The Program Project grant (yr 11-15) "Signaling of Endothelial Permeability and Lung Vascular Injury" addresses the critical mechanisms that mediate the loss of pulmonary vascular barrier function, in turn, inducing pulmonary edema. We have approached this subject in a multidisciplinary manner bringing to bear technologies of molecular and cellular biology, biochemistry, and cell imaging and functional analysis of the regulation of lung vascular barrier function in the mouse model. Project 1 addresses the potentially important and novel relationship between endothelial caveolin-1, the structural and signaling protein of caveolae, and adherens junctions (AJs), the structures known to regulate permeability of the junctions based on the postulate of a cross-talk between caveolae and AJs via eNOS. Project 2 addresses the mechanisms of a newly identified post-translational activation of iNOS activity and how the inordinately high-output NO generated regulates lung endothelial barrier function. Project 3 focuses on the signaling mechanisms by which TRPC6 (a prototypic receptor-operated calcium channel) activates both RhoA and the endothelial MLCK isoform to increase lung endothelial permeability. Project 4 addresses the fundamental observation of increased binding affinity on endothelial cell plasmalemma of the adhesive protein ICAM-1 and the feed-forward signaling mechanism of ICAM-1 activation of caveolae-mediated transcytosis and lung endothelial hyper-permeability. Our overall goal on the basis of these four highly interactive projects is to define signaling pathways regulating the increase in lung vascular permeability so that rational targets are identified for therapeutic purposes. Moreover the depth of understanding to be gained of the signaling pathways mediating the increase in lung vascular permeability will provide novel insights into the mechanisms of protein-rich pulmonary edema and ARDS.
This renewal program project application consisting of 4 highly interactive projects deals with defining signaling mechanisms regulating the permeability of the lung endothelial barrier at the level of interendothelial junctions and via caveolae-mediated transcytosis. The focus of the work relates to the lung endothelium in which studies will delineate the signaling pathways to establish their role in pathophysiology of acute lung injury and its treatment.
|Liu, Yuru; Kumar, Varsha Suresh; Zhang, Wei et al. (2015) Activation of type II cells into regenerative stem cell antigen-1(+) cells during alveolar repair. Am J Respir Cell Mol Biol 53:113-24|
|Tang, Haiyang; Chen, Jiwang; Fraidenburg, Dustin R et al. (2015) Deficiency of Akt1, but not Akt2, attenuates the development of pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 308:L208-20|
|Piegeler, Tobias; Dull, Randal O; Hu, Guochang et al. (2014) Ropivacaine attenuates endotoxin plus hyperinflation-mediated acute lung injury via inhibition of early-onset Src-dependent signaling. BMC Anesthesiol 14:57|
|Mao, Mao; Varadarajan, Sudhahar; Fukai, Tohru et al. (2014) Nitroglycerin tolerance in caveolin-1 deficient mice. PLoS One 9:e104101|
|Chernaya, Olga; Shinin, Vasily; Liu, Yuru et al. (2014) Behavioral heterogeneity of adult mouse lung epithelial progenitor cells. Stem Cells Dev 23:2744-57|
|Thangavel, Jayakumar; Malik, Asrar B; Elias, Harold K et al. (2014) Combinatorial therapy with acetylation and methylation modifiers attenuates lung vascular hyperpermeability in endotoxemia-induced mouse inflammatory lung injury. Am J Pathol 184:2237-49|
|Tobin, Matthew K; Bonds, Jacqueline A; Minshall, Richard D et al. (2014) Neurogenesis and inflammation after ischemic stroke: what is known and where we go from here. J Cereb Blood Flow Metab 34:1573-84|
|Yang, Kai-Chien; Rutledge, Cody A; Mao, Mao et al. (2014) Caveolin-1 modulates cardiac gap junction homeostasis and arrhythmogenecity by regulating cSrc tyrosine kinase. Circ Arrhythm Electrophysiol 7:701-10|
|Mehta, Dolly; Ravindran, Krishnan; Kuebler, Wolfgang M (2014) Novel regulators of endothelial barrier function. Am J Physiol Lung Cell Mol Physiol 307:L924-35|
|Mittal, Manish; Siddiqui, Mohammad Rizwan; Tran, Khiem et al. (2014) Reactive oxygen species in inflammation and tissue injury. Antioxid Redox Signal 20:1126-67|
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