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.
|Marsboom, Glenn; Rehman, Jalees (2018) Hypoxia Signaling in Vascular Homeostasis. Physiology (Bethesda) 33:328-337|
|Lv, Yang; Kim, Kyungho; Sheng, Yue et al. (2018) YAP Controls Endothelial Activation and Vascular Inflammation Through TRAF6. Circ Res 123:43-56|
|Christoforidis, Theodore; Driver, Tom G; Rehman, Jalees et al. (2018) Generation of controllable gaseous H2S concentrations using microfluidics. RSC Adv 8:4078-4083|
|Di, Anke; Xiong, Shiqin; Ye, Zhiming et al. (2018) The TWIK2 Potassium Efflux Channel in Macrophages Mediates NLRP3 Inflammasome-Induced Inflammation. Immunity 49:56-65.e4|
|Chen, Zhenlong; D S Oliveira, Suellen; Zimnicka, Adriana M et al. (2018) Reciprocal regulation of eNOS and caveolin-1 functions in endothelial cells. Mol Biol Cell 29:1190-1202|
|Le Master, Elizabeth; Huang, Ru-Ting; Zhang, Chongxu et al. (2018) Proatherogenic Flow Increases Endothelial Stiffness via Enhanced CD36-Mediated Uptake of Oxidized Low-Density Lipoproteins. Arterioscler Thromb Vasc Biol 38:64-75|
|Marsboom, Glenn; Chen, Zhenlong; Yuan, Yang et al. (2017) Aberrant Caveolin-1-Mediated Smad Signaling and Proliferation Identified by Analysis of Adenine 474 Deletion Mutation (c.474delA) in Patient Fibroblasts: A New Perspective in the Mechanism of Pulmonary Hypertension. Mol Biol Cell :|
|Yazbeck, Pascal; Tauseef, Mohammad; Kruse, Kevin et al. (2017) STIM1 Phosphorylation at Y361 Recruits Orai1 to STIM1 Puncta and Induces Ca2+ Entry. Sci Rep 7:42758|
|Gong, Haixia; Liu, Menglin; Klomp, Jeff et al. (2017) Method for Dual Viral Vector Mediated CRISPR-Cas9 Gene Disruption in Primary Human Endothelial Cells. Sci Rep 7:42127|
|Komarova, Yulia A; Kruse, Kevin; Mehta, Dolly et al. (2017) Protein Interactions at Endothelial Junctions and Signaling Mechanisms Regulating Endothelial Permeability. Circ Res 120:179-206|
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