This proposal describes a 5-year training program for the development of an academic research career in gastroenterology. The PI has previous experience in laboratory investigation and is fellowship trained in gastroenterology with a focus in the inflammatory bowel diseases. He is currently expanding his scientific skills in investigation of intestinal inflammation, particularly as it relates to inflammation associated carcinogenesis. Dr William Stenson, an internationally recognized expert in laboratory investigations in intestinal inflammation has an established record of training independent scientists and will provide principle mentorship. To further promote the investigator's scientific development an advisory committee comprising of highly regarded physician scientist with expertise in intestinal inflammation as well as cancer and epithelial cell biology has been established. The research environment at the PI's institution provides a rich network of intellectual and investigational resources to support career development. The proposed research focuses on an enzyme with recognized immunomodulatory properties, Indoleamine 2,3 Dioxygenase (IDO), and its role in chronic intestinal inflammation and inflammation-associated colon-rectal cancer (CRC). The inflammatory bowel diseases and their complications lead to significant morbidity in affected individuals and their families. Colitis associated cancer is one of the most feared complications. Several lines of evidence suggest a role for IDO in these processes;however the area remains largely unexplored. IDO is seen as acting through the inhibition of lymphocyte activation. Our evidence shows that IDO is highly expressed in gut epithelial cells in response to inflammation and toll-like receptor activation. This expression of IDO in epithelial cells serves a protective function in dextran sodium sulfate colitis, a model of epithelial dysfunction which is T-cell independent. The goal of these studies is provide critical insight into the T-cell dependent and epithelial cell dependent functions of IDO in chronic colitis and colitis associated colon cancer, clarifying the potential role of therapeutic agents directed at affecting IDO activity in both colitis and malignancy of the colon. Scientific tools including knockout and transgenic mouse lines will assist in addressing the specific aims including 1) Evaluating the role of IDO in both T-cell dependent and independent models of chronic colitis 2) Determining the role of IDO in colon epithelial and cancer cell proliferation, and 3) Defining T-cell dependent &independent functions of IDO in a model of colitis associated cancer. The larger goal of the applicant and this mentored research grant is to develop the knowledge and skill sets required to become an independent investigator and ask relevant basic questions in mucosal immunology that aid in our understanding of human inflammatory diseases of the gastrointestinal tract.

Public Health Relevance

The goal of these studies is provide critical insight into the lymphocyte dependent and epithelial cell dependent functions of IDO in chronic colitis as and colitis associated colon cancer as occurs in human Crohn's and Ulcerative Colitis. The relevance of this work is to clarifying the potential role of therapeutic agents directed at affecting IDO activity in both colitis and malignancy of the colon.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Clinical Investigator Award (CIA) (K08)
Project #
Application #
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Internal Medicine/Medicine
Schools of Medicine
Saint Louis
United States
Zip Code
VanDussen, Kelli L; Marinshaw, Jeffrey M; Shaikh, Nurmohammad et al. (2015) Development of an enhanced human gastrointestinal epithelial culture system to facilitate patient-based assays. Gut 64:911-20
Iskandar, Heba N; Cassell, Benjamin; Kanuri, Navya et al. (2014) Tricyclic antidepressants for management of residual symptoms in inflammatory bowel disease. J Clin Gastroenterol 48:423-9
Ciorba, Matthew A (2013) Kynurenine pathway metabolites: relevant to vitamin B-6 deficiency and beyond. Am J Clin Nutr 98:863-4
Thaker, Ameet I; Rao, M Suprada; Bishnupuri, Kumar S et al. (2013) IDO1 metabolites activate *-catenin signaling to promote cancer cell proliferation and colon tumorigenesis in mice. Gastroenterology 145:416-25.e1-4
Ciorba, Matthew A (2013) Indoleamine 2,3 dioxygenase in intestinal disease. Curr Opin Gastroenterol 29:146-52
Ciorba, Matthew A; Riehl, Terrence E; Rao, M Suprada et al. (2012) Lactobacillus probiotic protects intestinal epithelium from radiation injury in a TLR-2/cyclo-oxygenase-2-dependent manner. Gut 61:829-38
Ciorba, Matthew A (2012) A gastroenterologist's guide to probiotics. Clin Gastroenterol Hepatol 10:960-8
Kerr, T A; Ciorba, M A; Matsumoto, H et al. (2012) Dextran sodium sulfate inhibition of real-time polymerase chain reaction amplification: a poly-A purification solution. Inflamm Bowel Dis 18:344-8
Ha, Christina Y; Kumar, Nitin; Raptis, Constantine A et al. (2011) Magnetic resonance enterography: safe and effective imaging for stricturing Crohn's disease. Dig Dis Sci 56:2906-13
Chen, Hongyan; Lee, Alexander; Bowcock, Anne et al. (2011) Influence of Crohn's disease risk alleles and smoking on disease location. Dis Colon Rectum 54:1020-5