Understanding a gene’s role in inflammatory bowel disease

A protein-coding gene associated with autoimmune diseases such as Crohn’s disease and ulcerative colitis, collectively referred to as inflammatory bowel disease, or IBD, will be the focus of new research in the School of Medicine at the University of California, Riverside.

The work is made possible by a National Institutes of Health grant exceeding $2.5 million.

The gene, called protein tyrosine phosphatase non-receptor type 2, or PTPN2, is expressed in all the body's cells but has particularly important roles in immune cells and intestinal epithelial cells. It is also associated with Type 1 diabetes and rheumatoid arthritis.

The research, performed on mice, will aim to identify the mechanisms by which PTPN2 regulates immune interactions between macrophages — a type of white blood cell — and epithelial cells and how this regulation affects the barrier properties of the intestinal epithelium in health and disease.

A single layer of cells that plays a critical role in human health, the intestinal epithelium provides a barrier while also allowing nutrient and water absorption. Intestinal epithelial cells are critical for regulating immune function, communicating with the intestinal microbiota, and protecting the gut from pathogen infection — all of which critically depend on an intact epithelial barrier.

“While some studies have partially identified the functions of PTPN2 in macrophages and epithelial cells, the role of PTPN2 in regulating how these cells talk to each other has not been studied,” said Declan F. McCole, a professor of biomedical sciences and the principal investigator of the five-year grant. “We hope to increase our understanding of the role PTPN2 ultimately plays in maintaining a protective gut barrier and regulating appropriate immune responses.”

Preliminary mouse studies in McCole’s lab strongly indicate PTPN2 plays a crucial role in health and disease by strengthening the gut barrier and preventing the immune system from launching an overly aggressive and damaging immune response.

IBD affects about 3 million people in the United States. The disease, whose common symptoms include diarrhea, abdominal pain, and weight loss, is characterized by chronic inflammation of the gastrointestinal tract, leading to several serious complications. The cause of the disease remains unknown.

McCole will be joined in the project by grant co-investigator Meera G. Nair, an associate professor of biomedical sciences at UCR, whose lab will help characterize PTPN2 regulation of how macrophages change their properties and functions in the presence or absence of inflammation.

“We hope to identify the mechanisms governing how macrophages regulate functions to maintain gut barrier function and what goes wrong when PTPN2 is not present to regulate these interactions,” McCole said. “We expect this will generate fundamentally new insights into how loss-of-function mutations — mutations that result in reduced protein functions — in the PTPN2 gene contribute to the onset of autoimmune diseases such as IBD.”

Postdoctoral researcher Marianne Spalinger, a member of McCole’s lab whose preliminary data helped secure the NIH funding, noted IBD cases are increasing in the United States and globally, including parts of the world that have traditionally not seen high numbers of cases.

“We will aim to identify novel targets for therapeutic intervention in IBD patients in this project,” she said.

Meli’sa Crawford, a postdoctoral researcher and new recruit to the McCole lab, will also take part in the research. The grant will also support the research of one graduate student and one junior specialist. Two undergraduates will receive lab experience working on the project.

Source: UC Riverside