Inflammatory bowel disease (IBD) affects approximately 1.4 million people in the United States. The pathogenesis of IBD is thought to involve an exaggerated immune response to the colonic flora in the genetically susceptible host. When IBD, either ulcerative colitis or Crohn's disease, affects the colon and/or rectum, patients are at a signficantly [sic] higher risk of developing colitis associated-colorectal cancer. In patients with pancolitis for greater than 20 years the risk of cancer approaches 20%. Although colonic epithelial cell genetic and epigenetic alterations are inevitable in colitis associated cancer, what triggers colonic epithelia cell oncogenic transformation is poorly understood. We found that Min (APC ) mice colonized with an human colonic commensal, enterotoxigenic Bacteriodes fragilis (ETBF) demonstrate marked colonic inflammation and rapid colon tumor formation dependent, in part, on a predominant and selective Th17 response with early activation of signal transducer and activator of transcription 3 (Stat3) in colonic epithelial cells and immune cells. These results support the hypothesis that the microbiota can precipitate specific mucosal signaling and immune responses important in early neoplastic changes in IBD. We further hypothesize that Stat3, a key oncogenic transcriptional regulator, is a coordinate regulator of the epithelial and mucosal immune signaling and is critical to colon inflammation and, ultimately, tumorigenesis. The goals of this project are: 1. To define in ETBF-infected mice, how Stat3 activation in distinct cell types (lymphocytes, colonic epithelial cells and myeloid cells) contributes to coitis [sic] and 2. To define the mucosal immune profile (Th1/Th17 balance) in IBD patients who develop dysplasia and/or colitis-associated cancer compared to controls. These integrated mouse and human experiments, that will be completed under the mentorship of Dr. Cynthia Sears, expert in bacterial pathogenesis, and Dr. Drew Pardoll, expert in tumor immunology, will provide the applicant with practical experience in state of the art pathogenesis and immunology research methods. To complete gaps in her knowledge, the applicant has designed a complementary didactic program in immunology and translational research design. Together the practical and didactic experience gained by completing this career development plan will enable the applicant to transition to an independent investigator over the next five years.

Public Health Relevance

Inflammatory bowel disease (IBD) affects approximately 1.4 million people in the United States. When IBD, either ulcerative colitis or Crohn's disease, affects the colon and/or rectum, patients are at a signficantly [sic] higher risk of developing colorectal cancer. In patients with pancolitis for greater than 20 years the risk of colorectal cancer approaches 20%. Understanding the relationship between intestinal inflammation and colonic neoplasia may help in identifying strategies for preventing cancer in IBD patients and for treating colitis associated cancers.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08DK087856-03
Application #
8312726
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
2010-07-01
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
3
Fiscal Year
2012
Total Cost
$158,220
Indirect Cost
$11,720
Name
Johns Hopkins University
Department
Surgery
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Llosa, Nicolas J; Cruise, Michael; Tam, Ada et al. (2015) The vigorous immune microenvironment of microsatellite instable colon cancer is balanced by multiple counter-inhibitory checkpoints. Cancer Discov 5:43-51
Wick, Elizabeth C; Rabizadeh, Shervin; Albesiano, Emilia et al. (2014) Stat3 activation in murine colitis induced by enterotoxigenic Bacteroides fragilis. Inflamm Bowel Dis 20:821-34
Dejea, Christine; Wick, Elizabeth; Sears, Cynthia L (2013) Bacterial oncogenesis in the colon. Future Microbiol 8:445-60