Diseases characterized by endothelial (EC) injury are a major cause of surgical morbidity and represent a significant public health problem. They include post-traumatic inflammatory and infectious syndromes, such as systemic inflammatory response syndrome (SIRS), multiple organ dysfunction (MOD) and acute respiratory distress syndrome (ARDS). Preliminary studies suggest that phosphorylation and dissociation of endothelial adherens junctions, combined with endothelial retraction, may represent the final common pathway for mediators that cause EC barrier dysfunction. Less clear are the mechanisms that lead to junctional phosphorylation and dissociation, including the role of oxidants, rho pathways, MAPK and Src kinases. Our objective is to identify the dominant pathways that regulate junctional dissociation and EC retraction. Major experimental problems include understanding the enzymatic source of intracellular oxidants and their role in junctional phosphorylation, and determining the role of the cytoskeleton in EC retraction during regulation of EC barrier function. Our central hypothesis is that EC oxidant production induced by tumor necrosis factor-alpha (TNF) ultimately results in tyrosine phosphorylation of adherens junction proteins and EC retraction; both events together weaken the adherens junction, causing junctional dissociation and intercellular gap formation. The overall objectives are to determine the role of intracellular oxidants, rho and MAPK pathways on junctional phosphorylation and endothelial dysfunction. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM067674-01A1
Application #
6770865
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Somers, Scott D
Project Start
2004-05-01
Project End
2009-04-30
Budget Start
2004-05-01
Budget End
2005-04-30
Support Year
1
Fiscal Year
2004
Total Cost
$234,000
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Surgery
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Pozo, Karine; Hillmann, Antje; Augustyn, Alexander et al. (2015) Differential expression of cell cycle regulators in CDK5-dependent medullary thyroid carcinoma tumorigenesis. Oncotarget 6:12080-93
Pozo, Karine; Castro-Rivera, Emely; Tan, Chunfeng et al. (2013) The role of Cdk5 in neuroendocrine thyroid cancer. Cancer Cell 24:499-511
Wang, Youxue; Zang, Qun S; Liu, Zijuan et al. (2011) Regulation of VEGF-induced endothelial cell migration by mitochondrial reactive oxygen species. Am J Physiol Cell Physiol 301:C695-704
Mitchell, Ian C; Brown, Timothy S; Terada, Lance S et al. (2010) Effect of vascular cadherin knockdown on zebrafish vasculature during development. PLoS One 5:e8807
Nahari, Dorit; Satchi-Fainaro, Ronit; Chen, Ming et al. (2007) Tumor cytotoxicity and endothelial Rac inhibition induced by TNP-470 in anaplastic thyroid cancer. Mol Cancer Ther 6:1329-37
Wu, Ru Feng; Xu, You Cheng; Ma, Zhenyi et al. (2005) Subcellular targeting of oxidants during endothelial cell migration. J Cell Biol 171:893-904
Nwariaku, Fiemu E; Liu, Zijuan; Zhu, Xudong et al. (2004) NADPH oxidase mediates vascular endothelial cadherin phosphorylation and endothelial dysfunction. Blood 104:3214-20