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Viswanathan Natarajan, PhD
My laboratory is investigating the role of reactive oxygen species (ROS) and bioactive lipids such as sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA) and their G-protein coupled receptors in vascular endothelial signaling using animal models and cells in culture. ROS have been implicated in the pathophysiology of several respiratory diseases including ARDS, COPD, pulmonary hypertension and bronchopulmonary dysplasia and our current primary focus is on the role and regulation of NADPH oxidase and other NOX proteins in hyperoxia- and sepsis-induced lung injury. We were the first to demonstrate that sphingosine-1-phosphate (S1P) is an agonist in endothelial cell signal transduction and S1P is the most potent angiogenic naturally occurring bioactive lipid that is present in plasma and tissues. My laboratory has been studying mechanisms of generation of intracellular S1P mediated by sphingosine kinases (SphKs) and degradation catalyzed by lipid phosphate phosphatases and S1P lyase in the endothelium and S1P lyase as a novel target of sepsis-mediated lung injury. In contrast to sepsis-induced lung injury, deletion of SphK1, but not SphK2, confered protection against pulmonary fibrosis, bronchopulmonary dysplasia and pulmonary hypertension in murine models. Thus, our investigations suggest a differential role for S1P in various pulmonary diseases. We are also investigating the role of HATS and HDACs and potential regulation of HATs/HDACs by sphingosine kinases and S1P lyase. These studies involve basic and translational research with the interest of developing novel therapeutic strategies to limit the adverse effects of inflammatory lung injury.
Harijith A, Pendyala S, Reddy NM, Bai T, Usatyuk PV, Berdyshev E, Gorshkova I, Huang LS, Mohan V, Garzon S, Kanteti P, Reddy SP, Raj JU, Natarajan V. Sphingosine kinase 1 deficiency confers protection against hyperoxia-induced bronchopulmonary dysplasia in a murine model: role of S1P signaling and Nox proteins. Am J Pathol. 183:1169-82, 2013.
Usatyuk PV, Singleton PA, Pendyala S, Kalari SK, He D, Gorshkova IA, Camp SM, Moitra J, Dudek SM, Garcia JG, Natarajan V. Novel role for non-muscle myosin light chain kinase (MLCK) in hyperoxia-induced recruitment of cytoskeletal proteins, NADPH oxidase activation, and reactive oxygen species generation in lung endothelium. J Biol Chem. 287:9360-75, 2012.
Usatyuk PV, Gorshkova IA, He D, Zhao Y, Kalari SK, Garcia JG, Natarajan V. Phospholipase D-mediated activation of IQGAP1 through Rac1 regulates hyperoxia-induced p47phox translocation and reactive oxygen species generation in lung endothelial cells. Biol Chem. 284:15339-52, 2009.
Singleton PA, Pendyala S, Gorshkova IA, Mambetsariev N, Moitra J, Garcia JG, Natarajan V. Dynamin 2 and c-Abl are novel regulators of hyperoxia-mediated NADPH oxidase activation and reactive oxygen species production in caveolin-enriched microdomains of the endothelium. J Biol Chem. 284:34964-75, 2009.
Chowdhury AK, Watkins T, Parinandi NL, Saatian B, Kleinberg ME, Usatyuk PV, Natarajan V. Src-mediated tyrosine phosphorylation of p47phox in hyperoxia-induced activation of NADPH oxidase and generation of reactive oxygen species in lung endothelial cells. J Biol Chem. 280:20700-11, 2005.
Usatyuk PV, Natarajan V. Role of mitogen-activated protein kinases in 4-hydroxy-2-nonenal-induced actin remodeling and barrier function in endothelial cells. J Biol Chem. 279:11789-97, 2004.
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