Tracheobronchial mucociliary dysfunction in HIV patients

HIV患者的气管支气管粘液纤毛功能障碍

• 批准号: 9204078
• 负责人: HOSHANG JEHANGIR UNWALLA
• 金额: $ 22.67万
• 依托单位: FLORIDA INTERNATIONAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9204078
• 关键词: 3' Untranslated Regions; Address; Adrenergic Agonists; Adult; Agonist; Allergens; Alveolar Macrophages; Asthma; Attenuated; Bacterial Pneumonia; Basic Science; Biogenesis; Biological Markers; Bronchodilator Agents; Bypass; CD4 Lymphocyte Count; Cells; Charge; Chronic; Chronic Bronchitis; Chronic Disease; Chronic Obstructive Airway Disease; Cilia; Comorbidity; Coupled; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Data; Defense Mechanisms; Disease; Disease Progression; Epithelial Cells; Epithelium; Frequencies; Functional disorder; Gene Silencing; Genes; Genetic Transcription; Goals; HIV; HIV Envelope Protein gp120; HIV Infections; HIV Seropositivity; Health; Homeostasis; Human; Immune; Incidence; Individual; Infection; Inflammation; Lead; Life; Longevity; Mediating; Messenger RNA; MicroRNAs; Modeling; Molecular; Morbidity - disease rate; Mucociliary Clearance; Mucous body substance; Nose; Obstructive Lung Diseases; Pathway interactions; Patients; Physiological; Play; Pneumonia; Proteins; Public Health; RNA; RNA Interference; Receptor Signaling; Recruitment Activity; Recurrence; Regulation; Respiratory physiology; Risk Factors; Role; Signal Transduction; Smoke; Smoker; Smoking; Source; TGFBR2 gene; Testing; Therapeutic; Time; Tobacco; Tracheobronchial; Transforming Growth Factor beta; Treatment Protocols; Viral Proteins; airway surface liquid; antiretroviral therapy; aptamer; base; beta-2 Adrenergic Receptors; bronchial epithelium; cigarette smoking; cigarette smoking; co-infection; extracellular; improved; microbial; microbial colonization; microbiota; mortality; pathogen; pollutant; prevent; promoter; working group

PROJECT SUMMARY: Bacterial pneumonia continues to be an important comorbidity in HIV- infected patients even though anti- retrovial therapy has succeded in restoring CD4 cell counts. HIV patients demonstrate increased microbial colonization of the lower airways and the microbial flora is similar to that observed in diseases with impaired mucociliary clearance (MCC) like cystic fibrosis and COPD. HIV patients demonstrate impaired nasal mucociliary clearance. Since the physiological mechanisms regulating nasal MCC is similar to tracheobronchial MCC it is possible that HIV suppresses this as well. The three principal components of the MCC apparatus are, a mucus layer, ciliary beating and a periciliary airway surface liquid layer that facilitates ciliary beating. cystic fibrosis transmembrane conductance regulator (CFTR) plays a pivotal role in regulating the pericilary airway surface liquid. Our preliminary data show that HIV protiens Tat and gp120 can suppress components of the MCC apparatus. HIV Tat and cigarette smoke suppress CFTR biogenesis and function via a common pathway involving TGF-β signaling. Moreover, HIV Tat and cigarette smoke synergize to cause an additive suppression of CFTR function. Suppression of CFTR mRNA is not due to transcriptional suppression and strongly posits a role for miRNA mediated post-transcriptional gene silencing. HIV gp120 and cigarette smoke suppress baseline ciliary beating. This is significant since 60% of HIV patients also smoke tobacco. Beta-2-adrenergic receptor agonists primarily used as bronchodilators can restore ciliary beating and CFTR function (if CFTR availabiltiy can be restored) thereby restoring MCC. Based on these observations, Aim 1 will elucidate the role of miRNA mediated gene silencing in CFTR suppression by TGF-beta and identify the miRNAs involved. Aim 2 will confirm that HIV patients demonstrate decreased CFTR biogenesis and this is possibly due to increased TGF-β1 levels. We will also confirm that HIV patients demonstrate suppressed ciliary beating and this can be restored by β2-agonists that are routinely prescribed as bronchodilators in airway diseases like asthma and COPD. Together, these aims will examine basic molecular mechanisms relating to increased bacterial pneumonia in HIV patients while simultaneously testing therapeutic approaches to restore components of the MCC apparatus in these patients. The proposal aims will address one of the major basic research scientific gaps identified by the Working group namely, “Interplay of HIV, inflammation, ART, co-infections, and traditional risk factors in the progression of HIV-related HLB diseases”, for RFA-HL-14-029, and identify therapeutic leads to restore MCC and decrease the incidence of bacterial pneumonia in HIV patients.

项目概要： 尽管抗病毒治疗，细菌性肺炎仍然是 HIV 感染患者的重要合并症。 逆转录疗法已成功恢复 HIV 患者的 CD4 细胞计数，显示微生物数量有所增加。 下呼吸道和微生物菌群的定植与在受损疾病中观察到的相似 粘液纤毛清除（MCC）如囊性纤维化和慢性阻塞性肺病（COPD）患者表现出鼻腔受损。 由于调节鼻 MCC 的生理机制与气管支气管相似。 MCC HIV 也可能抑制这种作用 MCC 装置的三个主要组成部分是： 粘液层、纤毛跳动和促进纤毛跳动的纤毛周围气道表面液体层。 纤维化跨膜电导调节器（CFTR）在调节毛细血管周围气道中发挥着关键作用 我们的初步数据表明，HIV 蛋白 Tat 和 gp120 可以抑制 MCC 装置。HIV Tat 和香烟烟雾通过共同途径抑制 CFTR 生物发生和功能。 此外，HIV Tat 和香烟烟雾协同作用，产生累加抑制。 CFTR mRNA 的抑制不是由于转录抑制，并且强烈推测 miRNA 介导的转录后基因沉默和香烟烟雾抑制的作用。 这很重要，因为 60% 的 HIV 患者也吸烟。 主要用作支气管扩张剂的受体激动剂可以恢复纤毛跳动和 CFTR 功能（如果 CFTR 可用性可以恢复）从而恢复 MCC。 基于这些观察结果，目标 1 将阐明 miRNA 介导的基因沉默在 CFTR 中的作用 目标 2 将证实 HIV 患者表现出 TGF-β 抑制并鉴定相关 miRNA。 CFTR 生物合成，这可能是由于 TGF-β1 水平升高所致。我们还将证实 HIV 降低。 患者表现出纤毛跳动受到抑制，这可以通过常规的 β2 激动剂来恢复 作为哮喘和慢性阻塞性肺病等气道疾病的支气管扩张剂，这些目标将一起进行检查。 与 HIV 患者细菌性肺炎增加相关的基本分子机制，同时 恢复这些患者 MCC 装置组件的治疗测试方法。 目标将解决工作组确定的主要基础研究科学差距之一，即 “HIV、炎症、ART、合并感染和传统危险因素在 HIV 相关疾病进展中的相互作用 HLB 疾病”，针对 RFA-HL-14-029，并确定治疗线索以恢复 MCC 并降低发病率 HIV 患者的细菌性肺炎。