Clinical ResearchSteven Kleeberger, Ph.D.(http://www.niehs.nih.gov/research/atniehs/labs/lrb/enviro-gen/index.cfm)
Principal Investigator Research SummaryOxidative 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. Overall ObjectiveThe 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 ThemeThe 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:
Current projects:
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