Sunday, November 24, 2024
11/24/2024
PROJECT SUMMARY Inflammation underlies the pathogenesis of many chronic lung diseases. Thus, defining mechanisms by which pulmonary inflammation is regulated and resolved is of high clinical importance. Understanding those mechanisms is especially relevant to chronic obstructive pulmonary disease (COPD), a condition that typically develops following decades of cigarette smoking (CS) and in which repeated respiratory infections are linked to non-resolving inflammation and can cause disease flares (COPD exacerbations). Lung macrophages are critical for both initiation and resolution of inflammation, and the control of exacerbations. They can adopt different phenotypes (i.e., pro-inflammatory or pro-repair) that are characterized by an interplay of transcriptional and metabolic programming dictating macrophage function and ensuring tissue integrity. We previously demonstrated that fatty acid binding protein 5 (FABP5) mediates pro-repair macrophage function via interaction with the nuclear receptor Peroxisome Proliferator-Activated Receptor γ (PPARγ) and identified a novel single nucleotide polymorphism (SNP), rs202275, linked with a FABP5 enhancer region and COPD exacerbations. However, the critical role of the FABP5/PPARg axis and the genetic variation rs202275 (T) in macrophage phenotypic programming and whether they can be targeted for therapeutic purposes remains unknown. We propose 3 aims to interrogate the role of the FABP5/PPARg axis in macrophage pro-repair phenotype relying on 1) metabolism, 2) transcription, and 3) function of lung macrophages. This work will provide an in-depth clinically relevant understanding of the mechanisms by which decreased FABP5 leads to chronic lung inflammation in COPD exacerbations, identify a novel target to reverse chronic inflammation in COPD, and validate the repurposing of FDA approved PPARγ agonists used in type 2 diabetes.
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