Molecular Toxicology of DNA Adducts

State University New York Stony Brook, Stony Brook NY

Investigators

Linked publications & trials

Abstract

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