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The Role of HuR in HIV related COPD

HuR 在 HIV 相关 COPD 中的作用

基本信息

批准号：
10693939
负责人：
Robert F Foronjy
金额：
$ 72.42万
依托单位：
SUNY DOWNSTATE MEDICAL CENTER
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：
2022-09-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10693939
关键词：
Acceleration Air Movements Airway Disease Antigens Antioxidants Binding Biological Assay Biology Cell Differentiation process Cell Nucleus Cell Proliferation Cell Separation Cells Cellular biology Chronic Chronic Obstructive Pulmonary Disease Cilia Code Cohort Analysis Collecting Cell Complex Computer software Cysteine Cytosol Data Development Disease Disease model Epithelial Cells Equilibrium Female Functional disorder Gene Expression Gene Expression Profile Gene Expression Profiling Genes HIV HIV Envelope Protein gp120 HIV Infections HIV tat Protein Human Image Impairment In Vitro Individual Inhalation Injury Intervention Knockout Mice Left Longevity Longitudinal cohort Lung Measures Mediating Mediator Messenger RNA MicroRNAs Modeling Molecular Morbidity - disease rate Mus Outcome Pathway interactions Persons Physiological Principal Investigator Production Proteins Proto-Oncogenes Public Health RNA RNA-Binding Proteins Random Allocation Repression Retrospective cohort Risk Factors Role SRC gene Smoke Stains Structure of parenchyma of lung Testing Trachea Translations Viral Virus adeno-associated viral vector airway epithelium airway obstruction airway remodeling cell type cigarette smoke cigarette smoke-induced COPD cohort drinking water early onset epithelial injury epithelial repair exposure to cigarette smoke human disease improved in vivo injured airway knock-down knockout gene mRNA Decay mRNA Export male mortality mouse model nef Protein novel oxidative damage patient population pharmacologic premature prevent programs protein-tyrosine kinase c-src pulmonary function repaired respiratory imaging response single cell sequencing trafficking transcriptome transcriptome sequencing transcriptomic profiling transcriptomics

项目摘要

Summary: Both retrospective and longitudinal cohort analyses strongly associate HIV infection with the premature initiation and progression of chronic obstructive pulmonary disease (COPD). Improving long-term pulmonary outcomes and longevity in people living with HIV (PLWH) will require a better understanding of how cigarette smoke accelerates COPD in this patient population. We know that exposure to cigarette smoke causes proliferative and oxidative responses in airway epithelial cells that promote HIV-related COPD. Our prior studies showed that the HIV protein Tat and chronic smoke exposure both reduced lung levels of the RNA binding protein human antigen R (HuR), which regulates the balance between decay and translation of multiple mRNA targets. Similarly, we determined that prolonged smoke exposure reduces HuR levels in primary human airway epithelial cells (HAECs) isolated from COPD subjects and in lung tissue sections from COPD airways. The loss of HuR is important since we found that chronic smoke exposure worsened airflow obstruction in airway specific HuR knockout mice. Moreover, our RNA-seq studies discovered that knocking down HuR in HAECs dysregulates cell proliferation and reduces antioxidant gene expression. Another line of evidence indicates that the proto- oncogene tyrosine-protein kinase c-Src negatively regulates HuR expression. We identified enhanced c-Src activation in HAECs from COPD subjects and in the lungs of EcoHIV infected mice. Thus, we hypothesize that chronic smoke exposure and HIV induce c-Src to down regulate HuR and thereby impair airway epithelial repair mechanisms in COPD. This loss of HuR alters the airway transcriptome to promote airflow obstruction in PLWH. We will test the hypothesis in three aims: Aim 1: We will use transcriptomic analysis to determine how HIV and cigarette smoke induce COPD by altering gene expression in human airway epithelial cells from healthy, COPD and HIV/COPD subjects Aim 2. We will employ in vivo HIV COPD models to ascertain how HuR in the airway epithelium counters the oxidative damage that promotes airway injury and airflow obstruction in HIV. Aim 3. We will employ in vitro and in vivo HIV COPD models to determine how c-Src regulates HuR to alter oxidative and proliferative responses that promote airway injury and airflow obstruction in HIV. These studies will set the stage for novel pharmacologic interventions that restore HuR expression to counter the airway epithelial injury that impairs lung function and tissue integrity in HIV infected COPD subjects.

总结：回顾性和纵向队列分析均将HIV感染与慢性阻塞性肺疾病（COPD）过早开始和进展。改善长期肺的结果和艾滋病毒感染者（PLWH）的寿命将需要更好地了解如何吸烟会加速该患者人群中的COPD。我们知道暴露在香烟烟雾中会导致呼吸道上皮细胞的增殖和氧化反应，促进HIV相关的COPD。我们之前的研究表明HIV蛋白达特和长期吸烟都降低了肺中RNA结合的水平，蛋白人类抗原R（HuR），调节多种mRNA的衰变和翻译之间的平衡目标的类似地，我们确定，长期烟雾暴露降低了人体主要气道中的HuR水平，从COPD受试者分离的上皮细胞（HAEC）和来自COPD气道的肺组织切片。损失由于我们发现慢性烟雾暴露加重了气道特异性的气流阻塞， HuR敲除小鼠。此外，我们的RNA-seq研究发现，敲低HAECs中的HuR会使HAECs中的HuR失调，细胞增殖并降低抗氧化基因表达。另一个证据表明，原- 癌基因酪氨酸蛋白激酶c-Src负调控HuR表达。我们发现了增强型c-Src 在来自COPD受试者的HAEC和EcoHIV感染的小鼠的肺中的活化。因此，我们假设，慢性烟雾暴露和HIV诱导c-Src下调HuR，从而损害气道上皮修复 COPD的机制这种HuR的丢失改变了气道转录组，从而促进PLWH中的气流阻塞。我们将从三个方面来检验这个假设：目的1：我们将使用转录组学分析来确定HIV和香烟烟雾如何通过以下方式诱导COPD：改变来自健康、COPD和HIV/COPD受试者的人气道上皮细胞中的基因表达目标二。我们将采用体内HIV COPD模型来确定呼吸道上皮细胞中的HuR如何对抗氧化损伤，促进艾滋病毒的气道损伤和气流阻塞。目标3.我们将采用体外和体内HIV COPD模型来确定c-Src如何调节HuR，改变氧化和增殖反应，促进HIV的气道损伤和气流阻塞。这些研究将为新的药理学干预奠定基础，恢复HuR表达，以对抗在HIV感染的COPD受试者中损害肺功能和组织完整性的气道上皮损伤。