Grant: Project Grant

Our gastrointestinal tract establishes a physical barrier that allows essential nutrients to enter circulation, and keeps harmful microbes at bay. This barrier is maintained throughout our lives by a population of stem cells that grow and replace dead or dying cells at the gut surface. If stem cells fail to divide at an adequate rate, gut barriers break down, and noxious molecules breach the animal interior. In contrast, excess stem cell growth often disturbs gut architecture. In many cases, prolonged overgrowth of stem cells enables the development of intestinal tumors. For example, in inflammatory bowel disease, persistent activation of immune responses to gut bacteria drives excess growth of stem cells. The subsequent disruptions to intestinal function negatively impact quality of life, and elevate the risk of colorectal cancer in patients by approximately twenty-fold. Researchers in my group generated a transgenic fly that allows us to experimentally mimic the immune-dependent growth of stem cells. We showed that persistent immune responses to gut bacteria caused a rapid expansion of stem cells and a harmful loss of gut organization. In follow-up work, we identified the bacteria responsible for immune-dependent overgrowth of stem cells. We showed that immune responses to the bacterial cell wall interrupts conventional growth programs, and fuels the disorganized expansion of stem cells. In this project, we will determine the exact effects of immune activity on gut stem cell growth and determine how bacteria modify these responses. Flies are excellent models for this work, as the biological blueprint for gut formation and function was established very early in animal evolution. Thus, work in flies provides important insights into critical aspects of human gut biology.