MOLECULAR CHARACTERIZATION OF A LUNG SPHINGOMYELINASE

Project: Research project

Description

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.
StatusFinished
Effective start/end date7/1/0111/30/14

Funding

  • National Institutes of Health: $383,020.00
  • National Institutes of Health: $297,000.00
  • National Institutes of Health: $374,550.00
  • National Institutes of Health: $321,000.00
  • National Institutes of Health: $362,364.00
  • National Institutes of Health: $297,000.00
  • National Institutes of Health: $380,429.00
  • National Institutes of Health: $297,000.00

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Sphingomyelin Phosphodiesterase
Ceramides
Lung
Lung Injury
Apoptosis
Oxidants
Lung Diseases
Oxidative Stress
Epithelial Cells
Cell Death
Reactive Oxygen Species
Epithelium
Smoke
Tobacco Products
Peroxynitrous Acid
Airway Management
Proteins
Sphingomyelins
Haplorhini
Second Messenger Systems

ASJC

  • Medicine(all)