Nicotinic Acid Receptor Activation and Brain Proinflammatory Responses in HIV-1 Transgenic Rat

HIV-1 转基因大鼠烟酸受体激活和脑促炎反应

• 批准号: 10160861
• 负责人: WALTER ROYAL
• 金额: $ 35.5万
• 依托单位: MOREHOUSE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10160861
• 关键词: Acute; Adult; Agonist; Animals; Astrocytes; Brain; Cells; Choline; Chronic; Cigarette; Cigarette Smoker; Development; Exposure to; General Population; Generations; Genes; Grant; HIV; HIV Envelope Protein gp120; HIV Infections; HIV-1; Human; Immune; Immunologic Markers; Impairment; In Vitro; Inbred F344 Rats; Individual; Inflammation; Inflammation Mediators; Inflammatory; Inhalation; Injury; Interleukin-1 beta; Leukocytosis; Mediating; Metabolic; Metabolic Pathway; Metabolism; Microglia; Mitochondria; Modeling; Nervous System Trauma; Neurocognitive Deficit; Neurologic; Neuronal Dysfunction; Nicotinamide adenine dinucleotide; Nicotine; Nicotinic Acids; Nicotinic Receptors; Oxidative Stress; Pathway interactions; Performance; Plasma; Production; Property; Proteins; Rattus; Receptor Activation; Risk; SIRT1 gene; Smoker; Smoking; TNF gene; Testing; Tobacco; Toxin; Transgenic Organisms; Translating; Up-Regulation; Viral Load result; alpha-bungarotoxin receptor; antiretroviral therapy; behavior test; biological adaptation to stress; cigarette smoke; cigarette smoking; clinical effect; cytokine; desensitization; exposure to cigarette smoke; immune activation; improved; in vivo; in vivo Model; inhibitor/antagonist; innovation; mortality; nicotine exposure; nicotine vapor; novel strategies; receptor; receptor downregulation; receptor expression; receptor function; response; smoking prevalence; vaping

Neurological complications occur commonly in HIV infection, with over 40% of individuals being at risk for developing HIV-related neurocognitive impairment (NCI), with the numbers increasing in the era of effective antiretroviral therapy (1). Factors that underlie the development of NCI include neuronal dysfunction due to enhanced production of proinflammatory cytokines (e.g., TNF-α and IL-1β) and other inflammatory mediators that are secreted by HIV-infected cells in the brain (2,3). Contributing to such responses is impairment metabolism mediated by nicotinamide adenine dinucleotide (NAD), which is essential for normal mitochondrial function and the production of energy substrates in cells. In this grant, we will analyze potential effects of exposure to cigarette smoke (CS) and nicotine as co-factors for increasing the risk of NCI in HIV infected individuals. Cigarette smoking has been shown to alter a number of innate and adaptive immune mechanisms and can elicit cellular oxidative stress responses that can promote injury. Most marketed brands of cigarettes contain varying amounts of nicotine. In smokers, CS causes a leukocytosis and, in HIV-infected individuals, smoking is associated with higher plasma HIV viral loads and an increased mortality. It has been estimated that over 40% of HIV+ individuals are cigarette smokers (6), a number that is twice the estimated prevalence of smoking among adults in the general population (7). Nicotine, via activation of nicotinic acetylcholine receptors (nAChR), promotes cigarette smoking through its addictive properties. By activating these receptors, nicotine has been also shown to suppress immune activation and proinflammatory responses through direct effects on immune cells as well as through pathways that are mediated by activation of nicotine receptors (8-10). However, due to effects of HIV protein and with chronic nicotine exposure and upregulation of nAChR, proinflammatory responses have been observed to increase, thereby potentially contributing to CNS damage that occurs in the context of HIV infection. In previous studies in adult Lewis rats, we demonstrated that CS exposure can result in marked inflammatory and oxidative stress responses in the brains of the exposed animals (11). We have subsequently demonstrated that such effects can be also observed in HIV-1 transgenic rats, with more prominent responses developing than what are observed in corresponding wild-type animals. We also provide evidence that such responses can be driven by nicotine that is present in the CS. Activation of nAChR can also regulate cellular levels of NAD and activation of associated metabolic pathways. The potential effects of such activation in HIV infection and the generation of chronic inflammation in brain has not been previously studied. The proposed studies will be performed in vivo utilizing the transgenic rat model as well as in vitro utilizing primary astrocyte cultures that express the same HIV genes as the transgenic rat in vivo.

神经系统并发症通常发生在HIV感染中，超过40%的人有神经系统并发症的风险。 发展艾滋病毒相关的神经认知障碍（NCI），在有效的时代， 抗逆转录病毒治疗（1）。NCI发展的基础因素包括神经元功能障碍， 促炎细胞因子的产生增强（例如，TNF-α和IL-1 β）和其他炎症介质 由大脑中的HIV感染细胞分泌（2，3）。造成这种反应的是损害 由烟酰胺腺嘌呤二核苷酸（NAD）介导的代谢，这是正常线粒体 功能和生产的能量基板在细胞中。在本研究中，我们将分析 暴露于香烟烟雾（CS）和尼古丁作为增加HIV感染者NCI风险的辅助因素 个体吸烟已被证明会改变许多先天和适应性免疫机制 并可引发可促进损伤的细胞氧化应激反应。大多数市场上销售的香烟品牌 含有不同数量的尼古丁。在吸烟者中，CS引起白细胞增多，在HIV感染者中， 吸烟与较高的血浆HIV病毒载量和增加的死亡率有关。据估计 超过40%的HIV+个体是吸烟者（6），这一数字是估计患病率的两倍， 在一般人群中吸烟的成年人（7）。尼古丁，通过激活烟碱乙酰胆碱受体 （nAChR）通过其成瘾特性促进吸烟。通过激活这些受体，尼古丁 还显示通过直接作用于 免疫细胞以及通过尼古丁受体激活介导的途径（8 - 10）。 然而，由于HIV蛋白的影响以及慢性尼古丁暴露和nAChR的上调， 已经观察到促炎反应增加，从而可能导致CNS损伤 发生在艾滋病感染的背景下。在以前对成年刘易斯大鼠的研究中，我们证明CS 暴露可导致暴露者大脑中显著的炎症和氧化应激反应 动物（11）我们随后证明，这种效应也可以在HIV-1转基因小鼠中观察到。 大鼠，与在相应的野生型动物中观察到的相比，出现了更显著的反应。 我们还提供了证据表明，这种反应可以由存在于CS中的尼古丁驱动。激活 nAChR还可以调节NAD的细胞水平和相关代谢途径的激活。的潜在 这种激活在HIV感染和脑中慢性炎症的产生中的作用还没有被证实。 以前研究过。将利用转基因大鼠模型以及 在体外利用表达与体内转基因大鼠相同的HIV基因的原代星形胶质细胞培养物。