Department of Biomedical Sciences
Sponsor: College of Veterinary Medicine - Resident Research Grants Program
Grant Number: N/A
Title: Protection Against Dietary Fat-Induced DNA Damage by the The Fanconi Anemia Pathway
Project Amount: $7,975
Project Period: 8/1/13-7/31/14
DESCRIPTION: Our long-term goal is to identify endogenous sources of DNA damage contributing to disease phenotypes in Fanconi Anemia and to further characterize the mechanistic connection between fatty liver disease, DNA damage, and hepatocellular cancer. We predict that fatty acid metabolism is an endogenous source of damage repaired by the FA pathway. Our central hypothesis is that ROS and lipid peroxidation products are a source of endogenous damage repaired by the FA pathway and Fancd2-null mice will be deficient in repairing HFD induced DNA damage (Fig. 1C). This can be tested by determining if HFD feeding leads to greater oxidative DNA damage and DNA damage response activation in Fancd2-null mice, and by testing if Fancd2-deficient mice accumulate more pathologic changes in response to HFD feeding than WT controls. Significance: The endogenous stresses to which the FA pathway responds is a major unanswered question of fundamental significance to our understanding of genome maintenance and disease pathogenesis in FA patients. NALFD is increasing in prevalence worldwide and is associated with a rise in hepatocellular carcinoma. Understanding the mechanistic connection between fatty liver disease and DNA damage can lead to better clinical management and interventions. Moreover, the FA pathway is evolutionarily conserved and we anticipate that mechanisms of genome protection identified here will have broad relevance in animals. Innovation: To our knowledge, this is the first HFD feeding model to be employed in the investigation of the endogenous sources of damage repaired by the FA pathway and will be the first report to characterize specific effects of HFD feeding in a FA-deficient animal model.