This Program project is focused on the role of vascular endothelial cell (EC) permeability as a key component in acute lung injury (ALI). The overall goals of this Program Project Grant are to develop a better understanding of the mechanisms underlying disturbances in EC RhoA/Rac 1 balance and in developing therapeutic agents that restore barrier integrity during the development of ALI. The Program Project is led by a team of highly productive experts and comprised of four inter-related projects and 3 cores. Project 1 will focus on the role of protein nitration as a newly described mechanism to regulate RhoA and Rac 1 signaling during the development of EC barrier disruption and ALI. Molecular, cellular, biochemical, and whole animal studies are proposed to further elucidate the mechanisms by which nitration alters RhoA and Rac 1 nucleotide cycling while developing novel reagents to restore the RhoA/Rac 1 balance during ALI. Project 2 is thematically linked to Project 1 by focusing on the role of Hsp90 in regulating RhoA activation and downstream RhoA signaling and will compare and contrast the therapeutic possibilities of broad-based Hsp90 inhibitors with decoy peptides that target specific protein interactions. Project 3 continues the focus on RhoA/Rac 1 balance and will focus on the therapeutic effects of adenosine-induced Rac 1 activation and will elucidate new downstream effectors of Rac 1 and determine the therapeutic potential of modulating their expression both in vitro and in vivo. Projects 1-3 will focus predominantly on the G- toxin, LPS and Project 4 will round out our studies to investigate the barrier disruptive effects of the G-i- pore forming toxins, pneumolysin and Lysteriolysin. Studies in Project 4 will elucidate mechanisms of RhoA/Rac 1 imbalance and focus on the therapeutic potential of enhanced NO signaling in restoring this balance during G-imediated ALI. Two scientific cores (Human Cell &Animal and Analytical) and an Administrative Core provide multi-project support, expertise and service in a cost-effective manner leading to significant strengthening of the entire scientific Program. It is anticipated that the highly integrated Projects using stateof- the-art cellular, molecular, biochemical, and physiological approaches that will not only increase our understanding of the mechanisms by which RhoA and Rac 1 are regulated during both gram negative- and gram positive-induced ALI but will facilitate the development of new strategies and targets for the treatment of a disease that has not seen a significant drop in mortality in 40 years.
PUBLIC RELEVANCE: The overall goal of this Program Project is to develop a better understanding of the mechanisms linking loss of RhoA/Rac 1 balance in the endothelial hyper-permeability associated with acute lung injury (ALI). Emphasis is placed on understanding both novel mechanisms underlying EC barrier disruption and on developing novel reagents to restore EC barrier function during ALI.
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|Aggarwal, Saurabh; Gross, Christine M; Rafikov, Ruslan et al. (2014) Nitration of tyrosine 247 inhibits protein kinase G-1? activity by attenuating cyclic guanosine monophosphate binding. J Biol Chem 289:7948-61|
|Gonzales, Joyce N; Gorshkov, Boris; Varn, Matthew N et al. (2014) Protective effect of adenosine receptors against lipopolysaccharide-induced acute lung injury. Am J Physiol Lung Cell Mol Physiol 306:L497-507|
|Xu, Yiming; An, Xiaofei; Guo, Xin et al. (2014) Endothelial PFKFB3 plays a critical role in angiogenesis. Arterioscler Thromb Vasc Biol 34:1231-9|
|Gross, Christine M; Aggarwal, Saurabh; Kumar, Sanjiv et al. (2014) Sox18 preserves the pulmonary endothelial barrier under conditions of increased shear stress. J Cell Physiol 229:1802-16|
|Chen, Feng; Yu, Yanfang; Haigh, Steven et al. (2014) Regulation of NADPH oxidase 5 by protein kinase C isoforms. PLoS One 9:e88405|
|Czikora, István; Alli, Abdel; Bao, Hui-Fang et al. (2014) A novel tumor necrosis factor-mediated mechanism of direct epithelial sodium channel activation. Am J Respir Crit Care Med 190:522-32|
|Chen, Feng; Kumar, Sanjiv; Yu, Yanfang et al. (2014) PKC-dependent phosphorylation of eNOS at T495 regulates eNOS coupling and endothelial barrier function in response to G+ -toxins. PLoS One 9:e99823|
|Gonzales, Joyce N; Kim, Kyung-mi; Zemskova, Marina A et al. (2014) Low anticoagulant heparin blocks thrombin-induced endothelial permeability in a PAR-dependent manner. Vascul Pharmacol 62:63-71|
|Rafikov, Ruslan; Dimitropoulou, Christiana; Aggarwal, Saurabh et al. (2014) Lipopolysaccharide-induced lung injury involves the nitration-mediated activation of RhoA. J Biol Chem 289:4710-22|
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