UA Steele Center Receives $1.65 Million to Continue Research in Protein that Affects Autoimmune Disease Development

The study, “Development of Intestinal Ion Transport,” is led by Fayez K. Ghishan, MD, professor and head of the Department of Pediatrics and Steele Center director, and Pawel R. Kiela, PhD, associate professor in pediatrics and immunobiology.
The University of Arizona Steele Children’s Research Center received a $1.65 million, five-year continuation grant from the National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Disorders.  
 
The study, “Development of Intestinal Ion Transport,” is led by Fayez K. Ghishan, MD, professor and head of the Department of Pediatrics and Steele Center director, and Pawel R. Kiela, PhD, associate professor in pediatrics and immunobiology.
 
Dr. Ghishan started this research in 1988, and it has been continuously supported for the past 25 years—one of the longest-funded studies in the history of the NIH. 
 
In this phase of their research, Drs. Ghishan and Kiela and their research team seek to decipher how the sodium-hydrogen transporter NHE3 contributes to the health of the gastrointestinal tract, and why its inhibition has such profound effects on the outcome of intestinal inflammation.
 
Individuals have nine sodium-hydrogen exchangers, or “transporters,” known as NHE (Na-H-Exchanger). NHEs are proteins responsible for transporting sodium across the GI tract for absorption. NHE3 is the predominant sodium-hydrogen transporter responsible for the majority of sodium transport across the GI tract.
 
“When the intestines become inflamed, NHE3 becomes inhibited, so it can’t move sodium through the GI tract, causing diarrhea and other ailments common in those suffering from Inflammatory Bowel Disease (IBD) and similar autoimmune disorders,” said Dr. Ghishan.
Past work from Drs. Ghishan and Kiela’s lab focused on changes and regulation of NHE3 during postnatal development. Their research revealed that in addition to transporting salt to the GI tract for absorption NHE3 is involved in preserving the integrity of the epithelial lining—the cellular structure that creates the intestinal wall, which separates the gut contents from the bloodstream. They showed that when NHE3 is inhibited, or “knocked down” by inflammation, the intestinal wall is breached, the gut becomes leaky and bacteria escape from the intestines into the bloodstream. Consequently, deadly sepsis may develop.
 
Moreover, NHE3 plays a critical role in shaping the intestinal microbiota (the microorganisms that live in the digestive tract). The latter aspect of the new study is particularly intriguing as mice lacking the NHE3 gene have altered microbial gut ecology in ways resembling that observed in IBD patients.
 
“Changes in the composition of intestinal microbiota, which is comprised of 10-times more cells than we have in our entire body, are of profound importance not only in IBD patients, but in the entire body’s metabolism,” said Dr. Kiela.
 
“Therefore, linking dysfunction of this one intestinal transporter to the intestinal microbial community potentially has  much  clinical importance,” said Dr. Ghishan.