Pfizer Awards Grant to UC Riverside Researchers for Discovery of IBD Therapeutic Target

Pfizer Awards Grant to UC Riverside Researchers for Discovery of IBD Therapeutic Target

Pfizer has awarded $150,000 to Declan McCole, PhD, and his team to find a therapeutic target for correcting intestinal barrier defects for patients with inflammatory bowel disease (IBD) who have mutations in the T-cell protein tyrosine phosphatase (TCPTP) protein.

TCPTP, which plays a key role in IBD, protects the intestinal epithelial barrier function and is encoded by a gene associated with IBD, type 1 diabetes and celiac disease. Some patients with these conditions have mutations in this gene, stripping TCPTP of its protective function.

With the two-year grant, McCole — an associate professor of biomedical sciences at the University of California Riverside — will lead his colleagues in testing different approaches to restore barrier function in intestinal epithelial cells that have a reduced activity of the TCPTP protein.

The intestinal epithelium lines the surface of the gut as a single layer of closely adhering cells and forms an efficient physical boundary to the body’s interior, ensuring that gut bacteria  do not pass into the rest of the body.

In their experiments, researchers will use these intestinal epithelial cells to test what happens when they interrupt a signaling pathway termed JAK-STAT, which is known to increase intestinal barrier defects. When TCPTP is functioning properly, this pathway is deactivated, but in individuals with TCPTP mutations, the JAK-STAT pathway remains activated.

“These defects result in increased intestinal permeability, a major contributor to chronic inflammatory diseases of the intestine such as IBD,” McCole said in a news release.

While TCPTP mutations increase the risk for IBD, no therapeutics exist today to correct the consequences of these mutations. In their studies, the team will explore the potential of using JAK-STAT inhibitors to restore intestinal barrier defects that results when TCPTP’s activity is lost. These compounds are currently under clinical testing in 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.”

Using cell lines and intestinal tissues from mice with TCPTP mutations, McCole’s lab will initially characterize the panel of JAK-STAT proteins that have increased activation in cells with mutated TCPTP. They’ll then test whether reducing expression of certain JAK-STAT proteins can restore the intestinal barrier function of the mutated TCPTP cells, and reduce expression of a biomarker called claudin-2, which is associated with IBD intestinal permeability.

“We expect our findings from this research project will ultimately improve diagnostic and treatment options for patients with IBD,” McCole said.

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