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Protein found that fixes Crohn's disease gene

Kathleen Blanchard's picture
Researchers have uncovered a protein that stabilizes Crohn's disease gene

Researchers say they have identified a protein that stabilizes another protein involved in Crohn's disease. University of Delaware researchers discovered how certain proteins can trigger an abnormal immune response to lead to inflammation associated with Crohn's and other inflammatory bowel disorders.

New target for treating Crohn's disease

Past research has focused on the role of gut bacteria as a contributor to Crohn's disease. The new research conducted by Catherine Leimkuhler Grimes, assistant professor of chemistry and biochemistry at UD, and Vishnu Mohanan, doctoral student in biological sciences focused on mutation of a gene called NOD2 — nucleotide-binding oligomerization domain containing protein 2 - that is strongly associated with Crohn's disease.

Mohanan discovered HSP70 that stands for "heat shock protein 70" plays a role in helping the body attack "bad" gut bacteria, which essentially "fixes" mutations of NOD2.

HSP70 is referenced as a chaperone molecule that helps proteins maintain their three dimensional shape.

According to a press release, "..we stumbled on this chaperone molecule," says Mohanan, who was the lead author of article.published in the July 4, 2014 Journal of Biological Chemistry.''

Bad versus good gut bacteria

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The study authors explain how the body sorts out which bacteria in the gut are "good" and which are "bad" through receptors that can distinguish between the two based on bacterial composition including fragments of the bacteria's cell wall.

If one of the receptors mutates or breaks down an autoimmune response can occur that destroys beneficial bacteria, which is what is believed to lead to diseases like Crohn's.

The researchers said they were skeptical about pursuing HSP70 because it is a well known protein. The researchers inadvertently discovered the chaperone molecule when they were looking at where NOD2's signaling mechanism breaks down.

Protein helps 'fix' Crohn's gene mutation

The researchers went on to test cell lines with HSP70 including kidney cells, colon cells and white blood cells. They discovered NOD2 degraded more slowly with HSP70 treatment.

"Vishnu found that if we increased the expression level of HSP70, the NOD2 Crohn's mutants were able to respond to bacterial cell wall fragments. A hallmark of the NOD2 mutations is inability to respond to these fragments. Essentially, Vishnu found a fix for NOD2, and we wanted to determine how we were fixing it: Grimes said. HSP70 basically keep NOD2 from "going to the cellular trash can," Grimes adds.

Crohn's disease is emerging globally and now may affect as many as 700,000 people in the United States alone. The disease primarily affects young people and can cause significant pain, frequent hospitalizations, anxiety and inability to socialize during flare-ups that are different for everyone.

The disease can affect any part of the gastrointestinal tract and can also produce skin lesions and other extraneous symptoms.

The new finding shows there could be new targets for treating Crohn's disease. "We want to figure out why the mutation in NOD2 results in an increase in inflammation," says Mohanan. "Right now, we have limited knowledge. Once the signaling mechanism is figured out, we will have the keystone."