The Role of HuR in HIV related COPD

摘要：回顾和纵向队列分析都强烈地将艾滋病毒感染与 慢性阻塞性肺疾病(COPD)的过早发病和进展。改善长期发展 艾滋病病毒携带者(PLWH)的肺部结局和寿命需要更好地了解 在这些患者中，香烟烟雾会加速COPD的发生。我们知道暴露在香烟烟雾中会导致 促进HIV相关COPD的呼吸道上皮细胞的增殖和氧化反应。我们之前的研究 结果表明，HIV蛋白TAT和长期吸烟都降低了肺内与RNA结合的水平 蛋白质人类抗原R(Hur)，调节多种mRNA的衰变和翻译之间的平衡 目标。同样，我们确定长时间的烟雾暴露会降低人体主要呼吸道的HUR水平。 从COPD患者和COPD呼吸道的肺组织切片中分离出上皮细胞(HAEC)。损失 HUR是很重要的，因为我们发现慢性烟雾暴露会加重特定呼吸道的气流阻塞 HUR基因敲除小鼠。此外，我们的rna-seq研究发现，在hAECs中敲除hur会导致失调。 促进细胞增殖，减少抗氧化剂基因表达。另一条证据表明，原始人- 癌基因酪氨酸蛋白激酶c-Src负性调节Hur的表达。我们确定了增强的c-Src COPD患者HAECs和EcoHIV感染小鼠肺内HAECs的激活。因此，我们假设 慢性吸烟暴露和HIV诱导c-Src下调HUR，从而损害呼吸道上皮修复 慢性阻塞性肺疾病的发病机制。这种Hur的丢失改变了呼吸道转录组，促进了PLWH的气流阻塞。 我们将从三个方面检验这一假设： 目标1：我们将使用转录分析来确定HIV和香烟烟雾是如何通过以下方式诱发COPD的 正常人、COPD和HIV/COPD患者呼吸道上皮细胞基因表达的改变 目的2.我们将使用体内HIV COPD模型来确定呼吸道上皮中的HUR是如何起作用的 在HIV中促进呼吸道损伤和气流阻塞的氧化损伤。 目的3.我们将使用体外和体内HIV COPD模型来确定c-Src如何调节HUR到 改变氧化和增殖反应，促进HIV患者的呼吸道损伤和气流阻塞。 这些研究将为恢复HUR表达的新型药物干预奠定基础 HIV感染的COPD患者中损害肺功能和组织完整性的呼吸道上皮损伤。

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.