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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要当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病健康）状况。然而，艾滋病毒感染者（PLWH）的寿命较长，使他们更容易受到感染其他感染和合并症。在调整潜在的混杂因素后，感染者的数量增加了 50-60% 可能会患上慢性阻塞性肺病 (COPD)，而且在更年轻的时候也会患上这种疾病。吸烟在 PLWH 中非常普遍，而感染艾滋病毒的吸烟者 (SLWH) 表现出早发性慢性阻塞性肺病（COPD），肺功能加速下降。此外，HIV也是肺病的独立危险因素。病理学。 HIV 会改变多个器官的上皮稳态，包括肺部；然而，蜂窝 HIV 对肺上皮炎症反应的影响尚不清楚。此前，利用大型动物模型，我们报告了 HIV 和 CS 之间的强烈相互作用对肺部病理生理学的影响。我们的数据建议 HIV是导致上皮屏障功能障碍和慢性肺部病变的一个强大的独立危险因素，和CS暴露协同加剧了肺上皮重塑。尽管如此，人们知道的并不多关于 SLWH 中导致这种情况的宿主肺部因素。分析肺的遗传决定因素上皮反应，进行 RNA 测序，并鉴定长非编码 RNA (lncRNA) 与上皮炎症反应显着相关。基于实验验证 LncRNA Anti-Sense to ICAM-1 (LASI) 在基因调控和调节炎症方面的潜力选择进行进一步分析。细胞内粘附分子 1 (ICAM-1) 是一种细胞表面糖蛋白，表达存在于上皮细胞中，包括支气管上皮，与气道炎症有关，并可能将病毒感染传播到其他细胞并导致对慢性疾病的易感性增加。激光辅助手术与 ICAM-1 重叠并在反义链上编码，并且在 CS 治疗正常情况下高度上调人类气道上皮细胞（HAEC）以及 COPD 受试者与对照组的比较。此外，击倒 HAEC 中的这种 lncRNA 抑制了炎症因子。因此，这些数据表明 lncRNA LASI 可能是 HIV 感染情况下气道上皮反应和 COPD 发病机制的重要调节剂。因此，我们认为 HIV 感染和 CS 暴露会改变 lncRNA LASI 表达和亚细胞气道中的定位导致宿主易感气道炎症和 COPD 恶化。我们将通过 1) 通过功能获得和丧失直接调节气道上皮细胞中的 LASI 水平来检验这一假设研究； 2) 通过分析 LASI 调节炎症反应的机制作为 microRNA 或微生物蛋白的前体，或作为结合 microRNA 的海绵的潜力。这因此，拟议的研究将有助于提高我们对 CS 等环境暴露影响的理解和肺上皮细胞中的艾滋病毒，可能为恢复和改善肺和肺功能提供新的见解。 SLWH 的整体健康状况。