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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Moore, Timothy M
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University of Illinois at Chicago
Schools of Medicine
United States
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Di, Anke; Mehta, Dolly; Malik, Asrar B (2016) ROS-activated calcium signaling mechanisms regulating endothelial barrier function. Cell Calcium 60:163-71
Tauseef, Mohammad; Farazuddin, Mohammad; Sukriti, Sukriti et al. (2016) Transient receptor potential channel 1 maintains adherens junction plasticity by suppressing sphingosine kinase 1 expression to induce endothelial hyperpermeability. FASEB J 30:102-10
Gong, Haixia; An, Shejuan; Sassmann, Antonia et al. (2016) PAR1 Scaffolds TGFβRII to Downregulate TGF-β Signaling and Activate ESC Differentiation to Endothelial Cells. Stem Cell Reports 7:1050-1058
Rajput, Charu; Tauseef, Mohammad; Farazuddin, Mohammad et al. (2016) MicroRNA-150 Suppression of Angiopoetin-2 Generation and Signaling Is Crucial for Resolving Vascular Injury. Arterioscler Thromb Vasc Biol 36:380-8
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Zimnicka, Adriana M; Husain, Yawer S; Shajahan, Ayesha N et al. (2016) Src-dependent phosphorylation of caveolin-1 Tyr-14 promotes swelling and release of caveolae. Mol Biol Cell 27:2090-106
Jiang, Ying; Sverdlov, Maria S; Toth, Peter T et al. (2016) Phosphatidic Acid Produced by RalA-activated PLD2 Stimulates Caveolae-mediated Endocytosis and Trafficking in Endothelial Cells. J Biol Chem 291:20729-38
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
Geyer, Melissa; Huang, Fei; Sun, Ying et al. (2015) Microtubule-Associated Protein EB3 Regulates IP3 Receptor Clustering and Ca(2+) Signaling in Endothelial Cells. Cell Rep 12:79-89
Zhang, Xianming; Brovkovych, Viktor; Zhang, Yongkang et al. (2015) Downregulation of kinin B1 receptor function by B2 receptor heterodimerization and signaling. Cell Signal 27:90-103

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