animals; Biochemical; Biological; Biological Factors; Brain region; Cardiopulmonary; Cardiovascular Diseases; Cardiovascular system; Cells; Chronic; Chronic Disease; Chronic lung disease; Complex; Control Groups; Coronary Arteriosclerosis; Data; Defect; Development; Diabetes Mellitus; Disease Marker; Down-Regulation; Endothelium; Epidemiology; Functional disorder; Generations; HIV; HIV Infections; Health; Heart Diseases; High Prevalence; Hour; Human; Immune; Immunologic Markers; Impairment; Individual; Inflammation; Inflammatory; Intervention; Lead; Leukocytes; Lung; Lung diseases; Lung infections; Measures; Mediating; Morbidity - disease rate; Neuraxis; Obesity; Outcome; Pathway interactions; Patient Self-Report; Peripheral; Play; Population; Premature Mortality; Production; Psychological Factors; Pulmonary Heart Disease; Purinergic P1 Receptors; Purines; Regulation; Research; Risk; Risk Factors; Role; Schedule; Signal Pathway; Signal Transduction; Sleep; Sleep Apnea Syndromes; Sleep Deprivation; Sleep disturbances; Socioeconomic Factors; T-Cell Activation; T-Lymphocyte; Testing; Up-Regulation; Urine; Viral; Wakefulness; Walking; Work; antiretroviral therapy; basal forebrain; cohort; coronary artery calcium; endothelial dysfunction; experience; experimental study; extracellular; immune activation; immune function; immunoregulation; inflammatory marker; insight; novel; novel therapeutic intervention; poor sleep; premature; prevent; pulmonary function; receptor expression; sleep behavior; sleep pattern; sleep quality; sleep regulation; systemic inflammatory response

ABSTRACT HIV infection, despite the development and implementation of antiretroviral therapy (ART), is associated with high levels of inflammation, which appears to be a major factor underlying the elevated risk for premature cardiovascular and pulmonary disease among people living with HIV. Recent work from our group identifies impairments in the adenosine signaling pathway as an important mechanism leading to an inability to normally regulate pro-inflammatory pathways. Adenosine signaling is also a key component to normal sleep-wake regulation, with extracellular adenosine levels in the basal forebrain and other parts of the central nervous system serving as the biochemical driver of the homeostatic drive for sleep. Chronically poor sleep, which is highly prevalent among people living with HIV, has been demonstrated to alter adenosine signaling in the central nervous system and acute sleep deprivation has been found to alter adenosine receptor expression in leukocytes. Epidemiologic and experimental data suggest both acute and chronic disruption of normal sleep leads to elevated inflammation and to many of the same downstream cardiopulmonary health consequences experienced by people living with HIV. We have found self-reported poor sleep in an HIV(+) population is an independent predictor of cardiopulmonary disease. In this proposal, we seek to test the hypothesis that one mechanism by which poor sleep may impact inflammation and cardiopulmonary risk is via effects on peripheral adenosine signaling. We will assess the association between objectively assessed sleep habits, inflammation and cardiopulmonary disease markers in an ART-treated HIV(+) population and compare relationships with an HIV(-) control group. In the setting of HIV infection, we will further compare levels of T-cell immune activation and peripheral adenosine signaling in those with and without chronic sleep deprivation to assess the impact of chronic sleep habits on adenosine signaling pathways among people living with HIV. Finally, we will assess the impact of 24 hours of acute sleep deprivation on adenosine signaling, inflammation, immune activation, and endothelial function in an HIV(+) population with healthy sleep habits to assess the impact of acute sleep loss on peripheral adenosine signaling and downstream effects. In total, these experiments will evaluate the role of poor sleep on inflammation and cardiopulmonary function in people living with HIV and evaluate the extent to which both acute sleep loss and chronic sleep disruption impact inflammation and immune function in HIV and the role of defects in peripheral adenosine signaling in mediating these effects. This work will provide insights regarding novel therapeutic strategies towards preventing the long term cardiovascular and pulmonary complications of HIV infection.

抽象的 尽管抗逆转录病毒疗法（ART）的发展和实施，HIV感染与 高水平的炎症，这似乎是过早风险升高的主要因素 艾滋病毒患者中的心血管和肺部疾病。我们小组的最新工作确定 腺苷信号通路中的损伤是一种重要机制，导致正常无法 调节促炎途径。腺苷信号传导也是正常睡眠效果的关键组成部分 调节，基础前脑和中枢神经系统其他部位的细胞外腺苷水平 作为稳态驱动器的生化驱动力。长期睡眠不佳，这是高度的 在艾滋病毒感染者中流行，已被证明会改变中枢神经中的腺苷信号传导 已经发现系统和急性睡眠剥夺会改变白细胞中腺苷受体的表达。 流行病学和实验数据表明，正常睡眠的急性和慢性破坏导致升高 炎症以及许多人所经历的许多相同的下游心肺健康后果 与艾滋病毒一起生活。我们发现在艾滋病毒（+）种群中自我报告的睡眠不良是独立的预测指标 心肺疾病。在此提案中，我们试图检验以下假设，即睡眠不佳的一种机制 可能会影响炎症和心肺风险是对外围腺苷信号传导的影响。我们将 评估客观评估的睡眠习惯，炎症和心肺疾病之间的关联 经过艺术处理的艾滋病毒（+）种群中的标记，并将关系与艾滋病毒（ - ）对照组进行比较。在 艾滋病毒感染的设置，我们将进一步比较T细胞免疫激活和周围腺苷的水平 有或没有慢性睡眠剥夺者的信号传导，以评估慢性睡眠习惯的影响 艾滋病毒患者的腺苷信号通路。最后，我们将评估24小时的影响 腺苷信号传导，炎症，免疫激活和内皮功能的急性睡眠剥夺 具有健康睡眠习惯的HIV（+）人群，以评估急性睡眠损失对周围腺苷的影响 信号传导和下游效果。总的来说，这些实验将评估睡眠不良对炎症的作用 和艾滋病毒患者的心肺功能以及评估急性睡眠丧失的程度 慢性睡眠中断影响艾滋病毒中的炎症和免疫功能以及缺陷在 介导这些作用的周围腺苷信号传导。这项工作将提供有关小说的见解 防止艾滋病毒的长期心血管和肺并发症的治疗策略 感染。