Chronic inflammation and metaplasia are precursors to gastrointestinal diseases, including gastric cancer. Although the increased risk of gastric cancer in individuals with chronic inflammation in the stomach has been known for many years, there is still a fundamental gap in our knowledge of the molecular and cellular processes by which inflammation influences the progression from chronic atrophic gastritis to gastric cancer. A more mechanistic understanding of these processes is likely to improve strategies to identify those at risk of gastric cancer, to diagnoses individuals at an earlier stage of disease, and/or to develop new immune-based treatments. Cytokines play a critical role in carcinogenesis by acting on immune cells to regulate severity of inflammation and the release of DNA-damaging chemicals, and by acting on epithelial cells and regulating proliferation and differentiation. This is especially relevant to gastritis and gastric cancer because >90% of all gastric cancers are adenocarcinomas, which are derived from epithelial cells, and most develop in a setting of chronic inflammation (e.g. Helicobacter infection). We recently discovered, using a mouse model of inflammation- induced gastric cancer, that expression of the Ebi3 gene is critical for slowing the progression of gastric carcinogenesis. The EBI3 protein is a component of two cytokines, IL-27 and IL-35. The goal of this proposal is to identify how EBI3 (IL-27/IL-35) regulates the progression of gastric carcinogenesis. Our central hypothesis, based on strong preliminary data, is that IL-27 and/or IL-35 slow the progression of gastritis and gastric cancer by two novel mechanisms: 1) by regulating cytokine production by CD4+ T cells, and 2) regulating epithelial cell injury and repair mechanisms.
The specific aims of this proposal are to: 1) Determine whether IL-27 regulates gastritis severity by inhibiting Th17 and Th22 cells; 2) Test the direct effects of EBI3 on gastric epithelial cells homeostasis and/or metaplasia-repair; and 3) Determine whether EBI3 expressed by immune cells, epithelial cells, or both types regulate inflammation and epithelial changes during gastric cancer progression. Studies will be performed in tissue from mice and in human biopsies, and in mouse and human gastroids. The proposed research is innovative because it identifies a novel functions for EBI3 in regulating the biology of immune cells and epithelial cells in the gastric mucosa and uses innovative approaches. The proposed research is significant because it is expected to expand our mechanistic understanding of the cellular and molecular processes that regulate both inflammation and metaplasia in the gastric mucosa.

Public Health Relevance

. The proposed research addresses a novel role for Ebi3 gene (Epstein Bar Virus Induced gene 3) and EBI3 containing cytokines (IL-27 and IL-35) in regulating the severity of inflammation and metaplasia in the gastric mucosa. This research is relevant to public health because it is expected to provide novel insights into the mechanism of cytokine-regulated inflammation and metaplasia in the gastric mucosa. Ultimately, this knowledge could be used to improve the ability to diagnose and treat chronic inflammatory diseases in the stomach and throughout the GI tract.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK110406-02
Application #
9316596
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Perrin, Peter J
Project Start
2016-08-01
Project End
2021-07-31
Budget Start
2017-08-01
Budget End
2018-07-31
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Saint Louis University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
050220722
City
Saint Louis
State
MO
Country
United States
Zip Code
63103
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Willet, Spencer G; Lewis, Mark A; Miao, Zhi-Feng et al. (2018) Regenerative proliferation of differentiated cells by mTORC1-dependent paligenosis. EMBO J 37:
Jin, Ramon U; Mills, Jason C (2018) Are Gastric and Esophageal Metaplasia Relatives? The Case for Barrett's Stemming from SPEM. Dig Dis Sci 63:2028-2041
Radyk, Megan D; Burclaff, Joseph; Willet, Spencer G et al. (2018) Metaplastic Cells in the Stomach Arise, Independently of Stem Cells, via Dedifferentiation or Transdifferentiation of Chief Cells. Gastroenterology 154:839-843.e2
Osaki, Luciana H; Bockerstett, Kevin A; Wong, Chun Fung et al. (2018) Interferon-? directly induces gastric epithelial cell death and is required for progression to metaplasia. J Pathol :
Bockerstett, Kevin A; Osaki, Luciana H; Petersen, Christine P et al. (2018) Interleukin-17A Promotes Parietal Cell Atrophy by Inducing Apoptosis. Cell Mol Gastroenterol Hepatol 5:678-690.e1
Burclaff, Joseph; Mills, Jason C (2018) Plasticity of differentiated cells in wound repair and tumorigenesis, part II: skin and intestine. Dis Model Mech 11:
Bockerstett, Kevin A; Wong, Chun Fung; Koehm, Sherri et al. (2018) Molecular Characterization of Gastric Epithelial Cells Using Flow Cytometry. Int J Mol Sci 19:
Mills, Jason C; Samuelson, Linda C (2018) Past Questions and Current Understanding About Gastric Cancer. Gastroenterology 155:939-944
Sáenz, José B; Mills, Jason C (2018) Acid and the basis for cellular plasticity and reprogramming in gastric repair and cancer. Nat Rev Gastroenterol Hepatol 15:257-273

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