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.

摘要 尽管抗逆转录病毒疗法（ART）得到发展和实施，但艾滋病毒感染与以下因素有关： 高水平的炎症，这似乎是导致早产儿风险升高的主要因素。 心血管疾病和肺部疾病。我们小组最近的工作确定了 腺苷信号通路的损伤是导致不能正常 调节促炎途径。腺苷信号也是正常睡眠-觉醒的关键组成部分 调节，与基底前脑和中枢神经系统其他部分的细胞外腺苷水平 作为睡眠自我平衡的生化驱动器。长期睡眠不好，这是非常严重的 在艾滋病病毒感染者中流行，已被证明可以改变中枢神经系统中的腺苷信号 系统和急性睡眠剥夺已被发现改变白细胞中腺苷受体表达。 流行病学和实验数据表明，急性和慢性正常睡眠中断都会导致 炎症和许多相同的下游心肺健康后果的人所经历的 艾滋病毒携带者我们发现，HIV（+）人群中自我报告的睡眠不佳是一个独立的预测因子， 心肺疾病在这个提议中，我们试图验证一个假设，即睡眠不好的一种机制， 可能通过影响外周腺苷信号传导影响炎症和心肺风险。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 ART治疗的HIV（+）人群中的标记物，并与HIV（-）对照组进行比较。在 在HIV感染的情况下，我们将进一步比较T细胞免疫激活和外周腺苷水平， 在那些有和没有慢性睡眠剥夺的人中， 艾滋病病毒感染者之间的腺苷信号通路。最后，我们将评估24小时 急性睡眠剥夺对腺苷信号传导、炎症、免疫激活和内皮功能的影响， HIV（+）人群健康睡眠习惯评估急性睡眠缺失对外周腺苷酸的影响 信号和下游效应。总的来说，这些实验将评估睡眠不佳对炎症的作用 和心肺功能，并评估在何种程度上， 和慢性睡眠中断影响炎症和免疫功能的艾滋病毒和缺陷的作用， 外周腺苷信号传导介导这些作用。这项工作将提供有关小说的见解 预防艾滋病毒长期心血管和肺部并发症的治疗策略 感染