Increased intestinal permeability plays a crucial role in a number of chronic intestinal inflammatory conditions including Type 1 Diabetes (T1D), celiac disease, as well as Crohn's disease (CD) and ulcerative colitis (UC), collectively referred to as inflammatory bowel disease (IBD). More than 1.4 million Americans suffer from IBD. While the exact cause(s) of IBD are unknown, there is considerable evidence that a permeability defect in the intestinal epithelial layer plays a major role in the development of IBD. The intestinal epithelial lining is a single layer of cells that forms the interface between the bactera that reside in the intestine (intestinal microbiota), and the rest of the body. During inflammation the epithelium is exposed to high levels of inflammatory mediators such as interferon-g (IFNg). These mediators activate signaling pathways that alter various functions of the epithelium, such as barrier maintenance. Termination of these signals is mediated largely by the activity of phosphatases. One such phosphatase, protein tyrosine phosphatase non-receptor type 2 (PTPN2), negatively regulates IFNg signaling in non-epithelial cells. However, little is known about the function of PTPN2 in the intestinal epithelium. Recently, single nucleotide polymorphisms (SNP) in the PTPN2 gene have been identified as a genetic marker associated with Crohn's disease, UC, T1D and celiac disease. Thus, these diseases share a common gene association and an elevation in intestinal permeability. We have recently identified a completely novel involvement of PTPN2 in the regulation of epithelial barrier function. Therefore, the specific objectives of this proposal are to understand the role of PTPN2 in regulating intestinal barrier function, and to identify how PTPN2 may be involved in the pathogenesis of chronic intestinal inflammatory diseases. This will be addressed in three specific aims.
Aim 1 will investigate how PTPN2 modulates inflammation-induced intestinal barrier dysfunction by determining how PTPN2 restricts intestinal epithelial barrier dysfunction caused by inflammatory cytokines.
Aim 2 will identify how the expression, activity and cellular localization of PTPN2 are regulated by inflammatory cytokines.
Aim 3 will identify how PTPN2 regulates intestinal permeability in vivo using PTPN2-deficient mice. Expected Outcomes &Impact: These studies will provide fundamental insights into the role of PTPN2 in the regulation of intestinal barrier function, the effect of inflammatory mediators on PTPN2 expression and activity, and the functional consequences of a loss of PTPN2 on epithelial cytokine signaling. On a broader scale, we will identify a unifying link for a gene (PTPN2) and a pathophysiological phenomenon (increased intestinal permeability) that are both fundamentally involved in CD, UC, Type 1 diabetes and celiac disease. These studies may also identify new diagnostic and treatment approaches for IBD patients expressing a PTPN2 SNP.
Inflammatory bowel diseases (IBD), according to NIDDK statistics, affect approximately 1.4 million individuals in the U.S. alone. We have discovered a completely novel role for the protein tyrosine phosphatase non- receptor type 2 (PTPN2) in the regulation of intestinal epithelial permeability, an event that is increased and plays a major role in the pathogenesis of IBD and other chronic diseases, such as type 1 diabetes (T1D) and celiac disease. This project will investigate how PTPN2, which is a candidate gene common to IBD, T1D and celiac disease, plays a critical role in regulating the intestinal barrier in the settng of inflammation and thus connects the genetics to the pathophysiology of multiple inflammatory diseases of the intestines.
|McCole, Declan F (2014) IBD candidate genes and intestinal barrier regulation. Inflamm Bowel Dis 20:1829-49|
|Penrose, Harrison M; Marchelletta, Ronald R; Krishnan, Moorthy et al. (2013) Spermidine stimulates T cell protein-tyrosine phosphatase-mediated protection of intestinal epithelial barrier function. J Biol Chem 288:32651-62|