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 cell (IEC) 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 bacteria 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-? (IFN?). 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 IFN? signaling in non-epithelial cells. However, little is known about the function of PTPN2 in the intestinal epithelium. Single nucleotide polymorphisms (SNP) in the PTPN2 gene have been confirmed 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 identified a completely novel involvement of PTPN2 in the regulation of epithelial barrier function. Therefore, the specific objectives of this proposal are to better understand how PTPN2 loss-of-function mutations alter phosphorylation signaling networks impacting upon intestinal barrier function, and if this can be corrected by a clinically-effective therapeutic agent. This will be addressed in three specific aims.
Aim 1 : Determine the molecular mechanisms causing epithelial barrier defects due to PTPN2 loss of function Aim 2: PTPN2 is a negative regulator of JAK-STAT inflammatory signaling pathways. We will investigate if the JAK inhibitor, Tofacitinib can correct the consequences of PTPN2 loss of function through inhibiting JAK-STAT pathways normally restricted by PTPN2.
Aim 3 : Identify how loss of PTPN2 phosphatase activity alters its ?phospho- interactome? in IEC and how does this impact upon tight junction protein phosphoregulation. Expected Outcomes & Impact: These studies will not only build a more accurate mechanistic understanding of the consequences of loss-of-function PTPN2 mutations for barrier function regulation and associated signaling networks, but will also identify a possible therapeutic approach to resolve these defects.

Public Health Relevance

Inflammatory bowel diseases (IBD), according to NIDDK statistics, affect approximately 1.5 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 the mechanisms by which loss-of-function mutations in PTPN2, a candidate gene common to IBD, T1D and celiac disease, compromises expression and localization of key tight junction proteins and intestinal barrier properties in the setting of inflammation thus connecting the genetics of multiple inflammatory diseases of the intestines to their pathophysiology.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
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Hamilton, Frank A
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University of California Riverside
Schools of Medicine
United States
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Krishnan, Moorthy; McCole, Declan F (2017) T cell protein tyrosine phosphatase prevents STAT1 induction of claudin-2 expression in intestinal epithelial cells. Ann N Y Acad Sci 1405:116-130
Shawki, Ali; McCole, Declan F (2017) Mechanisms of Intestinal Epithelial Barrier Dysfunction by Adherent-InvasiveEscherichia coli. Cell Mol Gastroenterol Hepatol 3:41-50
Barrett, Kim E; McCole, Declan F (2016) Hydrogen peroxide scavenger, catalase, alleviates ion transport dysfunction in murine colitis. Clin Exp Pharmacol Physiol 43:1097-1106
Krishnan, Moorthy; Penrose, Harrison M; Shah, Nilay N et al. (2016) VSL#3 Probiotic Stimulates T-cell Protein Tyrosine Phosphatase-mediated Recovery of IFN-?-induced Intestinal Epithelial Barrier Defects. Inflamm Bowel Dis 22:2811-2823
Spalinger, Marianne R; McCole, Declan F; Rogler, Gerhard et al. (2015) Role of protein tyrosine phosphatases in regulating the immune system: implications for chronic intestinal inflammation. Inflamm Bowel Dis 21:645-55
Kang, Sang Bum; Marchelletta, Ronald R; Penrose, Harrison et al. (2015) A comparison of linaclotide and lubiprostone dosing regimens on ion transport responses in human colonic mucosa. Pharmacol Res Perspect 3:e00128
McCole, Declan F (2014) IBD candidate genes and intestinal barrier regulation. Inflamm Bowel Dis 20:1829-49
Morón, Belén; Spalinger, Marianne; Kasper, Stephanie et al. (2013) Activation of protein tyrosine phosphatase non-receptor type 2 by spermidine exerts anti-inflammatory effects in human THP-1 monocytes and in a mouse model of acute colitis. PLoS One 8:e73703
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
Marchelletta, Ronald R; Gareau, Melanie G; McCole, Declan F et al. (2013) Altered expression and localization of ion transporters contribute to diarrhea in mice with Salmonella-induced enteritis. Gastroenterology 145:1358-1368.e1-4

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