Regulation of lipid metabolism in pulmonary Type 2 cells

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Surfactant insufficiency compromises pulmonary compliance and respiratory function in multiple pulmonary pathologies. Our understanding of surfactant metabolism in adult pulmonary disease is very limited and this restricts the potential for therapeutic targeting. In this project, we have generated a new genetic model of surfactant insufficiency in adult disease by deleting the low-density lipoprotein receptor related protein 1 (LRP1) specifically in surfactant producing type 2 cells (AEC2). LRP1 functions as lipoprotein receptor and extracellular protease clearing receptor and it is associated with decreased respiratory function in patients with COPD and pulmonary arterial hypertension. Studies in our generated cell line of LRP1 knockdown AEC2 (LRP1 KD) and tamoxifen-inducible AEC2-specific LRP1 knockout mice (SPC-LRP1-/-) show that LRP1 is required to maintain surfactant lipid secretion and intracellular lipid homeostasis to ensure optimal pulmonary compliance and respiratory function. We hypothesize that LRP1 controls surfactant metabolism in AEC2 and we will study the regulatory mechanisms. In Aim 1 we will decipher the mechanism of action of LRP1 at the membrane level in AEC2 and its regulation of the lipid source for surfactant synthesis in AEC2. In Aim 2 we will investigate the epithelial to mesenchymal cross talk and the role of LRP1 in the progressive decline in lung function during profibrotic challenges and molecular mechanisms responsible. We will attempt a new therapeutic approach to stop the decline. This proposal is innovative conceptually and technically. The role of AEC2 lipid metabolism during adult pulmonary disease is unknown. LRP1 regulates many cellular functions through lipid metabolism in different tissues and our study shows that it also regulates pulmonary function through surfactant lipid metabolism. In addition, we use novel techniques that include inducible and cell-specific genetic knockout models in vivo lipid tracing and -omics analysis. Surfactant homeostasis enables basic pulmonary function, but the regulation of surfactant homeostasis in adult disease is very little understood. The significance of this research is further underscored by the fact that surfactant lipid is altered in multiple pulmonary pathologies, including the most prevalent ones.