Lung tissue fluid homeostasis is regulated by endothelial permeability to albumin and liquid such that disruption of the endothelial barrier leads to pulmonary edema. We propose to address the potentially important and novel relationship between endothelial caveolin-1, the signaling protein of caveolae, and adherens junctions (AJs), structures known to regulate permeability of the junctions. We posit that cross-talk between caveolae and AJs, which up to now have been studied independently, may be of fundamental importance in regulating AJ permeability. The focus of Project 1 is on addressing the role of NO signaling via eNOS translocation from caveolin-1 to AJs in regulating the p120-catenin interaction with p190RhoGAP at the level of AJs. We will determine how the spatially regulated GAP activity of p190RhoGAP controls RhoA activation and endothelial barrier function. The proposed studies will address the following Specific Aims:
Aim 1. To determine the role of eNOS translocation to AJs induced by activation of caveolae-mediated endocytosis in the mechanism of hyperpermeability of lung vessels.
Aim 2. To delineate the role of NO redox signaling in mediating the nitration of p190RhoGAP, a crucial regulator of AJs, in the mechanism of RhoA activation, AJ destabilization, and increased permeability of the lung endothelial barrier. To address these aims, Project 1 will utilize approaches including live cell imaging and the use of genetically-modified mouse models to delineate the role of NO signaling in mediating post-translational modifications of p120-catenin and p190RhoGAP and the mechanisms by which these signaling pathways induce increased lung endothelial permeability and edema formation.

Public Health Relevance

The proposed studies in Project 1 will help to define the molecular and cellular bases of leaky lung vascular syndrome that leads to lung failure associated with the adult respiratory distress syndrome (ARDS). The studies will pin-point how the syndrome develops and progresses so that specific therapeutics targets can be identified to reverse or treat the syndrome in lung diseases.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Heart, Lung, and Blood Initial Review Group (HLBP)
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University of Illinois at Chicago
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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
Tang, Haiyang; Chen, Jiwang; Fraidenburg, Dustin R et al. (2015) Deficiency of Akt1, but not Akt2, attenuates the development of pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 308:L208-20
Piegeler, Tobias; Dull, Randal O; Hu, Guochang et al. (2014) Ropivacaine attenuates endotoxin plus hyperinflation-mediated acute lung injury via inhibition of early-onset Src-dependent signaling. BMC Anesthesiol 14:57
Mao, Mao; Varadarajan, Sudhahar; Fukai, Tohru et al. (2014) Nitroglycerin tolerance in caveolin-1 deficient mice. PLoS One 9:e104101
Chernaya, Olga; Shinin, Vasily; Liu, Yuru et al. (2014) Behavioral heterogeneity of adult mouse lung epithelial progenitor cells. Stem Cells Dev 23:2744-57
Thangavel, Jayakumar; Malik, Asrar B; Elias, Harold K et al. (2014) Combinatorial therapy with acetylation and methylation modifiers attenuates lung vascular hyperpermeability in endotoxemia-induced mouse inflammatory lung injury. Am J Pathol 184:2237-49
Tobin, Matthew K; Bonds, Jacqueline A; Minshall, Richard D et al. (2014) Neurogenesis and inflammation after ischemic stroke: what is known and where we go from here. J Cereb Blood Flow Metab 34:1573-84
Yang, Kai-Chien; Rutledge, Cody A; Mao, Mao et al. (2014) Caveolin-1 modulates cardiac gap junction homeostasis and arrhythmogenecity by regulating cSrc tyrosine kinase. Circ Arrhythm Electrophysiol 7:701-10
Mehta, Dolly; Ravindran, Krishnan; Kuebler, Wolfgang M (2014) Novel regulators of endothelial barrier function. Am J Physiol Lung Cell Mol Physiol 307:L924-35
Mittal, Manish; Siddiqui, Mohammad Rizwan; Tran, Khiem et al. (2014) Reactive oxygen species in inflammation and tissue injury. Antioxid Redox Signal 20:1126-67

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