Loss of lung vascular barrier function and inflammatory cell infiltration are two cardinal features of acute lung injury (ALI). The project wil investigate the fundamental concept that endothelial focal adhesion kinase (FAK) modulates the increase in lung vascular permeability and the inflammatory response by suppressing intracellular Ca2+ rise. We will test the hypothesis that FAK induces microRNA-150 (miR-150) expression which targets the Ca2+ sensor, stromal interacting molecule 1 (STIM1). We postulate that STIM1 downregulation by this mechanism is crucial for blocking Ca2+ signaling in endothelial cells and thereby prevents disruption of lung vascular barrier and inflammation. To address this hypothesis, we have generated a novel tamoxifen-inducible endothelial cell (EC)-specific FAK knockout (EC-FAK-/-) as well as EC-STIM1-/- mouse models. We will address the following aims:
Aim #1, To define the role of FAK in regulating lung fluid balance and modulating lung inflammation using endothelial cell-specific FAK null mice;
Aim #2, To determine the role of FAK in suppressing STIM1 activity and thereby blocking Ca2+ entry signals mediating increased lung vascular permeability and inflammation;
and Aim #3, To define the role of miR-150 as an essential effector of FAK that targets STIM1 and thus prevents increased lung vascular permeability and inflammation. These studies will use a combination of imaging, genetic, and physiological approaches to develop a comprehensive and integrated picture of the role of endothelial FAK in regulating lung fluid homeostasis and inflammation. The results of these studies will have the potential of defining novel therapeutic targets directed against ALI.

Public Health Relevance

Acute lung injury (ALI) characterized by plasma leakage, increased white blood cell influx and cytokine generation is a life threatening disease. Although great strides have been made in effectively supporting ALI patients, current treatment strategies have demonstrated limited success in preventing ALI. Therefore the search continues for more effective treatments to reduce the unacceptably high rate of mortality caused by ALI. Proposed studies will investigate the role of endothelial protein, focal adhesion kinase (FAK) in maintaining lung fluid homeostasis and moderating lung inflammatory injury. We hope these studies will offer novel insights and therapeutic targets that we think will lead to the developmen of more effective treatments with improved outcomes for patients suffering from ALI.

National Institute of Health (NIH)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Moore, Timothy M
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University of Illinois at Chicago
Schools of Medicine
United States
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Lei, Lei; Lu, Shaoying; Wang, Yi et al. (2014) The role of mechanical tension on lipid raft dependent PDGF-induced TRPC6 activation. Biomaterials 35:2868-77
Mehta, Dolly; Ravindran, Krishnan; Kuebler, Wolfgang M (2014) Novel regulators of endothelial barrier function. Am J Physiol Lung Cell Mol Physiol 307:L924-35
Gong, Haixia; Gao, Xiaopei; Feng, Shaoting et al. (2014) Evidence of a common mechanism of disassembly of adherens junctions through G?13 targeting of VE-cadherin. J Exp Med 211:579-91
Rajput, Charu; Kini, Vidisha; Smith, Monica et al. (2013) Neural Wiskott-Aldrich syndrome protein (N-WASP)-mediated p120-catenin interaction with Arp2-Actin complex stabilizes endothelial adherens junctions. J Biol Chem 288:4241-50
Schmidt, Tracy Thennes; Tauseef, Mohammad; Yue, Lili et al. (2013) Conditional deletion of FAK in mice endothelium disrupts lung vascular barrier function due to destabilization of RhoA and Rac1 activities. Am J Physiol Lung Cell Mol Physiol 305:L291-300
Thennes, Tracy; Mehta, Dolly (2012) Heterotrimeric G proteins, focal adhesion kinase, and endothelial barrier function. Microvasc Res 83:31-44
Chava, Koteswara Rao; Tauseef, Mohammad; Sharma, Tiffany et al. (2012) Cyclic AMP response element-binding protein prevents endothelial permeability increase through transcriptional controlling p190RhoGAP expression. Blood 119:308-19
Chavez, Alejandra; Smith, Monica; Mehta, Dolly (2011) New insights into the regulation of vascular permeability. Int Rev Cell Mol Biol 290:205-48
Kini, Vidisha; Chavez, Alejandra; Mehta, Dolly (2010) A new role for PTEN in regulating transient receptor potential canonical channel 6-mediated Ca2+ entry, endothelial permeability, and angiogenesis. J Biol Chem 285:33082-91
Knezevic, Nebojsa; Tauseef, Mohammad; Thennes, Tracy et al. (2009) The G protein betagamma subunit mediates reannealing of adherens junctions to reverse endothelial permeability increase by thrombin. J Exp Med 206:2761-77

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