Resetting the Clock in HIV associated COPD

Document text

Principal Investigator: IRFAN  RAHMAN
Organization: FLORIDA INTERNATIONAL UNIVERSITY
Fiscal Year: 2024
Award: $517,266
Funding agency: National Heart Lung and Blood Institute

Title: Resetting the Clock on HIV associated COPD
PROJECT SUMMARY
 The long-term goal of this proposal is identifying the role of aberrant circadian-coupled gene expression
linking HIV and lung inflammation as a fundamental starting point to understand the pathophysiological
mechanism in HIV associated COPD. People living with HIV demonstrate increased lung inflammation and
incidence of COPD even when compensated for smoking status. Disruption of the lung molecular clock has been
implicated in increased lung inflammation observed in COPD and smokers. SIRT1 is a principal circadian
deacetylase that serves as a critical link between core clock function and inflammatory responses in the lung.
HIV Tat, an immediate early protein of HIV that is secreted extracellularly, upregulates miR-142-5p in primary
bronchial epithelial cells. This upregulation results in suppression of SIRT1 and circadian disruption of core clock
genes BMAL1 and PER2. Likewise, cigarette smoking has also been shown to suppress SIRT1/BMAL1 pathway
and dysregulate the lung molecular clock with consequent increase in secretion of proinflammatory cytokines. A
significant proportion of people living with HIV smoke tobacco/cigarettes, possibly exacerbating their lung
molecular clock dysfunction. This could be one of the core mechanisms that results in COPD exacerbations in
HIV smokers. Therefore, determining the role of lung molecular clock dysfunction in HIV associated lung
inflammation and COPD is the goal of this proposal. Resetting the molecular clock could thus help reduce
underlying inflammation and/or arrest the lung function decline observed in HIV smokers. We propose three
aims. Aim 1 determine that lung molecular clock is dysregulated by HIV Tat and identify the mechanism involved
and its impact on inflammation. Aim 2 will test the role of miR-142-5p/SIRT1/BMAL1 axis in lung molecular clock
dysfunction in HIV smokers/non smokers and in transgenic mouse models. Aim 3 will test clinically feasible
strategies with established potential to neutralize HIV Tat and reset the lung molecular clock in vitro and in
transgenic molecular clock mouse models in vivo. Understanding the pathophysiological mechanisms by which
HIV disrupts the lung molecular clock will provide therapeutic targets for HIV-associated COPD.

Terms: <AIDS Virus><ARNTL><ARNTL gene><Abbreviations><Accounting><Acetylation><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Aging><Agonist><Air><Anatomic Sites><Anatomic structures><Anatomy><BMAL1><Biological><Bronchioalveolar Lavage><Bronchoalveolar Lavage><Bronchopulmonary Lavage><COPD><CXCL5><CXCL5 gene><Chemokine, CXC Motif, Ligand 5><Chronic><Chronic Obstruction Pulmonary Disease><Chronic Obstructive Lung Disease><Chronic Obstructive Pulmonary Disease><Cigarette><Circadian Dysregulation><Circadian Rhythms><Clinical><Compensation><Consequences of HIV><Continuity of Care><Continuity of Patient Care><Continuum of Care><Coupled><Cyclicity><DNA><Data><Deacetylase><Deacetylation><Deoxyribonucleic Acid><Development><Disease><Disease Progression><Disorder><Dysfunction><ENA-78><ENA78><Emphysema><Epithelial Cells><Functional disorder><Gene Expression><Genes><Goals><HIV><HIV Infections><HTLV-III Infections><HTLV-III-LAV Infections><Hour><Human><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Infections><Immediate-Early Proteins><In Vitro><Incidence><Inflammation><Inflammatory><Inflammatory Response><LAV-HTLV-III><LIX gene><LIX protein><Link><Lipopolysaccharide Induced CXC Chemokine><Liquid substance><Lung><Lung Inflammation><Lung Lavage><Lung Respiratory System><Lung damage><Lymphadenopathy-Associated Virus><Mediating><Modern Man><Molecular><Morbidity><Morbidity - disease rate><Mucous body substance><Mucus><Neutrophil-Activating Peptide ENA-78><Non-Polyadenylated RNA><Nyctohemeral Rhythm><Output><Pathway interactions><Patients><Periodicity><Peripheral><Persons><Physiology><Physiopathology><Play><Pneumonitis><Population><Pulmonary Emphysema><Pulmonary Inflammation><RNA><RNA Gene Products><Repression><Resistance><Respiratory Epithelium><Response Elements><Rhythmicity><Ribonucleic Acid><Risk Factors><Role><SCYB5><SIRT1><SIRT1 gene><Severity of illness><Sirtuin 1><Small Inducible Cytokine Subfamily B, Member 5><Smoker><Smoking Status><Stimulus><Structure of respiratory epithelium><Testing><Therapeutic><Tobacco smoke><Transactivation><Transgenic Mice><Transgenic Organisms><Twenty-Four Hour Rhythm><United States><Up-Regulation><Upregulation><Viral><Virus Replication><Virus-HIV><airway epithelium><airway epithelium inflammation><airway inflammation><antiretroviral therapy><antiretroviral treatment><aryl hydrocarbon receptor nuclear translocator-like><biologic><bronchial epithelium><bronchopulmonary lavage therapy><cell type><chronic obstructive pulmonary disorder><cigarette smoke><cigarette smoking><cigarette use><circadian><circadian abnormality><circadian clock><circadian disruption><circadian disturbance><circadian dysfunction><circadian impairment><circadian pacemaker><circadian process><co-morbid><co-morbidity><comorbidity><cytokine><daily biorhythm><developmental><disease severity><emphysematous><extracellular><fluid><in vivo><in vivo Model><liquid><lung function><lung function decline><lung injury><molecular clock><mortality><mouse model><mucous><mucus hyper-secretion><mucus hypersecretion><murine model><non-smoker><nonsmoker><novel><nuclease><overexpress><overexpression><pathophysiology><pathway><phosphoramidate><pulmonary><pulmonary damage><pulmonary function><pulmonary function decline><pulmonary injury><pulmonary tissue damage><pulmonary tissue injury><resistant><respiratory inflammation><respiratory tract epithelium><respiratory tract inflammation><social role><therapeutic evaluation><therapeutic target><therapeutic testing><tobacco smoke exposure><trans-activation><transcriptomics><transgenic><viral multiplication><viral replication><virus multiplication>