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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL060678-12
Application #
8374599
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Project Start
Project End
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
12
Fiscal Year
2012
Total Cost
$335,112
Indirect Cost
$121,664
Name
University of Illinois at Chicago
Department
Type
DUNS #
098987217
City
Chicago
State
IL
Country
United States
Zip Code
60612
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