Electronic Thesis and Dissertation Repository


Master of Science


Physiology and Pharmacology


Dr. Christopher Pin


Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with a five-year survival rate of 8%. Oncogenic KRAS mutation is found in greater than 95% of PDAC cases, but additional mutations or injury are required for disease initiation and progression. Chromatin remodeling protein ATRX has been previously implicated in DNA repair, replication and maintaining genomic stability. I hypothesized that loss of ATRX could increase the susceptibility of pancreatic tissue to pancreatic injury or KRAS-mediated damage. In this study, combination of inducible ATRX loss in adult mice with recurrent pancreatic injury or oncogenic KRAS activation resulted in increased pancreatic damage, including fibrosis, inflammation and acinar-to-ductal metaplasia. Interestingly, this effect was gender-specific, causing pancreatic damage exclusively in female mice with ATRX loss/KRAS activation. This study defines a novel role for ATRX within the exocrine pancreas, and provides insight into the epigenetic factors that can influence susceptibility to pancreatic disease.