In Project 4, we will test the hypotheses that (i) Nox2-dependent oxidant signaling activates Src kinasedependent ICAM-1-phosphorylation and thereby the recruitment of PMNs in the pulmonary circulation, and that (ii) Src phosphorylation of ICAM-1 in turn protracts Src activation and phosphorylation of caveolin-1 and dynamin-2, thereby triggering caveolae-mediated transcytosis of albumin and endothelial hyper-permeability. These studies will address the following Specific Aims: (1) role of PI3-kinase, PKC zeta, Nox2, and Src signaling, and of Akt phosphorylation of filamin A in the mechanism of ICAM-1 phosphorylation, clustering, and rapid increase in ICAM-1 binding affinity in lung microvascular endothelial cells and PMN uptake in lungs;(2) role of phospho-ICAM-1 in recruitment of SHP2 and protracting Src activation and thereby caveolin-1 and dynamin-2 activation, and thus stimulating caveolae-mediated transcytosis and hyper-permeability of albumin. Project 4 will delineate the signaling mechanisms mediating the post-translafional modification of ICAM-1 in pulmonary microvessel endothelial cells using imaging, cell biology, biochemical, and physiological approaches. We will thereby establish how endothelial cell ICAM-1 shifts to a high-affinity state and promotes PMN adhesion and sequestration and also induces caveolae-mediated hyper-permeability via the transcytosis of albumin. These studies it is hoped will lead to a new understanding of the early PMN-mediated lung inflammatory response and its coupling to lung vascular hyper-permeability. Identification of the key signaling hubs of ICAM-1-mediated endothelial adhesivity and activation of the caveolae-mediated albumin transport pathway is likely to provide novel therapeutic targets directed against infiammatory lung injury.
We will elucidate the role of Src-activated signaling mechanism regulating endothelial adhesivity and thereby permeability of lung microvessels. The proposed studies will for the first time establish the potentially important relationship between Src-activation of ICAM-1, neutrophil adhesion, and activation of the caveolar permeability machinery. Project 4 studies will thus define a novel pathogenic mechanism of ALI/ARDS.
|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 TGFÎ²RII to Downregulate TGF-Î² 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|
|Ebenezer, David L; Fu, Panfeng; Suryadevara, Vidyani et al. (2016) Epigenetic regulation of pro-inflammatory cytokine secretion by sphingosine 1-phosphate (S1P) in acute lung injury: Role of S1P lyase. Adv Biol Regul :|
|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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