Factors in chronic intestinal inflammation and cancer

Chronic inflammatory conditions are often linked to an elevated risk for developing cancer. The mechanisms underlying such disorders are genetic predisposition as well as infection with persistent pathogens. Excessive and unresolved stimulation of various types of innate immune cells induced by pathogens is assumed to lead to disturbed tissue homeostasis and neoplasia. A growing number of human cancers are now known to be associated with a microbial etiology including gastric cancer caused by Helicobacter pylori. Inflammatory bowel diseases (IBD), chronic diseases of the gastrointestinal tract comprising ulcerative colitis and Crohns disease (CD), are thought to arise from a dysregulated immune response to the intestinal microflora. Interestingly, mutations in NOD2/CARD15, a gene involved in a microbial pattern recognition pathway, were recently revealed to be associated with increased susceptibility for CD. Moreover, patients with IBD have a high risk to develop colon cancer. The goal of this project is to determine genetic susceptibility factors as well as inflammatory factors involved in gastrointestinal inflammation and cancer development. We will use a novel innate inflammatory mouse model where Helicobacter hepaticus, a pathogen closely related to H. pylori, induces chronic intestinal inflammation and colon cancer in susceptible mouse strains. Susceptibility factors are currently determined by crossing and mapping of susceptible and resistant mouse strains in a parallel project in Prof. Powrie s lab. We plan to analyze identified genes for their role in inflammation and tumorigenesis. Furthermore, we would like to investigate the innate immune activation status and the expression of a number of pro- and anti-inflammatory and tumorigenic factors upon H. hepaticus infection in these strains. A better understanding of the genetic and molecular factors contributing to the susceptibility for H. hepaticus induced chronic intestinal inflammation and cancer may lead to improved treatments for human chronic inflammatory diseases and their associated cancers.