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

基本信息

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
项目类别：
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

项目摘要

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：重置艾滋病毒相关慢性阻塞性肺病的时钟项目概要该提案的长期目标是确定异常昼夜节律耦合基因表达的作用将艾滋病毒和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COPD的机制。艾滋病毒感染者肺部炎症增加即使在补偿吸烟状况的情况下，慢性阻塞性肺病的发生率也会增加。肺部分子钟被破坏与慢性阻塞性肺病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是核心时钟功能和肺部炎症反应之间的关键联系。 HIV Tat 是一种细胞外分泌的 HIV 早期蛋白质，在原代细胞中上调 miR-142-5p 支气管上皮细胞。这种上调会导致 SIRT1 的抑制和核心时钟的昼夜节律中断基因 BMAL1 和 PER2。同样，吸烟也被证明会抑制 SIRT1/BMAL1 通路并导致肺分子时钟失调，从而导致促炎细胞因子的分泌增加。一个很大一部分艾滋病毒感染者吸烟，可能会加重肺部疾病分子钟功能障碍。这可能是导致 COPD 恶化的核心机制之一艾滋病毒吸烟者。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该提案的目标。因此，重置分子钟有助于减少潜在的炎症和/或阻止艾滋病毒吸烟者观察到的肺功能下降。我们提出三个目标。目标 1 确定 HIV Tat 导致肺分子时钟失调，并确定相关机制及其对炎症的影响。目标2将测试miR-142-5p/SIRT1/BMAL1轴在肺分子钟中的作用 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将测试临床可行性具有中和 HIV Tat 潜力并在体外和体内重置肺分子时钟的策略体内转基因分子时钟小鼠模型。了解其病理生理机制 HIV 扰乱肺部分子时钟将为 HIV 相关慢性阻塞性肺病提供治疗靶点。