APPLICATION OF FUNCTIONAL GENOMICS FOR IDENTIFYING MODIFIERS OF SUSCEPTIBILITY -
DESCRIPTION (provided by applicant): Protecting individuals from the adverse effects of occupational exposures requires addressing the variability in human response and identifying workers with increased susceptibility. Genetics, environmental, and lifestyle factors all contribute to the variability in the human response. The primary objective of this project is to develop an innovative approach to identify potential modifiers of susceptibility to occupational exposures. We hypothesize that variability in gene expression due to age, gender, nutritional state, chronic diseases, and lifestyle factors underlie some of the differences in worker susceptibility to adverse respiratory tract effects from occupational exposures. Large-scale gain-of-function and loss-of-function genomic screens can be used to model the inherent diversity in gene expression within a population and identify those genes whose increase or decrease in expression may modify the susceptibility to adverse effects from occupational exposures. To evaluate this hypothesis, we will use vanadium pentoxide (V2O5) treatment of human bronchial epithelial cells as a model for occupational bronchitis and IL-8 production as a surrogate for inflammation. In the first specific aim of this proposal, we will identify positive modifiers of susceptibility to vanadium-induced airway inflammation using large scale gain-of-function and loss-of-function genomic screens. The genomic screens will identify which genes, with altered expression, increase IL-8 production in the presence of a sub-inflammatory V2O5 exposure. In the second specific aim, we will identify negative modifiers of susceptibility to vanadium-induced airway inflammation using large scale gain-of-function and loss-of-function genetic screens. The genomic screens will identify which genes, with altered expression, decrease IL-8 production in the presence of an inflammatory V2O5 exposure. In the final specific aim, we will confirm the results of the primary screens and evaluate the activity of the positive and negative modifiers using other vanadium-responsive biomarkers. Through these specific aims, we will assemble a complete picture of the gene expression changes that affect vanadium-induced bronchitis and provide a means to address potential nutritional and lifestyle factors that may make workers more or less susceptible to the respiratory effects. On a larger scale, the development of this approach will be significant for the environmental health community as a whole by providing a generalizable method that can identify gene expression changes underlying susceptibility to numerous occupational and environmental hazards. PROJECT NARRATIVE: Protecting individuals from the adverse effects of occupational exposures requires understanding variability within the population and identifying workers with increased susceptibility. An individual's DNA, diet, chronic diseases (e.g., diabetes), and lifestyle factors all contribute to the variability between individual workers. In this research project, we will develop an approach to mimic differences in the amount of a gene that an individual worker expresses and whether those differences make the worker more or less susceptible to the adverse effects from occupational exposures.
