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Principal Investigator: Rafia Virk
Organization: UNIV OF NORTH CAROLINA CHAPEL HILL
Fiscal Year: 2024
Award: $40,583
Funding agency: National Heart Lung and Blood Institute
PROJECT SUMMARY
Significance. Pulmonary inflammation, which contributes toward the severity of lung diseases, is markedly
exacerbated by obesity. Thus, there is a need for novel therapeutic approaches for targeting pulmonary
inflammation in obesity. One promising strategy involves increased dietary consumption of docosahexaenoic
acid (DHA), an omega-3 polyunsaturated fatty acid, which exerts anti-inflammatory properties. The first step
toward developing DHA as a therapeutic for pulmonary inflammation in obesity is to establish the cellular targets
and mechanisms of this unique fatty acid. One key target of DHA is alveolar macrophages (AMs), which are
critical for maintaining respiratory homeostasis and drive pulmonary inflammation in obesity. Based on strong
preliminary data, we propose the central hypothesis that DHA targets AMs to improve the inflammatory
response through two key mechanisms. The first mechanism, tested in Aim 1, involves DHA esterification into
plasma membrane phospholipids of AMs and thereby controlling the biophysical organization of
sphingolipid/cholesterol-enriched lipid rafts to lower inflammatory signaling in obese mice. The second
mechanism, tested in Aim 2, involves DHA displacing arachidonic acid (AA) in the phospholipidome. AA is an
omega-6 PUFA which exerts pro-inflammatory effects through its conversion to hydroxylated derivatives such as
prostaglandins. Displacing AA with DHA would shift the balance from pro-inflammatory AA derivatives in obesity
to anti-inflammatory and pro-resolution DHA derivatives. One such DHA derivative is resolvin D1 (RvD1). RvD1
binds the G-protein coupled receptor ALX/FPR2 and decreases inflammation by driving macrophages to have
an anti-inflammatory phenotype. To test the central hypothesis, the applicant will rely on advanced imaging tools,
biochemical assays, and knockout mouse models including the innovative use of a newly generated myeloid
specific DHA-deficient mouse. Impact: The proposed studies will establish mechanisms by which DHA
improves pulmonary inflammation in obese mice and inform future clinical studies. This research will provide the
applicant with skills in developing and implementing rigorous study design, use of advanced laboratory
techniques (cutting-edge biophysical microscopy methods, flow cytometry, and biochemical assays), foster
interdisciplinary collaboration, and enhance leadership skills through writing, project management, and
mentoring. Ultimately, this will build the foundation for a successful biomedical research career.
Terms: <21+ years old><ALXR><Acute Lung Injury><Acute Pulmonary Injury><Adult><Adult Human><Alveolar Macrophages><Anti-Inflammatories><Anti-Inflammatory Agents><Anti-inflammatory><Antiinflammatory Effect><Arachidonic Acids><Assay><Automobile Driving><Autoregulation><Binding><Bioassay><Biochemical><Biological Assay><Biomedical Research><Biophysics><COPD><COVID-19><CV-19><Cause of Death><Cell Body><Cell Communication and Signaling><Cell Culture Techniques><Cell Membrane Lipid Rafts><Cell Signaling><Cell membrane><Cells><Chemotactic Cytokines><Cholesterol><Chronic Obstruction Pulmonary Disease><Chronic Obstructive Lung Disease><Chronic Obstructive Pulmonary Disease><Clinical><Clinical Research><Clinical Study><Consumption><Coronavirus Infectious Disease 2019><Cytoplasmic Membrane><DHA supplementation><Data><Disease><Disorder><Docosahexaenoate><Docosahexaenoic Acids><Docosahexaenoic acid supplementation><Docosahexenoic Acids><Equilibrium><Esterification><Exhibits><FPR2><FPR2 gene><FPRH1><FPRL1><Fatty Acids><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Formyl Peptide Receptor 2><Formyl Peptide Receptor Homolog 1><Formyl Peptide Receptor-Like 1><Fostering><Foundations><Future><G Protein-Complex Receptor><G Protein-Coupled Receptor Genes><G-Protein-Coupled Receptors><GPCR><HM63><Homeostasis><Homologous Chemotactic Cytokines><Hydroxylation><Imaging Device><Imaging Instrument><Imaging Procedures><Imaging Technics><Imaging Techniques><Imaging Tool><Immune><Immunes><Immunoassay><In Vitro><Individual><Inflammation><Inflammatory><Inflammatory Response><Intercrines><Intracellular Communication and Signaling><KO mice><Knock-out Mice><Knockout Mice><LXA4R><Laboratories><Leadership><Leukotrienes><Lipopolysaccharides><Lipoxin A4 Receptor><Lung><Lung Diseases><Lung Inflammation><Lung Respiratory System><Lung damage><Macrophage><Mass Photometry/Spectrum Analysis><Mass Spectrometry><Mass Spectroscopy><Mass Spectrum><Mass Spectrum Analyses><Mass Spectrum Analysis><Measures><Membrane><Membrane Microdomains><Mentors><Methods><Mice><Mice Mammals><Microscopy><Modeling><Molecular Dynamics Simulation><Molecular Interaction><Murine><Mus><Myelogenous><Myeloid><Mφ><N-6 Fatty Acids><Null Mouse><Obese Mice><Obesity><Omega-3 Fatty Acids><Omega-3 PUFA><Omega-3 Polyunsaturated Fatty Acid><Omega-6><Omega-6 Fatty Acids><Omega-6 PUFAs><Omega3><Persons><Phenotype><Phosphatides><Phospholipids><Physiological Homeostasis><Plasma Membrane><Pneumonitis><Polyunsaturated Fatty Acids><Population><Predisposition><Property><Prostaglandins><Prostanoids><Public Health><Pulmonary Diseases><Pulmonary Disorder><Pulmonary Inflammation><Pulmonary Macrophages><Receptor Protein><Research><Research Design><Research Proposals><Resolution><Role><SIS cytokines><Severities><Signal Transduction><Signal Transduction Systems><Signaling><Solid><Sphingolipid Microdomains><Sphingolipid-Cholesterol Rafts><Sphingolipids><Study Type><Susceptibility><Techniques><Testing><Therapeutic><Writing><adiposity><adulthood><anti-inflammatory effect><balance><balance function><biological signal transduction><biophysical foundation><biophysical principles><biophysical sciences><career><cell culture><cell cultures><cellular targeting><chemoattractant cytokine><chemokine><chronic obstructive pulmonary disorder><coronavirus disease 2019><coronavirus disease-19><coronavirus infectious disease-19><corpulence><cytokine><diet-associated obesity><diet-induced obesity><diet-related obesity><dietary><disease of the lung><disorder of the lung><driving><experiment><experimental research><experimental study><experiments><flow cytophotometry><global health><improved><inflammatory lung disease><innovate><innovation><innovative><interdisciplinary collaboration><lipid raft><lipidomics><lung disorder><lung health><lung injury><membrane structure><molecular dynamics><mouse model><murine model><n-3 Fatty Acids><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><ob/ob mouse><omega-3><plasmalemma><pulmonary><pulmonary damage><pulmonary health><pulmonary injury><pulmonary tissue damage><pulmonary tissue injury><receptor><resolutions><respiratory><response><skills><social role><study design><transdisciplinary collaboration><ω-3 fatty acids><ω-6>