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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK110352-03
Application #
9690707
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Perrin, Peter J
Project Start
2017-05-01
Project End
2021-04-30
Budget Start
2019-05-01
Budget End
2020-04-30
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Meisel, Marlies; Hinterleitner, Reinhard; Pacis, Alain et al. (2018) Microbial signals drive pre-leukaemic myeloproliferation in a Tet2-deficient host. Nature 557:580-584
Chen, Lili; He, Zhengxiang; Iuga, Alina Cornelia et al. (2018) Diet Modifies Colonic Microbiota and CD4+ T-Cell Repertoire to Induce Flares of Colitis in Mice With Myeloid-Cell Expression of Interleukin 23. Gastroenterology 155:1177-1191.e16
A Verghese, Divya; Demir, Markus; Chun, Nicholas et al. (2018) T Cell Expression of C5a Receptor 2 Augments Murine Regulatory T Cell (TREG) Generation and TREG-Dependent Cardiac Allograft Survival. J Immunol 200:2186-2198
He, Zhengxiang; Chen, Lili; Souto, Fabricio O et al. (2017) Epithelial-derived IL-33 promotes intestinal tumorigenesis in Apc Min/+ mice. Sci Rep 7:5520
Bardina, Susana V; Brown, Julia A; Michlmayr, Daniela et al. (2017) Chemokine Receptor Ccr7 Restricts Fatal West Nile Virus Encephalitis. J Virol 91:
Barsheshet, Yiftah; Wildbaum, Gizi; Levy, Eran et al. (2017) CCR8+FOXp3+ Treg cells as master drivers of immune regulation. Proc Natl Acad Sci U S A 114:6086-6091