Molecular and Cellular Characterization of Sphingomyelinase, a Regulator of Ceramide Path and Apoptosis in the Lung Reactive oxidants, such as hydrogen peroxide (H2)2) and peroxynitrite (ONOO-), are strongly associated with lung epithelium injury and with the increased incidence of lung disease. Yet, the cellular and molecular mechanisms that link exposure of lung cells to oxidants with the development of lung disease are poorly understood. Our previous work has shown that oxidants modulate the function of upstream receptors and therefore exert growth control on airway epithelial cells. Recently, we have shown that H2O2- mediated oxidative stress modulates ceramide, a second messenger in cellular processes, to induce apoptosis in the bronchial epithelium. These results support our hypothesis that there is coupling between oxidative stress, the ceramide/sphingomyelin pathway, and induction of apoptosis in airway epithelial cells. To test this hypothesis, we will first characterize the effects of oxidative stress on the ceramide pathway at the cellular level. We will elucidate the cellular sites of interaction and determine which sphingomyelinase (SMase) isozyme is regulated by reactive oxidants to induce apoptosis. Then, we will purify and cloe the specific SMase which acts as the coupler between oxidative stress and ceramide-mediated apoptosis. This will allow our studies to progress from cellular to molecular characterization of the mechanism(s) underlying the regulation of ceramide generation and apoptosis. Characterization of oxidant-mediated ceramide generation at the cellular level, followed by isolation of the pure SMase protein and gene are important milestones that would link this pathway to lung injury at the cellular and molecular levels. In the long run, this direction will lead to more precise targets for clinical intervention to control apoptosis in lung epithelial cells, thus preventing epithelial injury, a major problem in lung disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL066189-02
Application #
6537925
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Harabin, Andrea L
Project Start
2001-07-01
Project End
2005-05-31
Budget Start
2002-06-01
Budget End
2003-05-31
Support Year
2
Fiscal Year
2002
Total Cost
$297,000
Indirect Cost
Name
University of California Davis
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
Davis
State
CA
Country
United States
Zip Code
95618
Bratt, Jennifer M; Chang, Kevin Y; Rabowsky, Michelle et al. (2018) Farnesyltransferase Inhibition Exacerbates Eosinophilic Inflammation and Airway Hyperreactivity in Mice with Experimental Asthma: The Complex Roles of Ras GTPase and Farnesylpyrophosphate in Type 2 Allergic Inflammation. J Immunol 200:3840-3856
Chung, Samuel; Vu, Simon; Filosto, Simone et al. (2015) Src regulates cigarette smoke-induced ceramide generation via neutral sphingomyelinase 2 in the airway epithelium. Am J Respir Cell Mol Biol 52:738-48
Goldkorn, Tzipora; Filosto, Simone; Chung, Samuel (2014) Lung injury and lung cancer caused by cigarette smoke-induced oxidative stress: Molecular mechanisms and therapeutic opportunities involving the ceramide-generating machinery and epidermal growth factor receptor. Antioxid Redox Signal 21:2149-74
Goldkorn, Tzipora; Chung, Samuel; Filosto, Simone (2013) Lung cancer and lung injury: the dual role of ceramide. Handb Exp Pharmacol :93-113
Filosto, Simone; Baston, David S; Chung, Samuel et al. (2013) Src mediates cigarette smoke-induced resistance to tyrosine kinase inhibitors in NSCLC cells. Mol Cancer Ther 12:1579-90
Filosto, Simone; Becker, Cathleen R; Goldkorn, Tzipora (2012) Cigarette smoke induces aberrant EGF receptor activation that mediates lung cancer development and resistance to tyrosine kinase inhibitors. Mol Cancer Ther 11:795-804
Filosto, Simone; Ashfaq, Majid; Chung, Samuel et al. (2012) Neutral sphingomyelinase 2 activity and protein stability are modulated by phosphorylation of five conserved serines. J Biol Chem 287:514-22
Filosto, Simone; Khan, Elaine M; Tognon, Emiliana et al. (2011) EGF receptor exposed to oxidative stress acquires abnormal phosphorylation and aberrant activated conformation that impairs canonical dimerization. PLoS One 6:e23240
Filosto, Simone; Castillo, Sianna; Danielson, Aaron et al. (2011) Neutral sphingomyelinase 2: a novel target in cigarette smoke-induced apoptosis and lung injury. Am J Respir Cell Mol Biol 44:350-60
Zeki, Amir A; Kenyon, Nicholas J; Goldkorn, Tzipora (2011) Statin drugs, metabolic pathways, and asthma: a therapeutic opportunity needing further research. Drug Metab Lett 5:40-4

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