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.

项目摘要： 尽管抗菌 逆转疗法已成功恢复CD4细胞计数。 HIV患者表现出微生物的增加 下气道和微生物菌群的定殖类似于患有受损的疾病 粘膜纤毛清除率（MCC），例如囊性纤维化和COPD。 HIV患者表现出鼻腔受损 粘毛间隙。由于调查鼻腔MCC的物理机制类似于气管机构 MCC也有可能也抑制了这一点。 MCC设备的三个主要组成部分是 粘液层，睫状跳动和周围气道表面液体层，可促进纤毛跳动。囊性 纤维化跨膜电导调节剂（CFTR）在调节pericilar气道中起关键作用 表面液体。我们的初步数据表明，HIV Protiens TAT和GP120可以抑制组件 MCC设备。 HIV TAT和香烟烟雾抑制CFTR生物发生和通过公共途径的功能 涉及TGF-β信号传导。此外，HIV TAT和香烟烟协同以引起额外的抑制 CFTR函数的。 CFTR mRNA的抑制不是由于转录抑制作用，并且强烈假定 miRNA介导的转录后基因沉默的作用。艾滋病毒GP120和香烟烟雾抑制 基线睫状跳动。这很重要，因为60％的艾滋病毒患者也抽烟。 β-2-肾上腺素能 受体激动剂主要用作支气管扩张剂可以恢复睫状激动和CFTR功能（如果CFTR 可以恢复可用性），从而恢复MCC。 基于这些观察结果，AIM 1将阐明miRNA介导的基因沉默在CFTR中的作用 TGF-beta抑制并确定所涉及的miRNA。 AIM 2将确认HIV患者证明 CFTR生物发生降低，这可能是由于TGF-β1水平升高。我们还将确认艾滋病毒 患者表现出受抑制的睫毛跳动，这可以由常规的β2激动剂恢复 在哮喘和COPD等气道疾病中，处方为支气管扩张剂。这些目标将共同研究 与HIV患者肺炎增加的基本分子机制，同时同时 测试治疗方法以恢复这些患者MCC设备的组件。提案 AIMS将解决工作组确定的主要基础研究科学差距之一，即 “艾滋病毒，感染，艺术，共同感染和传统风险因素的相互作用在与HIV相关的进展中 HLB疾病”，用于RFA-HL-14-029，并确定治疗性导致恢复MCC并减少事件 HIV患者的细菌肺炎。