Resetting the Clock in HIV associated COPD

标题：重置HIV相关COPD的时钟 项目摘要 这项提案的长期目标是确定异常昼夜节律偶联基因表达的作用 将HIV和肺部炎症联系起来，作为理解病理生理学的基本起点， HIV相关COPD的发病机制。艾滋病毒感染者表现出肺部炎症增加， COPD的发病率，即使补偿吸烟状态。肺部分子钟的破坏 与COPD和吸烟者中观察到的肺部炎症增加有关。SIRT 1是一种主要的昼夜节律 脱乙酰酶，其作为核心生物钟功能和肺部炎症反应之间的关键联系。 HIV达特是一种分泌于细胞外的HIV立即早期蛋白，它上调原发性巨噬细胞中的miR-142- 5 p， 支气管上皮细胞这种上调导致SIRT 1的抑制和核心时钟的昼夜节律中断 基因BMAL 1和PER 2。同样，吸烟也被证明可以抑制SIRT 1/BMAL 1通路 并使肺分子钟失调，从而增加促炎细胞因子的分泌。一 很大一部分艾滋病毒感染者吸烟，这可能使他们肺部疾病加重 分子钟功能障碍这可能是导致COPD急性加重的核心机制之一， 艾滋病毒吸烟者。因此，确定肺分子钟功能障碍在HIV相关肺中的作用， 炎症和COPD是该提案的目标。因此，重置分子钟可以帮助减少 潜在的炎症和/或阻止在HIV吸烟者中观察到的肺功能下降。我们提出了三 目标。目的1确定HIV达特对肺分子生物钟的影响并确定其机制 及其对炎症的影响。目的2检测miR-142- 5 p/SIRT 1/BMAL 1轴在肺分子钟中的作用 在HIV吸烟者/非吸烟者和转基因小鼠模型中的功能障碍。目标3将测试临床可行性 已确定有可能中和HIV达特并在体外和体内重置肺分子钟的策略， 转基因分子钟小鼠体内模型。了解病理生理机制， HIV破坏肺分子钟将为HIV相关COPD提供治疗靶点。

Title: Resetting the Clock on HIV associated COPD PROJECT SUMMARY The long-term goal of this proposal is identifying the role of aberrant circadian-coupled gene expression linking HIV and lung inflammation as a fundamental starting point to understand the pathophysiological mechanism in HIV associated COPD. People living with HIV demonstrate increased lung inflammation and incidence of COPD even when compensated for smoking status. Disruption of the lung molecular clock has been implicated in increased lung inflammation observed in COPD and smokers. SIRT1 is a principal circadian deacetylase that serves as a critical link between core clock function and inflammatory responses in the lung. HIV Tat, an immediate early protein of HIV that is secreted extracellularly, upregulates miR-142-5p in primary bronchial epithelial cells. This upregulation results in suppression of SIRT1 and circadian disruption of core clock genes BMAL1 and PER2. Likewise, cigarette smoking has also been shown to suppress SIRT1/BMAL1 pathway and dysregulate the lung molecular clock with consequent increase in secretion of proinflammatory cytokines. A significant proportion of people living with HIV smoke tobacco/cigarettes, possibly exacerbating their lung molecular clock dysfunction. This could be one of the core mechanisms that results in COPD exacerbations in HIV smokers. Therefore, determining the role of lung molecular clock dysfunction in HIV associated lung inflammation and COPD is the goal of this proposal. Resetting the molecular clock could thus help reduce underlying inflammation and/or arrest the lung function decline observed in HIV smokers. We propose three aims. Aim 1 determine that lung molecular clock is dysregulated by HIV Tat and identify the mechanism involved and its impact on inflammation. Aim 2 will test the role of miR-142-5p/SIRT1/BMAL1 axis in lung molecular clock dysfunction in HIV smokers/non smokers and in transgenic mouse models. Aim 3 will test clinically feasible strategies with established potential to neutralize HIV Tat and reset the lung molecular clock in vitro and in transgenic molecular clock mouse models in vivo. Understanding the pathophysiological mechanisms by which HIV disrupts the lung molecular clock will provide therapeutic targets for HIV-associated COPD.