Molecular Toxicology of DNA Adducts

DESCRIPTION (provided by applicant): DESCRIPTION (provided by applicant): The central theme of this interdisciplinary translational research program revolves around the molecular toxicology of a nephrotoxic human carcinogen, aristolochic acid (AA). We will bring an interdisciplinary approach (chemistry, cell physiology and genetics) to bear on the pathogenesis of aristolochic acid nephropathy, combining molecular epidemiology and toxicogenomics to provide insights into genetic factors that contribute to susceptibility or resistance to this widespread disease,. Additionally, AAN serves as a model for currently idiopathic kidney diseases and disorders characterized by fibrogenesis, and this research provides a mechanistic strategic approach to environmental diseases in general. Our long-term goals are to: (a) establish the molecular mechanisms by which aristolochic acids exert their profound nephrotoxic and genotoxic effects in humans and animals; (b) relate the 3-D structures of AA-DNA adducts to the mutagenic potential of these lesions and to establish structure-function relationships involved in their removal by nucleotide excision repair; (c) utilize a mouse model of AAN to study biotransformation of AA and to validate AA-DNA adducts as potential biomarkers of exposure and risk of disease; (d) identify mouse and human genes involved in the cytotoxic response of renal proximal tubules to AA, differentiating this singular effect from the genotoxic effects of AA on urothelial cells; (e) dissect the genetic and cellular events involved in AA-induced renal interstitial fibrosis; (f) use molecular epidemiologic and toxicogenomic approaches to explore the pathogenesis of a similar disease, endemic nephropathy, and its associated urothelial cancer, and to identify genes that control development of this devastating disease. Findings emanating from this research are expected to impact directly on public health. Most obviously, establishing the relationship between dietary exposure to aristolochic acid and an increased risk of nephropathy and urothelial cancer suggests preventive strategies that will mitigate and potentially eliminate this nephropathy from the endemic region. In addition, as fibrogenesis is an irreversible process associated with end-stage renal disease, interstitial lung diseases, hepatic cirrhosis and heart disease, our research has the potential to impact disorders responsible for morbidity and mortality in the US and throughout the world.