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 Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Program Projects (P01)
Project #
5P01HL101902-03
Application #
8508287
Study Section
Heart, Lung, and Blood Initial Review Group (HLBP)
Program Officer
Eu, Jerry Pc
Project Start
2011-07-10
Project End
2016-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
3
Fiscal Year
2013
Total Cost
$2,163,419
Indirect Cost
$721,140
Name
Georgia Regents University
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
Barabutis, Nektarios; Dimitropoulou, Christiana; Gregory, Betsy et al. (2018) Wild-type p53 enhances endothelial barrier function by mediating RAC1 signalling and RhoA inhibition. J Cell Mol Med 22:1792-1804
Kovacs-Kasa, Anita; Kim, Kyung Mi; Cherian-Shaw, Mary et al. (2018) Extracellular adenosine-induced Rac1 activation in pulmonary endothelium: Molecular mechanisms and barrier-protective role. J Cell Physiol 233:5736-5746
Gross, Christine M; Kellner, Manuela; Wang, Ting et al. (2018) LPS-induced Acute Lung Injury Involves NF-?B-mediated Downregulation of SOX18. Am J Respir Cell Mol Biol 58:614-624
Chepurnova, D A; Samoilova, E V; Anisimov, A A et al. (2018) Compounds of IL-6 Receptor Complex during Acute Lung Injury. Bull Exp Biol Med 164:609-611
Yang, Guang; Pillich, Helena; White, Richard et al. (2018) Listeriolysin O Causes ENaC Dysfunction in Human Airway Epithelial Cells. Toxins (Basel) 10:
Barman, Scott A; Chen, Feng; Li, Xueyi et al. (2018) Galectin-3 Promotes Vascular Remodeling and Contributes to Pulmonary Hypertension. Am J Respir Crit Care Med 197:1488-1492
Wang, Ting; Gross, Christine; Desai, Ankit A et al. (2017) Endothelial cell signaling and ventilator-induced lung injury: molecular mechanisms, genomic analyses, and therapeutic targets. Am J Physiol Lung Cell Mol Physiol 312:L452-L476
Barabutis, Nektarios; Khangoora, Vikramjit; Marik, Paul E et al. (2017) Hydrocortisone and Ascorbic Acid Synergistically Prevent and Repair Lipopolysaccharide-Induced Pulmonary Endothelial Barrier Dysfunction. Chest 152:954-962
Dou, Huijuan; Feher, Attila; Davila, Alec C et al. (2017) Role of Adipose Tissue Endothelial ADAM17 in Age-Related Coronary Microvascular Dysfunction. Arterioscler Thromb Vasc Biol 37:1180-1193
Song, Shanshan; Ayon, Ramon J; Yamamura, Aya et al. (2017) Capsaicin-induced Ca2+ signaling is enhanced via upregulated TRPV1 channels in pulmonary artery smooth muscle cells from patients with idiopathic PAH. Am J Physiol Lung Cell Mol Physiol 312:L309-L325

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