Discovery of a new drug target for inflammatory bowel disease

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“Discovery of a new drug target for inflammatory bowel disease”

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UT Southwestern researchers report in a new study that a group of interacting molecules in the gut’s immune cells is responsible for preventing the inflammation seen in inflammatory bowel disease (IBD). the findings, published in cell reportsProposing a new drug target for the treatment of inflammatory bowel disease and related conditions.

“We’ve discovered an underlying mechanism that prevents inflammation in the gut,” he said. Venuprasad Poojary, Ph.D.associate professor of internal medicine and immunology at UT Southwestern and a member of Harold C Simmons Comprehensive Cancer Center. “Understanding these kinds of basic details about the immune system is essential to developing new strategies for treating inflammatory diseases.”

Inflammatory bowel diseases, which include Crohn’s disease and ulcerative colitis, are characterized by chronic and severe inflammation of the digestive tract. Treatments for diseases exist, but they often suppress the immune system throughout the body, leading to side effects and an increased risk of infection. Drugs that target the intestines more specifically are a long-term goal.

The researchers already knew that high levels of the immune molecule IL-17 are associated with worse IBD symptoms. But while drugs that target IL-17 have been developed for psoriasis, they have not been effective in treating IBD. They also pose a problem affecting immune cells throughout the body.

In the new study, Dr. Bujari and colleagues examined what other molecules interact in the inflammatory cells that produce interleukin-17 in the intestine. Their experiments yielded a protein called Pak2. When the researchers blocked Pac2 in mice, the animals lost weight, developed more colitis, and showed other symptoms of IBD, including diarrhea and blood in their stools. However, in the presence of Pak2, IBD-like inflammation abated.

Further experiments revealed that Pak2 binds to RORgt, a protein that activates the IL-17 gene. But while RORgt acts as an accelerator of inflammation by increasing IL-17 levels, Pak2 acts like a brake. Dr. Bujari’s team showed that Pak2 degrades RORgt and prevents it from activating the IL-17 gene.

“We have clearly shown that elevating this pathway can prevent colitis, and we believe that this pathway can be targeted to relieve that inflammation as well,” said Dr. Bujari.

His lab is now planning follow-up studies to develop drugs that could promote Pak2 brakes on inflammation. He added that the research may have implications beyond IBD.

“Although we studied this in the context of bowel disease, we believe this pathway is also applicable to other inflammatory diseases including multiple sclerosis and rheumatoid arthritis,” he said.

Reference: Kathania M, Kumar R, Lenou ET et al. Pak2-mediated phosphorylation enhances RORγt proliferation and prevents colitis. cell reports. 2022; 40 (11). dui: 10.1016 / j.celrep.2022.111345

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