In dogged pursuit of clues that may lead to the development of novel therapies for inflammatory disorders of the gastrointestinal tract, including Crohn’s disease, researchers at the University of Delaware have been sifting through dozens of gene mutations.
They have been trying to find out why the immune system sometimes launches unwarranted attacks on the microbes in the gut that help people digest the food they eat.
The UD researchers, led by Catherine Leimkuhler Grimes, assistant professor of chemistry and biochemistry, and biological sciences doctoral student Vishnu Mohanan, have been studying NOD2, a protein molecule that plays a key role in the immune system. Nearly 60 mutations of the gene that carries the code for NOD2 have been linked to various disorders, including nearly 50 that have been implicated in Crohn’s disease.
NOD2 is involved in pattern recognition, by which the immune system is able to tell the difference between the good guys and bad guys among bacteria. The good guys are the roughly 1 trillion bacteria that live in the gut and help extract key nutrients such as protein, vitamins and minerals from food. The bad guys are invading bacteria that can disrupt the ecology of the GI tract and cause various diseases and disorders.
The immune system is supposed to kill off the bad bacteria and control the population of good bacteria. Scientists believe the proteins created from mutated NOD2 genes aren’t able to recognize the good bacteria and as a result the immune system keeps attacking them.
The result is the chronic inflammation seen in Crohn’s disease and related GI disorders. Most current therapies for GI disorders such as Crohn’s are based on drugs that suppress inflammation.
While studying cellular signaling mechanisms involving NOD2, the UD researchers “stumbled on” another protein molecule, called HSP70, according to Mohanan, the lead author of a report on the research published July 4 in the Journal of Biological Chemistry.
HSP70 is a well-known “molecular chaperone.” Chaperone molecules help ensure that enzymes and other proteins are folded into and maintain the right three-dimensional shape within the crowded and often chemically hostile environment inside cells. Proteins that don’t have their proper 3-D configuration can’t function as they are supposed to.
Grimes admits she was initially skeptical when Mohanan suggested studying HSP70 because it is so well known, but eventually was persuaded.
What Mohanan discovered was that when the production of HSP70 was increased, the mutant NOD2 proteins were once again able to recognize good bacteria, sparing them from an immune system assault. “Essentially, Vishnu found a fix for NOD2, and we wanted to determine how we were fixing it,” Grimes said.
Further experiments have suggested HSP70 stabilized NOD2 and keeps it from degrading as fast. “Basically, HSP70 keeps the protein around — it kind of watches over and protects NOD2, and keeps it from going in the cellular trash can,” Grimes said.
The UD researchers’ next line of inquiry will be how the mutated NOD2 spurs inflammation.
“Right now, we have limited knowledge,” Mohanan said. “Once the signaling mechanism is figured out, we will have the keystone.”
The research was funded by grants from the National Institute of General Medical Sciences, part of the National Institutes of Health.