A LncRNA in Pulmonary Mucosal Immunity and HIV-Associated Comorbidities

肺粘膜免疫和 HIV 相关合并症中的 LncRNA

• 批准号: 10252766
• 负责人: Madepalli Krishnappa Lakshmana
• 金额: $ 17.96万
• 依托单位: FLORIDA INTERNATIONAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-03 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10252766
• 关键词: Abbreviations; Affect; Affinity; Age; Air; Animal Model; Archives; Autoimmunity; Binding; Bronchoalveolar Lavage; CXC Chemokines; Cardiovascular system; Cell Adhesion Molecules; Cells; Chronic; Chronic Disease; Chronic Obstructive Airway Disease; Chronic lung disease; Data; Development; Disease; Disease Management; Environmental Exposure; Epithelial; Epithelial Cells; Exhibits; Fluorescent in Situ Hybridization; Functional disorder; Gene Expression; Gene Expression Regulation; Gene Proteins; Generations; Genes; Genetic Determinism; HIV; HIV Envelope Protein gp120; HIV Infections; Health; High Prevalence; Homeostasis; Human; Human Genome; Immune; In Vitro; Incidence; Individual; Infection; Inflammation; Inflammatory; Inflammatory Response; Integration Host Factors; Intercellular adhesion molecule 1; Interleukin-6; Intervention; Kinetics; Lead; Ligands; Liquid substance; Longevity; Longitudinal Studies; Lung; Mediating; Medical; Membrane Glycoproteins; MicroRNAs; Modeling; Mucosal Immunity; National NeuroAids Tissue Consortium; Nucleotides; Organ; Pathogenesis; Pathogenicity; Patients; Porifera; Predisposition; Proteins; Pulmonary Pathology; RNA; RNA Interference; Reporting; Research; Respiratory Signs and Symptoms; Risk Factors; Role; SIV; Small Interfering RNA; Smoke; Smoker; Structure; Structure of parenchyma of lung; Testing; Three-dimensional analysis; Tissues; Untranslated RNA; Validation; Viremia; Virus Diseases; airway epithelium; airway inflammation; airway remodeling; antiretroviral therapy; base; bronchial epithelium; chemokine; cigarette smoke; cigarette smoke-induced; cigarette smoking; comorbidity; cytokine; early onset; epidemiology study; experimental study; exposure to cigarette smoke; former smoker; improved; in silico; in vivo; inflammatory lung disease; insight; knock-down; locked nucleic acid; loss of function; never smoker; nonhuman primate; novel; overexpression; pulmonary agents; pulmonary function; response; simian human immunodeficiency virus; smoking cessation; transcriptome sequencing

PROJECT ABSTRACT Contemporary antiretroviral therapy has transformed HIV infection into a medically manageable chronic condition. However, the longer lifespan of people living with HIV (PLWH) has made them more susceptible to other infections and comorbid diseases. After adjusting for potential confounders, the PLWH are 50-60% more likely to develop the chronic obstructive pulmonary disease (COPD) and that too at a much younger age. Cigarette smoking is highly prevalent among PLWH and smokers living with HIV (SLWH) exhibit an early onset of COPD with an accelerated decline in lung functions. Moreover, HIV is also an independent risk factor for lung pathologies. HIV alters the epithelial homeostasis in multiple organs, including lungs; however, the cellular impact of HIV on lung epithelial inflammatory responses is poorly defined. Previously, using a large animal model, we reported a strong interaction between HIV and CS in affecting the lung pathophysiology. Our data suggested that HIV is a strong independent risk factor in causing epithelial barrier dysfunction and chronic lung pathologies, and CS-exposure synergistically exacerbated the lung epithelial remodeling. Nonetheless, not much is known about the host lung factors contributing to this condition in SLWH. To analyze the genetic determinants of lung epithelial responses, RNA sequencing was performed, and the long noncoding RNAs (lncRNAs) were identified that were significantly associated with epithelial inflammatory responses. Based on the experimental validation and the potential in gene regulation and in modulating inflammation, LncRNA Anti-Sense to ICAM-1 (LASI) was selected for further analyses. Intracellular adhesion molecule 1 (ICAM-1) is a cell surface glycoprotein expressed in epithelial cells, including bronchial epithelia and is associated with airway inflammation and potentially propagates viral infection to other cells and lead to increased susceptibility to chronic diseases. The LASI overlaps with ICAM-1 and is encoded on the antisense strand and was highly upregulated in CS treated normal human airway epithelial cells (HAECs) and in COPD subjects compared to controls. Furthermore, knocking down this lncRNA in HAECs suppressed the inflammatory factors. These data thus posit that lncRNA LASI could be an essential modulator of airway epithelial response and COPD pathogenesis in the context of HIV infection. Therefore, we propose that HIV infection and CS exposure alters the lncRNA LASI expression and subcellular localization in airways resulting in host susceptibility to airway inflammation and COPD exacerbations. We will test this hypothesis by 1) directly modulating the LASI levels in airway epithelial cells by gain- and loss-of-function studies; 2) identifying the mechanisms by which LASI modulates inflammatory responses by analyzing its potential as the precursor for microRNAs or microproteins, or as the sponge that binds the microRNAs. The proposed studies will thus help in improving our understanding of the effect of environmental exposures like CS and HIV in lung epithelial cells and may provide new insights for restoring and improving the pulmonary and overall health of SLWH.

项目摘要 现代抗逆转录病毒疗法已将艾滋病毒感染转变为医学上可控制的慢性 条件。然而，艾滋病毒携带者(PLWH)的较长寿命使他们更容易患上 其他感染和并存疾病。在调整了潜在的混杂因素后，PLWH多了50%-60% 有可能患上慢性阻塞性肺疾病(COPD)，而且年龄也要小得多。 吸烟在PLWH中非常普遍，吸烟者感染艾滋病毒(SLWH)表现出早期发病 慢性阻塞性肺病的发病与肺功能加速下降有关。此外，爱滋病病毒也是肺部疾病的独立危险因素。 病理学。HIV改变了包括肺在内的多个器官的上皮内稳态；然而，细胞 HIV对肺上皮炎性反应的影响尚不清楚。此前，使用大型动物模型， 我们报道了HIV和CS在影响肺部病理生理学方面的强烈相互作用。我们的数据显示 艾滋病毒是导致上皮屏障功能障碍和慢性肺部病变的强大独立风险因素， CS暴露可协同加重肺上皮细胞重塑。尽管如此，我们知道的并不多。 关于导致SLWH这种情况的宿主肺因素。分析肺的遗传决定因素 上皮反应，进行RNA测序，并鉴定出长的非编码RNA(LncRNAs) 与上皮炎性反应显著相关。基于实验验证 而ICAM-1的反义lncRNA(LASI)在基因调控和炎症调控方面的潜力是 被选作进一步分析。细胞间黏附分子-1(ICAM-1)是一种细胞表面糖蛋白 在包括支气管上皮在内的上皮细胞中，它与呼吸道炎症有关，并可能 将病毒感染传播到其他细胞，并导致对慢性病的易感性增加。LASI 与ICAM-1重叠，编码在反义链上，在CS治疗正常时高度上调 人呼吸道上皮细胞(HAECs)和慢性阻塞性肺疾病患者与对照组的比较。此外，拆毁 HAECs中的这种lncRNA抑制炎症因子。这些数据因此假设lncRNA LASI可能是 在HIV感染的背景下，呼吸道上皮反应和COPD发病机制的基本调节因子。 因此，我们认为HIV感染和CS暴露改变了lncRNA LASI的表达和亚细胞 呼吸道的定位导致宿主对呼吸道炎症和COPD加重的易感性。我们会 通过1)通过功能的获得和丧失直接调节呼吸道上皮细胞中的LASI水平来验证这一假设 研究；2)通过分析LASI调节炎症反应的机制 有可能成为微RNA或微蛋白的前体，或作为结合微RNA的海绵。这个 因此，拟议的研究将有助于我们更好地了解CS等环境暴露的影响 和HIV在肺上皮细胞中的表达，可能为恢复和改善肺和 低收入妇女的总体健康状况。