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The Role of HuR in HIV related COPD

HuR 在 HIV 相关 COPD 中的作用

基本信息

批准号：
10548660
负责人：
Robert F Foronjy
金额：
$ 76.33万
依托单位：
SUNY DOWNSTATE MEDICAL CENTER
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：
2022-09-01 至 2026-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10548660
关键词：
Air Movements Airway Disease Antigens Antioxidants Binding Biological Assay Biology Cell Differentiation process Cell Proliferation Cells Cellular biology Chronic Chronic Obstructive Pulmonary Disease Cilia Code Cohort Analysis Complex Computer software Cysteine Cytosol Data Development Disease Disease model Epithelial Cells Equilibrium Female Functional disorder Gene Expression Gene Expression Profile Genes HIV HIV Envelope Protein gp120 HIV Infections HIV tat Protein Human Image Impairment In Vitro Individual Inhalation Injury Intervention Knock-out Knockout Mice Left Longevity Longitudinal cohort Lung Measures Mediating Mediator of activation protein Messenger RNA MicroRNAs Modeling Molecular Morbidity - disease rate Mus Outcome Pathway interactions Persons Pharmacology Physiological Principal Investigator Production Proteins Proto-Oncogenes Public Health RNA RNA-Binding Proteins Retrospective cohort Risk Factors Role SRC gene Smoke Stains Structure of parenchyma of lung Testing Trachea Translations Viral adeno-associated viral vector airway epithelium airway obstruction airway remodeling cell type cigarette smoke cigarette smoke-induced COPD cohort drinking water early onset epithelial injury epithelial repair exposure to cigarette smoke human disease improved in vivo injured airway knock-down locus ceruleus structure mRNA Decay mRNA Export male mortality mouse model nef Protein novel oxidative damage patient population premature prevent programs protein-tyrosine kinase c-src pulmonary function repaired response single cell sequencing trafficking transcriptome transcriptome sequencing transcriptomics

项目摘要

Summary: Both retrospective and longitudinal cohort analyses strongly associate HIV infection with the premature initiation and progression of chronic obstructive pulmonary disease (COPD). Improving long-term pulmonary outcomes and longevity in people living with HIV (PLWH) will require a better understanding of how cigarette smoke accelerates COPD in this patient population. We know that exposure to cigarette smoke causes proliferative and oxidative responses in airway epithelial cells that promote HIV-related COPD. Our prior studies showed that the HIV protein Tat and chronic smoke exposure both reduced lung levels of the RNA binding protein human antigen R (HuR), which regulates the balance between decay and translation of multiple mRNA targets. Similarly, we determined that prolonged smoke exposure reduces HuR levels in primary human airway epithelial cells (HAECs) isolated from COPD subjects and in lung tissue sections from COPD airways. The loss of HuR is important since we found that chronic smoke exposure worsened airflow obstruction in airway specific HuR knockout mice. Moreover, our RNA-seq studies discovered that knocking down HuR in HAECs dysregulates cell proliferation and reduces antioxidant gene expression. Another line of evidence indicates that the proto- oncogene tyrosine-protein kinase c-Src negatively regulates HuR expression. We identified enhanced c-Src activation in HAECs from COPD subjects and in the lungs of EcoHIV infected mice. Thus, we hypothesize that chronic smoke exposure and HIV induce c-Src to down regulate HuR and thereby impair airway epithelial repair mechanisms in COPD. This loss of HuR alters the airway transcriptome to promote airflow obstruction in PLWH. We will test the hypothesis in three aims: Aim 1: We will use transcriptomic analysis to determine how HIV and cigarette smoke induce COPD by altering gene expression in human airway epithelial cells from healthy, COPD and HIV/COPD subjects Aim 2. We will employ in vivo HIV COPD models to ascertain how HuR in the airway epithelium counters the oxidative damage that promotes airway injury and airflow obstruction in HIV. Aim 3. We will employ in vitro and in vivo HIV COPD models to determine how c-Src regulates HuR to alter oxidative and proliferative responses that promote airway injury and airflow obstruction in HIV. These studies will set the stage for novel pharmacologic interventions that restore HuR expression to counter the airway epithelial injury that impairs lung function and tissue integrity in HIV infected COPD subjects.

摘要：回顾性和纵向队列分析都强烈地将HIV感染与死亡联系在一起