Increases in lung vascular permeability result in protein-rich tissue edema, an important feature of adult respiratory distress syndrome. The role of the microtubule (MT) cytoskeleton in the mechanism of increased endothelial permeability is not well understood. MTs are known to undergo re-organization in response to pro- inflammatory mediators, and may thus contribute to the mechanism of increased endothelial permeability. The proposed studies will address the central role of End Binding protein-3 (EB3), a MT plus-end binding factor, in regulating increased lung vascular permeability. We will test the hypotheses that (i) EB3 is a major component of cross-talk between Vascular Endothelial (VE)-cadherin adhesion complexes and the MT cytoskeleton and (ii) EB3-mediated control of MT dynamics is critical for maintenance of basal permeability of lung microvessels and for permeability increase caused by inflammatory mediators. These studies will address the following Specific Aims: (1) role of VE-cadherin-mediated signaling in the mechanism of EB3 phosphorylation and inhibition of MT growth and, thereby the role of """"""""outside-in"""""""" signaling in establishing basal permeability of lung endothelia;and (2) critical role of EB3 in regulating Ca2+ signaling, thus in mediating increased endothelial permeability and development of lung edema. It is our expectation that by understanding how VE-cadherin adhesion signals EB3 phosphorylation and how EB3 thereby elicits the barrier permeability increase will provide novel insights into the mechanisms of dysregulation of lung fluid homeostasis. We will exploit state of the art technologies including live cell imaging, expression of mutant constructs, gene transfer, and murine models of lung inflammation to accomplish the specific aims.
The focus of the work is the lung endothelium, in which the planned studies will establish the relevance of EB3, a microtubule-binding protein, to the pathophysiology of ALI/ ARDS. The work leading up to this proposal has allowed us to design a potential therapeutic peptide that by inhibiting EB3 function prevents lung edema and lethality in sepsis.
|Komarova, Yulia; Kruse, Kevin J; Mehta, Dolly et al. (2017) Response by Komarova et al to Letter Regarding Article, ""Protein Interactions at Endothelial Junctions and Signaling Mechanisms Regulating Endothelial Permeability"". Circ Res 120:e28|
|Sun, Mitchell Y; Geyer, Melissa; Komarova, Yulia A (2017) IP3 receptor signaling and endothelial barrier function. Cell Mol Life Sci 74:4189-4207|
|Komarova, Yulia A; Kruse, Kevin; Mehta, Dolly et al. (2017) Protein Interactions at Endothelial Junctions and Signaling Mechanisms Regulating Endothelial Permeability. Circ Res 120:179-206|
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|Geyer, Melissa; Huang, Fei; Sun, Ying et al. (2015) Microtubule-Associated Protein EB3 Regulates IP3 Receptor Clustering and Ca(2+) Signaling in Endothelial Cells. Cell Rep 12:79-89|
|Yamada, Kaori H; Nakajima, Yuki; Geyer, Melissa et al. (2014) KIF13B regulates angiogenesis through Golgi to plasma membrane trafficking of VEGFR2. J Cell Sci 127:4518-30|
|Vandenbroucke St Amant, Emily; Tauseef, Mohammad; Vogel, Stephen M et al. (2012) PKC? activation of p120-catenin serine 879 phospho-switch disassembles VE-cadherin junctions and disrupts vascular integrity. Circ Res 111:739-49|
|Komarova, Yulia A; Huang, Fei; Geyer, Melissa et al. (2012) VE-cadherin signaling induces EB3 phosphorylation to suppress microtubule growth and assemble adherens junctions. Mol Cell 48:914-25|
|Siddiqui, M Rizwan; Komarova, Yulia A; Vogel, Stephen M et al. (2011) Caveolin-1-eNOS signaling promotes p190RhoGAP-A nitration and endothelial permeability. J Cell Biol 193:841-50|
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