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Oxidative Stress Mechanisms & Clinical Effects Group

Clinical Research Program

Steven Kleeberger, Ph.D.
Steven Kleeberger, Ph.D.(
Principal Investigator

Research Summary

Oxidative stress has been implicated in a wide variety of pathological processes, including cancer, diabetes mellitus, atherosclerosis, neurological degeneration, and autoimmune disorders. Reactive oxygen species (ROS) have been increasingly implicated in the pathogenesis of many diseases and important biological processes including carcinogenesis, atherosclerosis, aging, neurodegenerative diseases, and inflammatory disorders. Toxic effects of these oxidants, commonly referred to as oxidative stress, can cause cellular damage by oxidizing nucleic acids, proteins, and membrane lipids. The lung, because of its interface with the environment, is a major target organ for injury by exogenous oxidants such as environmental pollutants, cigarette smoke, drugs, chemotherapeutic agents and hyperoxia, as well as by endogenous ROS generated by inflammatory cells. In addition, many pulmonary diseases [e.g. adult respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), bronchopulmonary dysplasia (BPD)] require supplemental oxygen therapy to maintain lung function which further increases the oxidant burden of the lung. It is believed that the damaging effects of oxygen are mediated by superoxide radical, H2O2, and hydroxyl radicals products formed by epithelial cell mitochondria and neutrophil and macrophage NADPH oxidase, but the mechanisms are still not clear. Furthermore, identification of those factors that may influence susceptibility remains an important issue. An understanding of susceptibility factors could lead to better interventive strategies and, potentially, a means to identify and protect individuals at risk for the development of oxidative stress injury.

Discovery Models: Oxygen Exposures (Yeast/C. elegans, Mouse strains, Human cells, Human in vivo/Clinical) heads to Comparative Genomics. Both Comparative Genomics and Existing Model Studies head to Candidate Genes. Candidate Genes leads to two sections: Mechanism-Based Functional Exposure Models (Yeast/C. elegans, Mouse, Human cells) and Disease Model (Gene-environment interaction studies of lung disease, susceptibility/prognosis in O2-exposed neonates). The double arrow indicates that the two sections are interconnected. Mechanism-Based Functional Exposure Models and Disease Model lead to Test in OS-Related Diseases, which will occur in the future. Mechanism-Based Functional Exposure Models also leads to Mechanism-Based Therapeutic Hypotheses, which in turn, leads to Prevention Trial. The latter two indicate long-range future plans.
Schematic representation of the Research Projects and Clinical Research Core within the Program. Also represented are the projected flows of information and materials between the program. A larger view of this image is available.

Overall Objective

The overall objective of the program is to utilize genetic/genomic, molecular/cellular, and population-based experimental approaches to understand the mechanisms through which oxidative stress contributes to the pathogenesis of disease. In the initial phase of the program, we are utilizing hyperoxia in our models, as hyperoxia-induced lung injury is a relevant clinical problem, and is an excellent model for translational investigation. Additional advantages of this model are that exposures are easily standardized, are not complicated by additional gases or particles (i.e. complex mixtures) that could complicate interpretation. It is also an advantage that populations are enrolled at birth and monitored constantly during their stay in intensive care and that all get the same exposure.

Central Theme

The central theme of the program is to understand oxidant stress responses and identify and assess candidate genetic markers for risk of specific disease states as a function of exposures to oxidative stressors, and the strength of interaction between the genotype and the agent. To this end, we also plan to evaluate (in parallel and in the future) the role of candidate oxidant susceptibility genes identified and characterized in our Program in additional diseases (e.g. COPD, atherosclerosis, asthma) in which oxidant stress is suspected or known to be important in etiology. Two additional parallel themes are integrated into the Program. First, understanding of the mechanisms of susceptibility to oxidative stress should lead to validation of biomarkers of exposure and/or susceptibility that identify individuals who may be at risk for adverse response(s) to environmental exposures. Secondly, through better characterization of the definition of risk of genotype/exposure interaction, the program should improve our ability to design preventive interventions.

Major areas of research:

  • Understanding of the mechanisms of susceptibility to oxidative stress
  • Characterizing the definition of risk of genotype/exposure interaction

Current projects:

  • Susceptibility to oxidative stress: SNPs, gene expression, neonatal oxygen risk
  • Positional cloning of oxidant susceptibility genes in mice
  • Role of mitochondrial reactive oxygen species in hyperoxia-induced tissue injury
  • Candidate susceptibility gene function in lung oxidative stress damage
  • Oxidant susceptibility genes and neonatal diseases associated with hyperoxia
  • Human Airway Gene Profiling Core

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Last Reviewed: March 07, 2008