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Restoring mucociliary clearance apparatus to mitigate lung inflammation in the context of HIV and cigarette smoke

恢复粘膜纤毛清除装置以减轻艾滋病毒和香烟烟雾背景下的肺部炎症

基本信息

批准号：
10547928
负责人：
Srinivasan Chinnapaiyan
金额：
$ 14.75万
依托单位：
FLORIDA INTERNATIONAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10547928
关键词：
3&apos Untranslated Regions Abbreviations Accounting Affect Air Airway Disease Allergens Attenuated Bacteria Bacterial Infections Bacterial Pneumonia Bronchoalveolar Lavage Cells Chronic Chronic Bronchitis Chronic Obstructive Pulmonary Disease Cilia Clustered Regularly Interspaced Short Palindromic Repeats Core-Binding Factor Cystic Fibrosis Cystic Fibrosis Transmembrane Conductance Regulator Data Deacetylase Development Disease Epithelial Cells Etiology Event Feedback Frequencies Functional disorder Gene Expression Genes Goals Goblet Cells HIV HIV Receptors Human Hyperplasia Immediate-Early Proteins Impairment Incidence Individual Inflammation Intervention Lead Liquid substance Lung Lung diseases Lung infections MUC5AC gene Mediating MicroRNAs Morbidity - disease rate Mucociliary Clearance Mucous body substance Pathologic Pathology Pathway interactions Patients Peptide Hydrolases Persons Play Publishing Pulmonary Inflammation Quality of life Recurrence Respiratory Tract Infections Risk Risk Factors Role SIRT1 gene Severities Signal Transduction Site Smoker Smoking Smoking Status System TGFB1 gene Testing Thinness Untranslated Regions Up-Regulation Viral Load result airway epithelium airway surface liquid antagonist antiretroviral therapy bronchial epithelium chronic respiratory disease cigarette smoke cilium biogenesis comorbidity cytokine exposure to cigarette smoke improved lung microbiome microbial colonization mortality mucus clearance mucus hypersecretion notch protein novel pathogen pollutant preservation pulmonary function pulmonary function decline respiratory colonization therapeutic evaluation

项目摘要

PROJECT SUMMARY People living with HIV demonstrate increased incidence of lung inflammation and HIV is an independent risk factor development of COPD. HIV Tat, an immediate early protein of HIV and cigarette smoke suppress the deacetylase SIRT1 that regulates ADAM17, a protease involved in activating Notch signaling as well as proteolytic cleavage and activation of proinflammatory cytokines. This can lead to downstream deleterious effects on ciliogenesis, mucociliary clearance and lung function decline. While chronic inflammation in COPD is a multifactorial etiology, impaired mucociliary clearance leading to recurrent lung infections can play an important role in promoting lung inflammation. Optimal mucociliary clearance requires mucus, cilia, and a thin layer of airway surface liquid to facilitate ciliary beating. Abnormalities in any compartment of the mucociliary system can compromise mucus clearance leading to mucus impaction entrapping bacteria and promoting chronic bacterial infection. HIV Tat promotes an aberrant microRNAome in the primary bronchial epithelium and upregulates miR-142-5p, a microRNA known to suppress SIRT1. This proposal will identify mechanisms involved in HIV Tat promotes mucociliary dysfunction and identifying individual effects on ciliogenesis, mucus hypersecretion and inflammation. Given the causal role for SIRT1 suppression in mediating these effects, we will use a novel CRISPR-mediated gene specific microRNA antagonism approach to disrupt the miR-142-5p target site on the SIRT1 3’UTR. This will preserve SIRT1 expression in the context of HIV Tat and cigarette smoke without affecting other functions of miR-142-5p. Aim 1: HIV Tat upregulates miR-142-5p and suppress SIRT1 exacerbate upregulates ADAM17 levels by HIV and cigarette smoke exposure in NHBE ALI cultures. Given that HIV Tat and cigarette smoke mediated miR-142-5p dysregulation leading to SIRT1 suppression and aberrant Notch signaling. Specifically, we will analyze ADAM17 upregulation, ciliogenesis, goblet cell hyperplasia and ciliary beat frequency in NHBE ALI cultures. Aim 2: Since HIV Tat and cigarette smoke suppresses SIRT1, and SIRT1 suppression impairs mucociliary clearance apparatus, we will determine if gene-specific microRNA antagonism in combination with SIRT1 activator to rescue SIRT1 levels, suppression of inflammation and enhance mucociliary clearance apparatus in primary bronchial epithelial cells treated with HIV Tat and exposed to cigarette smoke.

项目总结