Pulmonary microvascular endothelial cells (PMVECs) form contiguous, semi-permeable barriers between the bloodstream and the interstitial space. Pseudomonas aeruginosa, a major contributor to acute lung injury. Injects an exotoxin, ExoY, that disrupts the PMVEC barrier and results in lung injury. ExoY is a soluble adenylyl cyclase that produces cAMP in the cytosol. Increased cytosolic cAMP levels lead to phosphorylation of cytosolic proteins such as tau, reorganization of the microtubule network, disruption of the endothelial barrier, and impaired O2/CO2 exchange. cAMP levels are lowered by phosphodiesterase (PDE) activity. Recent evidence suggests that a specific mutation in PDE4B is a major risk factor for the development of acute lung injury. It is not known whether this mutation causes an increase or decrease in PDE4B activity, or alters the subcellular localization of the enzyme. It is also not understood how alteration of PDE4B activity contributes to the increased risk for development of acute lung injury. In fact, few studies have examined how PDE4B activity contributes to the regulation of specific, cAMP-mediated cellular functions. The experiments outlined In this application will elucidate physiological roles of PDE4B in the pulmonary microvasculature and will give us a better understanding of how mutations in PDE4B lead to an increased risk of developing acute lung injury. If the results of the proposed studies are as anticipated then they will demonstrate that the subcellular localization of PDE4B is a critical factor in defining specificity in the cAMP signaling pathway. These results would also point to novel approaches for treatment of acute lung injury designing small molecules and peptides to redirect the subcellular distribution of PDE4B in pulmonary endothelium.
Acute lung injury (ALI) is a disease that damages the endothelial lining of the lung, limiting oxygen delivery to the blood. Recent studies have linked a specific genetic mutation with a siginificant increase in the risk of developing ALI. The mutation is In a protein called PDE4B. Our work focuses on understanding how mutations in PDE4B alter lung endothelial function and predispose individuals to develop ALI.
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