Resetting the Clock in HIV associated COPD

重置艾滋病毒相关慢性阻塞性肺病的时钟

• 批准号: 10403032
• 负责人: IRFAN RAHMAN
• 金额: $ 55.13万
• 依托单位: FLORIDA INTERNATIONAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-27 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10403032
• 关键词: ARNTL gene; Abbreviations; Accounting; Aging; Agonist; Air; Anatomy; Biological; Bronchoalveolar Lavage; CXCL5 gene; Centers for Disease Control and Prevention (U.S.); Chronic; Chronic Obstructive Pulmonary Disease; Cigarette; Circadian Dysregulation; Circadian Rhythms; Clinical; Consequences of HIV; Continuity of Patient Care; Coupled; DNA; Data; Deacetylase; Development; Disease; Disease Progression; Epithelial Cells; Functional disorder; Gene Expression; Genes; Goals; HIV; HIV Infections; Hour; Human; Immediate-Early Proteins; In Vitro; Incidence; Inflammation; Inflammatory Response; Link; Liquid substance; Lung; Mediating; Molecular; Morbidity - disease rate; Mucous body substance; Output; Pathway interactions; Patients; Periodicity; Peripheral; Persons; Physiology; Play; Population; Pulmonary Emphysema; Pulmonary Inflammation; RNA; Resistance; Response Elements; Risk Factors; Role; SIRT1 gene; Severity of illness; Smoker; Smoking Status; Stimulus; Testing; Therapeutic; Tobacco smoke; Transactivation; Transgenic Mice; Transgenic Organisms; United States; Up-Regulation; Viral; Virus; airway epithelium; airway inflammation; antiretroviral therapy; bronchial epithelium; cell type; cigarette smoke; cigarette smoking; circadian; circadian pacemaker; comorbidity; cytokine; extracellular; in vivo; in vivo Model; lung injury; molecular clock; mortality; mouse model; mucus hypersecretion; non-smoker; novel; nuclease; overexpression; phosphoramidate; pulmonary function; pulmonary function decline; therapeutic evaluation; therapeutic target; tobacco smoke exposure; transcriptomics

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.

标题：重置HIV相关性COPD的时钟 项目总结 这项建议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与肺部炎症联系起来作为了解病理生理学的基本起点 HIV相关性COPD的发病机制。艾滋病毒携带者表现为肺部炎症增加和 即使在扣除吸烟状况的情况下，COPD的发病率也是如此。肺分子时钟的破坏已经被 与COPD和吸烟者观察到的肺部炎症增加有关。SIRT1是主要的昼夜节律 脱乙酰酶，作为核心时钟功能和肺部炎症反应之间的关键纽带。 HIV Tat是HIV的一种直接早期蛋白，在细胞外分泌，在原代培养时上调miR-142-5p 支气管上皮细胞。这种上调导致抑制SIRT1和核心时钟的昼夜节律中断 基因BMAL1和PER2。同样，吸烟也被证明抑制SIRT1/BMAL1途径 并失调肺分子时钟，从而增加促炎细胞因子的分泌。一个 相当大比例的艾滋病毒携带者吸烟/吸烟，可能会加重他们的肺部 分子时钟功能障碍。这可能是导致COPD恶化的核心机制之一 艾滋病吸烟者。因此，确定肺分子时钟功能障碍在HIV相关肺中的作用 炎症和慢性阻塞性肺病是这项提案的目标。因此，重置分子时钟可以帮助减少 潜在的炎症和/或阻止艾滋病毒吸烟者的肺功能下降。我们提出三个建议 目标。目的1确定人类免疫缺陷病毒(HIV)TAT对肺分子时钟的调节作用，并探讨其机制 以及它对炎症的影响。Aim 2将检测miR-142-5p/SIRT1/BMAL1轴在肺分子钟中的作用 艾滋病毒吸烟者/非吸烟者和转基因小鼠模型中的功能障碍。目标3将在临床上进行可行性测试 已确定有潜力中和HIV TAT并在体外和体外重置肺分子时钟的策略 转基因分子钟小鼠体内模型的建立。了解其病理生理机制 HIV扰乱肺分子时钟将为HIV相关COPD提供治疗靶点。