Crohn's disease (CD) and ulcerative colitis (UC) are two distinct phenotypic patterns of inflammatory bowel disease (IBD) affecting ~1.5 million Americans, with >30,000 new cases diagnosed annually. They are both characterized by periods of asymptomatic remission interrupted by episodes of symptomatic disease flares or exacerbations. While its exact cause is unknown, IBD seems to be due to a combination of environmental factors and genetic predisposition. However, to date, it is unclear how faulty genes and the changed environment interact to cause colitis and to promote development of cycles of flares and remissions. To contribute to a better understanding of these processes we created a novel animal model (R23FR mice), in which a gene associated with colitis, IL-23 is conditionally expressed in the intestine of immune-competent mice. IL-23 expression triggers development of a colitis that is dependent on the microbiota and the diet, and that has a striking resemblance to human disease, with cycles of active disease (relapse/flares) followed by remission. The main objective of this application is to investigate how IL-23 and the microbiota interact to promote colitis and the development of cycles of flares and remission. Knowledge obtained from these studies is likely to open new directions for therapy.
In Aim 1 we will define the mechanisms triggered by IL-23 that contribute to colitis;
in Aim 2 we will define how the microbiota affects the development of colitis in R23FR mice; and in Aim 3 we will define how lymphocytes contribute to flares and remission

Public Health Relevance

Studies suggest that IBD results from faulty genes and altered gut microbiota, but there is little information on how these two processes interact to cause disease. We have created animals that mis-express a gene that has been associated with IBD (IL-23). These animals develop a disease that has striking similarities with human IBD. We will test if IL-23-induced colitis is worsened by the gut microflora (microbiota), how the body heals the disease and which factors contribute to its worsening. Our studies will likely provide new insights into how IBD happens in humans and should help identify new means for its treatment.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Perrin, Peter J
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Icahn School of Medicine at Mount Sinai
Internal Medicine/Medicine
Schools of Medicine
New York
United States
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