Measuring genomic DNA damage and DNA repair capacity in longitudinal population samples - a step towards precision prevention

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Project Summary Advanced technologies for characterizing human populations at the molecular level have set the stage for personalized therapeutic strategies that may also provide an opportunity for personalized prevention. Personalized or ‘Precision Prevention’ would therefore provide an opportunity to identify those at high risk for a given disease, in part based on defined functional defects (such as a defect in genome maintenance), so as to advise for targeted screening and primary prevention interventions early in life to alter disease susceptibility. DNA repair pathways maintain the integrity of the genome and thereby help prevent the onset of cancer, disease and aging phenotypes and play a significant role in the cellular and organismal response to environmental exposures. In the vein of precision prevention, identifying those with functional defects in the maintenance of genome integrity would be a first step as such ‘carriers’ would have an increased risk of exposure-associated pathologies. Many of these cancer- or disease-specific DNA repair defects can be detected using current "omics" technologies such as evaluating changes in mRNA expression, alterations in the DNA coding sequence or modulations in cellular metabolites such as NAD+ metabolites known to regulate mitochondrial function and regulate DNA repair pathways, as we have shown. However, there are many defects that can only be detected from a direct analysis of basal genome integrity and a direct measure of the cellular capacity to repair the genome in response to exogenous genotoxins. In response to RFA-ES-17-006: Expanding Genome Integrity Assays to Population Studies, we propose Aims that will advance our capacity to examine human populations for genome damage and genome repair capacity, illuminating variations between individuals at discrete time-points as well as within individuals across a five-year period. Genome integrity and DNA repair capacity in sentinel PBMCs at basal level and following challenge by environmental genotoxins will be evaluated using a newly developed next-generation high-throughput DNA damage detection platform. The advances of this new platform have now opened the door for the analysis of large-scale population cohorts, providing a huge step forward in human biomonitoring opportunities. These studies will provide the first look at a longitudinal measure of genome integrity in a community-based cohort of mostly African American descent and will advance our capacity to interrogate human populations for genome damage and genome repair capacity.