Project 175653

Changes in the inherent leakiness of the wall of the intestine (i.e., in the intestinal permeability) are thought to play a significant role in the development of inflammatory bowel diseases such as Crohn¿s disease and ulcerative colitis. Intestinal permeability is affected by a number of factors. Research using a new technology¿confocal endomicroscopy or CEM¿suggests that the rate at which cells are lost naturally from the interior surface of the intestine (the epithelium) is increased in inflammatory bowel disease. However, whether this abnormal shedding of epithelial cells causes abnormal permeability of the intestine remains unknown. The goal of our proposal is to determine how epithelial cell shedding affects intestinal permeability under both normal and disease conditions. Our first aim is to find a way to use CEM to accurately measure the rate of epithelial cell shedding in healthy rodents. The rate of cell shedding in healthy mice will be controlled using TNF-alpha, a protein that is naturally present in the body. With these calibration data from healthy animals, we will be able to develop a model that can determine various cellular features (including cell shedding) and intestinal permeability under healthy conditions. Our second aim is to determine the contributions of cellular shedding when intestinal permeability is increased to the levels found in disease states. The permeability will be altered in mice by changing either environmental or genetic factors (i.e., administering aspirin or using a genetically defective strain of mice, respectively). The contribution of cellular shedding to permeability of the small bowel in the disease states and in the healthy states will be determined. These studies will use new technology to provide crucial new insights into the basic mechanisms of changes in intestinal permeability, and how certain genetic predispositions can lead to inflammatory bowel disease.