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.
|Sellak, Hassan; Zhou, Chun; Liu, Bainan et al. (2014) Transcriptional regulation of ?1H T-type calcium channel under hypoxia. Am J Physiol Cell Physiol 307:C648-56|
|Rich, Thomas C; Webb, Kristal J; Leavesley, Silas J (2014) Can we decipher the information content contained within cyclic nucleotide signals? J Gen Physiol 143:17-27|
|Favreau, Peter F; Hernandez, Clarissa; Heaster, Tiffany et al. (2014) Excitation-scanning hyperspectral imaging microscope. J Biomed Opt 19:046010|
|Villalta, Patricia C; Rocic, Petra; Townsley, Mary I (2014) Role of MMP2 and MMP9 in TRPV4-induced lung injury. Am J Physiol Lung Cell Mol Physiol 307:L652-9|
|Stevens, Trevor C; Ochoa, Cristhiaan D; Morrow, K Adam et al. (2014) The Pseudomonas aeruginosa exoenzyme Y impairs endothelial cell proliferation and vascular repair following lung injury. Am J Physiol Lung Cell Mol Physiol 306:L915-24|
|Favreau, Peter; Hernandez, Clarissa; Lindsey, Ashley Stringfellow et al. (2014) Thin-film tunable filters for hyperspectral fluorescence microscopy. J Biomed Opt 19:011017|
|Xu, Ningyong; Francis, Michael; Cioffi, Donna L et al. (2014) Studies on the resolution of subcellular free calcium concentrations: a technological advance. Focus on "detection of differentially regulated subsarcolemmal calcium signals activated by vasoactive agonists in rat pulmonary artery smooth muscle cells". Am J Physiol Cell Physiol 306:C636-8|
|Hashizume, Masahiro; Mouner, Marc; Chouteau, Joshua M et al. (2013) Mitochondrial-targeted DNA repair enzyme 8-oxoguanine DNA glycosylase 1 protects against ventilator-induced lung injury in intact mice. Am J Physiol Lung Cell Mol Physiol 304:L287-97|
|Alexeyev, Mikhail; Shokolenko, Inna; Wilson, Glenn et al. (2013) The maintenance of mitochondrial DNA integrity--critical analysis and update. Cold Spring Harb Perspect Biol 5:a012641|
|Balczon, Ron; Prasain, Nutan; Ochoa, Cristhiaan et al. (2013) Pseudomonas aeruginosa exotoxin Y-mediated tau hyperphosphorylation impairs microtubule assembly in pulmonary microvascular endothelial cells. PLoS One 8:e74343|
Showing the most recent 10 out of 73 publications