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Findings from Upstate study may offer link to Crohn’s disease

The discovery that the expression of the SHIP1 gene is significantly altered in Crohn’s disease patients by Upstate Medical University researcher William G. Kerr, PhD, and his colleagues is showing promise as a possible link to the cause of this disease. If correct, the finding could lead to novel ways to treat the disease, including cell transplantation. Kerr is an Empire Scholar and the Murphy Family Professor of Childrens’ Oncology Research, and professor of pediatrics and microbiology and immunology at Upstate.

Kerr’s study has received support recently from the Crohn’s & Colitis Foundation of America (CCFA) through a three-year Senior Research Scholar Award totaling nearly $346,000. His study was selected for funding from among more than 160 studies submitted nationwide. In addition to the award, Kerr has been named by the foundation as a senior scholar.

Crohn’s disease, a major type of inflammatory bowel disease (IBD), is a chronic condition of the gastrointestinal tract that leads to cramping, diarrhea and gastrointestinal bleeding that can sometimes be fatal.

Kerr’s foray into Crohn’s disease was catalyzed by his finding that mutation of SHIP1 in mice triggered Crohn’s-like disease in the small intestine of the mutant mice.  He and his team then developed specialized assays to see if these findings translate to humans as well. In addition, they are also using exome sequencing—sequencing directly targeted to the SHIP1 gene — to examine its genetic content.

To obtain IBD samples, Kerr initially collaborated with a former fellow from his laboratory, Gwenny Fuhler, PhD, and with Maikel Peppelenbosch, PhD, at the Erasmus Medical Center in Rotterdam, Netherlands.  Samples also were received from Lloyd Mayer, MD, at Mt. Sinai Medical Center in New York.

“Our initial analysis of those IBD samples showed that the expression of the SHIP1 gene in a relatively small patient cohort is increased in Crohn’s disease patients at the RNA level, but decreased at the protein level,” Kerr said. “In addition, we found that a small subset of Crohn;s disease patients may lack or have very little SHIP1 protein expression.”

Kerr’s exome sequencing approach also identified four single nucleotide polymorphisms (SNPs) in SHIP1 increased in CD patients relative to healthy controls. According to the Genetics Home Reference (GHR) of the National Library of Medicine, when SNPs occur within a gene or in a regulatory region near a gene, they may play a more direct role in disease by affecting the gene’s function. Researchers have also found SNPs may help predict an individual’s response to certain drugs.

In the three-year funded project that started this January, Kerr will work with a California gastroenterology research group to assess the status of SHIP1 in a larger group of Crohn’s disease patients at Veterans Hospital San Francisco and the University of California at San Francisco. James Ryan, MD, a gastroenterologist who holds affiliations at both California sites, leads the California research group.

“Our study is really an international effort that increases the validity of our findings for IBD patients worldwide,” Kerr said. “If our CCFA funded study of a much larger Crohn’s disease patient cohort confirms that SHIP1 expression is absent or drastically reduced in a subset of Crohn’s disease patients, we will first try to determine the molecular and genetic basis for this defect. Then we will attempt to model potential treatments for these patients using immune cell transplants where SHIP1 expression is normal or by the use of small molecules that can ‘turn up’ SHIP1 activity in these patients to levels that are beneficial and could prevent gastrointestinal inflammation.”

The Crohn’s and Colitis Foundation of America is a non-profit organization dedicated to finding the cures for Crohn’s disease and ulcerative colitis. The foundation has remained at the forefront of research in Crohn’s disease and ulcerative colitis, providing more than $164 million for research on the treatment and cure of inflammatory bowel diseases.

Caption: William G. Kerr, PhD, is an Empire Scholar and the Murphy Family Professor of Childrens’ Oncology Research, and professor of pediatrics and microbiology and immunology at Upstate.

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