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 (T2C). LRP1 is associated with decreased respiratory function in COPD patients, and it also functions as lipoprotein receptor and extracellular protease clearing receptor. Studies in our generated LRP1 knockdown T2C (LRP1 KD) and tamoxifen-inducible T2C-specific LRP1 knockout mice (SPC-LRP1-/-) show that LRP1 is required to maintain surfactant lipid secretion and recycling homeostasis to ensure optimal pulmonary compliance and respiratory function. We hypothesize that LRP1 controls surfactant metabolism in T2C and we will study the regulatory mechanisms. In Aim 1 we will decipher the mechanism of action of LRP1 at the membrane level in T2C and the regulation of surfactant-producing enzymatic activities and of intracellular lipid metabolic trafficking by LRP1. In Aim 2 we will investigate the role of LRP1 in the apical membrane of T2C and the regulation of surfactant recycling in the endosomal route. This proposal is innovative conceptually and technically. The function of LRP1 in pulmonary surfactant 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 and -omics analysis. Surfactant homeostasis enables basic pulmonary function, but the regulation of surfactant homeostasis in adult disease is very little understood. Deregulation of surfactant metabolism may partake and exacerbate disease by decreasing pulmonary compliance. The significance of this research is further underscored by the fact that surfactant lipid composition is altered in multiple pulmonary pathologies, including the most prevalent ones.