The Role of HuR in HIV related COPD

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Principal Investigator: Robert F Foronjy
Organization: SUNY DOWNSTATE MEDICAL CENTER
Fiscal Year: 2024
Award: $708,757
Funding agency: National Heart Lung and Blood Institute

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.

Terms: <AAV vector><AAV-based vector><AIDS Virus><ASVSRC1><Acceleration><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Air Movements><Airway Disease><Airway imaging><Antigens><Antioxidants><Assay><Binding><Bioassay><Biological Assay><Biology><C-terminal Src kinase><COPD><CSK Protein Kinase><CSK-src><Cell Body><Cell Differentiation><Cell Differentiation process><Cell Growth in Number><Cell Isolation><Cell Multiplication><Cell Nucleus><Cell Proliferation><Cell Segregation><Cell Separation><Cell Separation Technology><Cells><Cellular Oncogene><Cellular Proliferation><Cellular biology><Chronic><Chronic Obstruction Pulmonary Disease><Chronic Obstructive Lung Disease><Chronic Obstructive Pulmonary Disease><Cilia><Code><Coding System><Cohort Analyses><Cohort Analysis><Collecting Cell><Complex><Computer software><Cysteine><Cytosol><Data><Development><Disease><Disorder><Dysfunction><Epithelial Cells><Equilibrium><Expression Signature><Female><Functional disorder><Gene Expression><Gene Expression Monitoring><Gene Expression Pattern Analysis><Gene Expression Profile><Gene Expression Profiling><Genes><HIV><HIV Envelope Glycoprotein gp120><HIV Envelope Protein gp120><HIV Infections><HIV env Protein gp120><HIV tat Protein><HTLV-III Infections><HTLV-III gp120><HTLV-III-LAV Infections><Half-Cystine><Human><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><Image><Impairment><In Vitro><Individual><Inhalation><Inhaling><Injury><Intervention><Intervention Strategies><KO mice><Knock-out Mice><Knockout Mice><L-Cysteine><LAV-HTLV-III><Left><Length of Life><Long-term cohort><Longevity><Longitudinal cohort><Longterm cohort><Lung><Lung Parenchyma><Lung Respiratory System><Lung Tissue><Lymphadenopathy-Associated Virus><Measures><Mediating><Mediator><Messenger RNA><Mice><Mice Mammals><Micro RNA><MicroRNAs><Modeling><Modern Man><Molecular><Molecular Interaction><Morbidity><Morbidity - disease rate><Murine><Mus><Non-Polyadenylated RNA><Nucleus><Null Mouse><Outcome><Pathway interactions><Persons><Physiologic><Physiological><Physiopathology><Principal Investigator><Production><Protein-Tyrosine Kinase CYL><Proteins><Proto-Oncogenes><Public Health><RNA><RNA Gene Products><RNA Seq><RNA sequencing><RNA-Binding Proteins><RNAseq><Random Allocation><Random Selection><Repression><Respiratory Epithelium><Retrospective cohort><Ribonucleic Acid><Risk Factors><Role><SRC Family Gene><SRC gene><Single cell seq><Smoke><Software><Staining method><Stains><Structure of parenchyma of lung><Structure of respiratory epithelium><Testing><Trachea><Trachea Proper><Transcript Expression Analyses><Transcript Expression Analysis><Translations><Tyrosine-Protein Kinase CSK><Viral><Virus><Virus-HIV><adeno-associated viral vector><adeno-associated virus vector><air flow><airflow><airflow limitation><airflow obstruction><airway epithelium><airway injury><airway limitation><airway obstruction><airway remodeling><analyze gene expression><balance><balance function><c src><c-ONC><c-src Genes><c-src Kinase><c-src Proto-Oncogenes><c-src Tyrosine Kinase><carboxy-terminal Src kinase><cell biology><cell sorting><cell type><cellular differentiation><chronic obstructive pulmonary disorder><cigarette smoke><cigarette smoke exposure><cigarette smoke-induced COPD><cigarette smoke-induced Chronic Obstructive Pulmonary Disease><cigarette smoking-induced COPD><cigarette smoking-induced Chronic Obstructive Pulmonary Disease><cohort><developmental><disease model><disorder model><drinking water><early onset><epithelial injury><epithelial repair><exposure to cigarette smoke><gene expression analysis><gene expression assay><gene expression pattern><gene expression signature><global gene expression><global transcription profile><gp120><gp120 ENV Glycoprotein><gp120(HIV)><human disease><imaging><immunogen><impaired airway><improved><in vivo><injured airway><injuries><interventional strategy><knock-down><knockdown><knockout gene><lung function><mRNA><mRNA Decay><mRNA Export><male><miRNA><miRNAs><mortality><mouse model><murine model><nef Protein><novel><obstructed airflow><obstructed airway><oxidative damage><oxidative injury><pathophysiology><pathway><patient population><pharmacologic><premature><prematurity><prevent><preventing><programs><protein-tyrosine kinase C-terminal Src kinase><protein-tyrosine kinase c-src><protooncogene><pulmonary><pulmonary function><repair><repaired><respiratory airway obstruction><respiratory imaging><respiratory injury><respiratory tract epithelium><respiratory tract injury><response><single cell next generation sequencing><single cell sequencing><social role><trafficking><transcriptional profile><transcriptional profiling><transcriptional signature><transcriptome><transcriptome profiling><transcriptome sequencing><transcriptomic profiling><transcriptomic sequencing><transcriptomics><translation><v-SRC Avian Sarcoma (Schmidt-Ruppin A-2) Viral Oncogene Homolog><windpipe>