Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the intestine that includes Crohn’s disease and ulcerative colitis. A protective protein that plays a key role in this disease is “T-cell protein tyrosine phosphatase” or TCPTP.
TCPTP protects the intestinal epithelial barrier function (the body’s intestinal lining has epithelial cells that form a barrier so that bacteria in the gut do not pass on into the rest of the body) and is encoded by a gene associated with not just IBD, but also celiac disease and type 1 diabetes. Some patients with these diseases exhibit loss-of-function mutations in this gene, resulting in loss of TCPTP activity, and have a compromised (or reduced) intestinal epithelial barrier function.
Declan McCole, Ph.D., an associate professor of biomedical sciences in the School of Medicine at the University of California, Riverside, has received a two-year grant of $150,000 from Pfizer Inc. to explore a therapeutic target for correcting intestinal barrier defects in IBD patients who have TCPTP mutations.
“These defects result in increased intestinal permeability – a major contributor to chronic inflammatory diseases of the intestine such as IBD,” McCole said.
He explained that although TCPTP mutations increase the risk of developing IBD, there are no therapeutic strategies aimed at correcting the consequences of these mutations.
The Pfizer Inc. grant will allow his lab to test multiple strategies to restore barrier function in intestinal epithelial cells affected by reduced TCPTP activity. In such cells, the lab plans to interrupt a signaling pathway called “JAK-STAT” that plays a role in increasing intestinal barrier defects. Normally functioning TCPTP deactivates this pathway; a mutated TCPTP does not.
McCole’s team will use molecular biology approaches to reduce expression of particular members of the JAK-STAT pathway to determine if this can correct barrier defects arising from loss of TCPTP activity in intestinal epithelial cells, setting the stage for planned studies to use pharmacologic JAK-STAT inhibitors to correct barrier defects caused by loss of TCPTP activity. (JAK-STAT inhibitors are currently being tested in clinical trials on IBD patients.)
“When TCPTP activity is compromised, errors occur in remodeling cell junctions – the structures that regulate barrier function,” McCole said. “Our preliminary data already indicate that our approach can help correct this. Our main goal – and hope – is to validate JAK-STAT as a therapeutic target for correcting intestinal barrier defects. In addition, we hope to identify if strategies to inhibit JAK-STAT signaling may prove particularly effective in patients with TCPTP genetic mutations.”
Declan will be joined in the research at UC Riverside by Moorthy Krishnan, an assistant project scientist, and Anica Sayoc, a fourth-year graduate student in biomedical sciences.
Studies in Year 1 will focus on characterizing the panel of JAK-STAT proteins that show increased activation in TCPTP-deficient cells using cell lines and intestinal tissues from mice lacking the TCPTP gene. Studies in Year 2 will determine if reducing expression of specific JAK-STAT proteins can improve barrier function of TCPTP-deficient epithelial cells and reduce expression of the IBD-associated permeability biomarker, claudin-2.
“We expect our findings from this research project will ultimately improve diagnostic and treatment options for patients with IBD,” McCole said.