With the goal of developing biomarkers of oxidative stress, we propose to build on results from the previous funding period by defining the chemical spectrum and biological consequences of deoxyribose oxidation in DNA. DNA oxidation is strongly associated with the pathophysiology of human disease, with a major research focus on nucleobase damage. However, emerging evidence points to deoxyribose oxidation as a critical factor in the toxicity of oxidative stress. We will continue to develop analytical methods to quantify deoxyribose oxidation in isolated DNA and cells exposed to oxidants, and to define the cellular responses to this damage.
Aim 1 : Develop analytical methods to quantify deoxyribose oxidation products. We propose to continue developing analytical methods to quantify the ribonolactone abasic site from 1'-oxidation, the erythose abasic site from 2'-oxidation, the 3'-oxo species from 3'-oxidation and the nucleoside-5'-aldehyde from 5'-oxidation. This will provide us with a nearly complete set of candidate biomarkers for the various chemistries of deoxyribose oxidation.
Aim 2 : Comparative analysis of deoxyribose oxidation. In the previous funding period, we initiated comparative studies of deoxyribose oxidation caused by a variety of oxidants to define the determinants of the damage spectrum. We propose to further characterize deoxyribose oxidation caused by ?-radiation, a-particles and FeEDTA, and to include studies of low energy electrons, the most abundant secondary species arising from ionizing radiation.
Aim 3 : Define the chemistry and biology of deoxyribose oxidation in cells. Using methods developed in Aim 1 and benchmarks determined in Aim 2, we will proceed to study the biological implications of deoxyribose oxidation in cells. There are three goals here: (1) define the biologically relevant spectrum of deoxyribose lesions caused by ?-radiation, a-particles and H2O2 in cells and to identify candidate biomarkers for development in coordination with Aim 4;(2) continue our collaboration with Prof. Bruce Demple to characterize the repair of deoxyribose oxidation products;and (3) pursue our observations of cellular responses to deoxyribose oxidation in yeast made in the previous funding period in terms of the kinetics and dose- dependence of the unique responses to double- and single-strand breaks.
Aim 4 : Define the metabolic fate of deoxyribose oxidation products. We propose to move our studies forward by defining the metabolic and biotransformational fate of deoxyribose oxidation products. The goal is to identify the chemical transformations that occur with the lesions and the potential utility of the released species as biomarkers.
The broad goal of the proposed studies is to identify candidate molecules for development as biomarkers or indicators of oxidative stress. DNA oxidation is strongly associated with the causative mechanisms of cancer and aging and the bulk of research in this area is focused on damage to the nucleobase components of DNA. However, emerging evidence points to deoxyribose oxidation as a critical factor in the genetic toxicology of oxidative stress and inflammation. We propose to continue our efforts to develop deoxyribose damage products as biomarkers of endogenous and environmentally-induced oxidative stress and inflammation, with the potential for developing predictive and clinically useful tools.
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