Grant: Operating Grant

The cells lining our intestinal tract are continuously renewed throughout our lifetime. As aging cells are sloughed off, they are replaced by newly-produced cells. The newly-produced cells must undergo a maturation process so that they can develop the ability to perform specific functions that are important for intestinal health, such as absorption of water and nutrients or secretion of mucus. This process must be tightly regulated in order to respond appropriately to insult or injury. However, inappropriate activation of this process can promote the development of intestinal cancer. Our lab's studies on the response of the intestine to infection, using a well-characterized and widely recognized mouse model, uncovered a role for a protein called R-spondin 2 as a key regulator of intestinal cell turnover during intestinal infection. R-spondin 2 is turned on following infection, leading to an overproduction of new intestinal cells that do not mature properly. The end result of this is a loss of intestinal function and high levels of mortality. Conversely, mouse strains that do not turn on R-spondin 2 following infection undergo milder, self-limiting disease with no mortality. Our finding has important implications for intestinal response to infection, and may be important in other inflammatory diseases of the intestine and in the development of intestinal cancer. In the current proposal, we are directing our efforts to understand how and why and under what circumstances R-spondin 2 is induced in the intestine of mice and humans, as well as to define how this regulation impacts intestinal health and disease.