Forward Genetic Analysis of Intestinal Homeostasis

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Abstract Inflammatory bowel disease is a debilitating chronic condition, which can affect any part of the intestine, often having by a relapsing and remitting course. In the United States, there are approximately 1.4 million people are affected by ulcerative colitis or Crohn's disease. The resulting inflammation in the colon and small intestine can lead to pain, infections and bleeding, which ultimately leads to a healthcare burden of increased hospitalizations, emergency surgeries and most importantly increased mortality. Although a hyper- inflammatory response to the intestinal micro flora certainly plays a role in the etiology of IBD, the exact etiology of inflammatory bowel disease, however, is not well understood and is most certainly multifactorial in nature. The maintenance of the mucosal immune system has many levels as has been seen in human genetics and experimental mouse models. These systems include immune and growth factor as well as epithelial proliferation, apoptosis, autophagy and cellular metabolism. Perturbation of any of these systems results in a defect of intestinal homeostasis and ultimately resulting in pathology. My recent studies have looked at the genetic factors necessary for maintaining intestinal homeostasis. Using a screen of randomly mutagenized mice, I have identified and mapped candidate genes for over 30 novel mouse strains that show either susceptibility or resistance to mouse experimental colitis. One such unexpected pathway involves the de novo synthesis of ceramide and phytoceramide. I plan to use genetically modified mice in which a key ceramide metabolic gene (Degs2) is deleted or mutated to elucidate a mechanistic understanding of these pathways and their regulation. The ultimate goal of my research is to determine new pathways, which can be targeted to better treat intestinal diseases, such as Crohn's and ulcerative colitis.