The Role of HuR in HIV related COPD

HuR 在 HIV 相关 COPD 中的作用

• 批准号: 10548660
• 负责人: Robert F Foronjy
• 金额: $ 76.33万
• 依托单位: SUNY DOWNSTATE MEDICAL CENTER
• 依托单位国家: 美国
• 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/10548660
• 关键词: Air Movements; Airway Disease; Antigens; Antioxidants; Binding; Biological Assay; Biology; Cell Differentiation process; Cell Proliferation; Cells; Cellular biology; Chronic; Chronic Obstructive Pulmonary Disease; Cilia; Code; Cohort Analysis; Complex; Computer software; Cysteine; Cytosol; Data; Development; Disease; Disease model; Epithelial Cells; Equilibrium; Female; Functional disorder; Gene Expression; Gene Expression Profile; Genes; HIV; HIV Envelope Protein gp120; HIV Infections; HIV tat Protein; Human; Image; Impairment; In Vitro; Individual; Inhalation; Injury; Intervention; Knock-out; Knockout Mice; Left; Longevity; Longitudinal cohort; Lung; Measures; Mediating; Mediator of activation protein; Messenger RNA; MicroRNAs; Modeling; Molecular; Morbidity - disease rate; Mus; Outcome; Pathway interactions; Persons; Pharmacology; Physiological; Principal Investigator; Production; Proteins; Proto-Oncogenes; Public Health; RNA; RNA-Binding Proteins; Retrospective cohort; Risk Factors; Role; SRC gene; Smoke; Stains; Structure of parenchyma of lung; Testing; Trachea; Translations; Viral; 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; locus ceruleus structure; mRNA Decay; mRNA Export; male; mortality; mouse model; nef Protein; novel; oxidative damage; patient population; premature; prevent; programs; protein-tyrosine kinase c-src; pulmonary function; repaired; response; single cell sequencing; trafficking; transcriptome; transcriptome sequencing; transcriptomics

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.

摘要：回顾性和纵向队列分析都将 HIV 感染与 慢性阻塞性肺疾病（COPD）的过早发生和进展。长期改善 艾滋病毒感染者 (PLWH) 的肺部结局和寿命需要更好地了解如何 香烟烟雾会加速该患者群体的慢性阻塞性肺病。我们知道，接触香烟烟雾会导致 气道上皮细胞的增殖和氧化反应促进 HIV 相关 COPD。我们之前的研究 研究表明，HIV 蛋白 Tat 和长期吸烟都会降低肺部 RNA 结合水平 蛋白质人类抗原 R (HuR)，调节多个 mRNA 的衰变和翻译之间的平衡 目标。同样，我们确定长期接触烟雾会降低人类初级气道中的 HuR 水平 从 COPD 受试者和 COPD 气道的肺组织切片中分离出上皮细胞 (HAEC)。损失 HuR 的研究非常重要，因为我们发现长期接触烟雾会加重气道特定部位的气流阻塞 HuR 基因敲除小鼠。此外，我们的 RNA-seq 研究发现，敲除 HAEC 中的 HuR 会导致失调 细胞增殖并降低抗氧化基因表达。另一条证据表明，原型 癌基因酪氨酸蛋白激酶 c-Src 负向调节 HuR 表达。我们确定了增强型 c-Src COPD 受试者的 HAEC 和 EcoHIV 感染小鼠肺部的 HAEC 激活。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。 HuR 的缺失会改变气道转录组，从而促进 PLWH 中的气流阻塞。 我们将从三个目标来检验该假设： 目标 1：我们将使用转录组分析来确定 HIV 和吸烟如何通过以下方式诱发 COPD： 改变健康、慢性阻塞性肺病和艾滋病毒/慢性阻塞性肺病受试者的人气道上皮细胞的基因表达 目标 2. 我们将采用体内 HIV COPD 模型来确定气道上皮细胞中的 HuR 如何对抗 氧化损伤会促进艾滋病毒中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，从而促进 HIV 中的气道损伤和气流阻塞。 这些研究将为恢复 HuR 表达以对抗 气道上皮损伤会损害 HIV 感染的 COPD 受试者的肺功能和组织完整性。