How do immune responses of the intestinal lining contribute to inflammatory bowel diseases (IBD)? The goals of this project are to determine how cells of the intestinal epithelium are “hardwired” to respond to immune stimuli and how stable changes to these responses are related to IBD. It is known that multiple inflammatory factors produced by the immune system are present in the intestinal tissue during IBD flares, and neutralization the inflammatory molecule TNF is among the most successful current treatment strategies. However, TNF neutralization is frequently insufficient to ameliorate disease. Studies from our lab and others have established that other immune signals called interferons can cooperate with TNF to promote epithelial cell damage. Additionally, there is evidence that interferon response may be amplified in diseased epithelial cells. We will use cutting edge genomic approaches and organoid cultures to determine how the inflammatory “wiring” of response genes in epithelial stem cells of IBD patients differ from healthy controls. Additionally, we will compare the amount of damage in response to inflammatory signals and determine the efficacy of novel inhibitors in preventing toxicity. These studies have the potential to reveal new targets that complement existing TNF therapeutics.