UC Riverside

Inflammatory Bowel Diseases (IBDs) are characterized by relapsing chronic inflammation of the gastrointestinal tract that occurs in patients with Ulcerative Colitis (UC) and Crohn’s disease (CD). Genome wide association studies have to-date identified 240 independent susceptibility loci associated with IBD. Single nucleotide polymorphisms (SNPs) were identified in the protein tyrosine phosphatase non-receptor type 2 (PTPN2) gene locus which decodes T-cell protein tyrosine phosphatase (TCPTP), a negative regulator of diverse intracellular pathways, including several members of the JAK-STAT signaling. Consequently, PTPN2 loss of function is unable to repress/regulate inflammatory signals.Intestinal epithelial homeostasis is maintained by active-cycling and slow cycling stem cells confined within the crypt-based niche, and subsequent differentiation into secretory and absorptive epithelial lineages as cells migrate up the crypt-villus axis. An imbalance in the population of epithelial subtypes can be detrimental for the function of the organ and make it more susceptible to microbial infection. This is demonstrated by studies using IBD patient biopsy and transgenic mice demonstrating that genetic variants, or deletion of IBD-associated genes, can modify IEC subtypes and their functional roles in intestinal homeostasis. Therefore, the goal of this study was to identify whether Ptpn2-deficient mice display altered intestinal epithelial cell differentiation and function that could contribute to increased infection susceptibility and onset of IBD. For this, we used two mouse models, one with a constitutive “whole-body” Ptpn2 deficiency, and another with inducible-tissue specific Ptpn2 deletion. Overall, this dissertation shows that the number and function of secretory IECs is negatively affected by whole-body Ptpn2 loss. Notably, Paneth cells were almost ablated, with a marked deficit in production of AMPs, contributing to higher susceptibility to microbial infection.