Increase in lung vascular permeability results in an array of pathological conditions including Adult Respiratory Distress Syndrome. The endothelial adherens junctions (AJs) consisting of VE-cadherin and its associated catenins is a major determinant of fluid and plasma protein permeability of the vessel endothelial barrier. Impairment of lung endothelial barrier function contributes to lung injury and inflammation. AJs disassemble in response to pro-inflammatory mediators producing an increase in endothelial permeability;however, AJs also have the capacity to re-assemble leading to restoration of endothelial barrier function. Activation of Cdc42, a member of the Rho family of monomeric GTPases, in particular may be obligatory signals regulating the re- annealing of AJs and reversal of the increase in endothelial permeability. This project has the following three Aims: (i) to determine the role of Cdc42 interactions with AJ proteins and the AJ-associated scaffold protein IQGAP in the mechanism of Cdc42-mediated lung vascular endothelial barrier repair and to address the specific role of activation of endothelial cell-specific expression of Cdc42 in a transgenic mouse in reversing the increase in lung vascular permeability and edema formation;(ii) to determine the role of p190RhoGAP interaction with the AJ protein p120-catenin in the mechanism of inactivation of RhoA signaling and in promoting Cdc42-mediated AJs re-assembly and restoration of endothelial barrier function;and (iii) to address RhoGTPase-dependent signaling mechanisms of endothelial barrier re-annealing induced by the activation of sphingosine kinase 1 and generation of sphingosine- 1-phosphate (S1P) and its interaction with endothelial receptor SIP1. We will exploit a variety of methodologies and approaches including cell imaging, expression of mutant constructs, gene transfer, and genetically-modified mouse models. It is our expectation that by understanding and unraveling the signaling mechanisms of reversal of the increased vascular permeability, we will be in a position to develop novel strategies directed against components of the AJ complex and its interacting proteins that will prevent vascular leakiness and formation of pulmonary edema.
The cellular and molecular mechanisms responsible for increased permeability of the lung vasculature will be studied utilizing a variety of methodologies including cell imaging, expression of mutant constructs, gene transfer, and evaluation of genetically-modified mouse models. By more fully understanding the signaling mechanisms of reversal of increased vascular permeability, we will be better able to develop novel strategies to prevent vascular leakiness and formation of pulmonary edema.
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