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 hyper-permeability 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.
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.
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