The specialized epithelial cells lining the gut's mucosal surface mediate important functions in digestive health and disease. Epithelial cell dysfunction can cause or contribute to disease states such as colon cancer and human inflammatory bowel disease (IBD: Crohn's disease and ulcerative colitis). Together gut epithelial related diseases cause substantial morbidity and mortality in the US. Indoleamine 2,3 dioxygenase (IDO1), an enzyme that catabolizes the essential amino acid tryptophan to kynurenine, is one of the most highly upregulated genes in human IBD and animal models of colitis. Over the current K08 funding period we have determined using animal models and fixed IBD patient samples that colon epithelial cells (CECs) upregulate IDO1 in human IBD and in mouse colitis models. Though it has been proposed that IDO's main function in the gut it to promote immune tolerance, our data demonstrate that IDO1 activity also correlates with epithelial proliferation in animal models of colitis and colitis-associated cancer. Though experimental models and cancer cell lines provide valuable insights, these findings often do not translate to human disease. In this proposal we will use a novel epithelial cell culture technique to study the function and regulation of IDO1 in human gut epithelial cells. We hypothesize that "Cell type specific induction and regulation of IDO1 mediates a cell-autonomous proliferative response in native human intestinal epithelial cells through kynurenine metabolites." IDO1 is an important therapeutic target in diseases of chronic inflammation and malignancy. IDO1 inhibitors as well as agents that induce IDO1 are moving to clinical trial, thus it will be important to understand the implications of modifying IDO1 activity in the gut epithelium. The overall goal of this RO3 is to establish the system's utility as a new tool for the study of IDO1 in human gut epithelial cells. Preliminary data will be generated to support an RO1 application directed at understanding the broader functions of epithelial IDO1 as relates to human IBD and colon malignancy.

Public Health Relevance

The specialized cells which line the gut have many important functions and if they are not working properly cancer or chronic inflammation can result. We have found that a protein called indoleamine 2,3 dioxygenase is expressed by epithelial cells. We aim to understand the function and regulation of this protein so that the knowledge can be applied to understanding new therapies for disorders of inflammation and malignancy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Small Research Grants (R03)
Project #
1R03DK100737-01
Application #
8624339
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
2014-01-15
Project End
2015-12-31
Budget Start
2014-01-15
Budget End
2014-12-31
Support Year
1
Fiscal Year
2014
Total Cost
$76,000
Indirect Cost
$26,000
Name
Washington University
Department
None
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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