In the past year, three researchers at the University of Oklahoma College of Medicine at OU Health Sciences have earned more than $5 million in grant money to study causes and potential treatments for necrotizing enterocolitis, a deadly intestinal disease that primarily affects infants born prematurely.

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Because NEC occurs suddenly and progresses rapidly, research is crucial for giving the most fragile babies a chance at life.

About 7% of all preterm babies are diagnosed with NEC, which occurs when the baby’s underdeveloped small intestines have an excessive reaction to naturally changing bacteria. Unless NEC can be stopped, the lining of the intestinal wall becomes inflamed, and the intestines can rupture or die.

In about 30% of cases, the infant dies, often hours or days after diagnosis. For preterm babies who are born weighing 2 pounds or less, the risk of death with NEC is as high as 50%. The babies who survive often face problems with growth, nutrition, walking and cognitive development. The growing NEC research program at the OU College of Medicine is tackling NEC from multiple angles.

Increasing investigators

“This is an exciting time for NEC research in the OU College of Medicine because we are increasing the number of investigators focused on the disease, and our projects represent several disciplines in pediatrics,” said Hala Chaaban, M.D., director of clinical and translational research in the college’s Department of Pediatrics, Section of Neonatal-Perinatal Medicine.

Chaaban, a neonatologist, is one of the three researchers in the OU College of Medicine who recently earned local, state and federal funding to study NEC. The other two are pediatric surgeon Catherine Hunter, M.D., Section Chief of Pediatric Surgery, and scientist Kathryn Burge, Ph.D., in the Section of Neonatal-Perinatal Medicine. Each leverages her unique vantage point in a variety of innovative research projects.

Creatine supplementation

Burge’s latest grants fund her focus on creatine. This natural compound is known for its ability to strengthen the intestinal barrier so that bacteria can’t cross it easily, as well as for supplying energy to intestinal cells. Because creatine accumulates in the fetus during the third trimester of pregnancy, babies born prematurely don’t receive enough of the nutrient from their mothers. And infants are not able to replenish their supply, even though creatine is present in breast milk in low levels. In her laboratory, Burge is testing tissues to determine whether creatine levels are low or drop suddenly before NEC develops.

“We will also be treating our cell-based models with creatine to see whether they are more resilient to NEC,” Burge said. “NEC doesn’t usually affect babies right after birth; it occurs several weeks later. So, we are studying the possibility of supplementing with creatine in the window before NEC develops. Can we give creatine and build it up to the level it should have been and therefore prevent NEC?”

Burge’s research is funded by the National Institutes of Health and the Oklahoma City-based Presbyterian Health Foundation. Her newest NIH grant establishes her as an independent researcher.

Protecting the barrier

As a pediatric surgeon, Hunter may remove dead portions of the intestine if antibiotics and nutrition fail to help a baby with NEC. Surgery is tricky — she must determine the best time to operate to preserve as much intestine as she can, yet not perform unnecessary surgeries on small and fragile babies.

“Unfortunately, many babies with NEC require surgery, and after surgery, mortality rates are very high. If they do survive, their chances of needing an intestinal transplant down the road are high, and that is not ideal,” Hunter said. “As a scientist, I want to develop strategies to prevent NEC. I’d rather babies not ever get to the point where they need me as a surgeon.”

Hunter’s research centers on the intestinal barrier, which keeps bacteria from entering the bloodstream. In particular, she is studying a specific signaling pathway called ROCK that acts like a zipper to keep the intestinal barrier strong. In the development of NEC, something happens in the ROCK pathway to weaken the intestinal barrier.

ROCK activated

“In our lab, we have discovered that ROCK is activated during the development of NEC and that inhibiting ROCK appears to protect some of the intestinal barrier function,” Hunter said. “This new grant will allow us to continue studying this pathway to better understand its potential in preventing NEC. Not every premature baby develops NEC, but this research may help us better understand why some are more susceptible to the condition.”

Hunter has received funding from the NIH and the Oklahoma Center for Adult Stem Cell Research. She is among a small group of surgeons nationwide to receive an NIH R01 grant, considered the gold standard in research funding.

Hyaluronic acid and proteins

One of Chaaban’s longtime research areas is hyaluronic acid in human breast milk, which is beneficial for the development of a baby’s intestines. Because preterm babies begin their lives with underdeveloped intestines, they don’t receive the same benefits from hyaluronic acid as term babies do. Chaaban’s research has shown that additional doses of hyaluronic acid in mice help the intestines mature more rapidly and protect from intestinal injury like NEC would cause.

Chaaban’s new R01 grant from the NIH will allow her to continue studying the role of hyaluronic acid in human breast milk and whether supplementation in preterm babies might one day be possible to prevent NEC.

Protection against inflammation

An additional research focus, funded by a subcontract through the federal government’s Small Business Innovation Research program, is a group of proteins made in the body called inter-alpha inhibitor proteins, or IAIP, which protect against inflammation. Babies with NEC have lower levels of IAIP, putting them at risk for problems. Chaaban is testing whether giving additional IALP reduces inflammation and the chance of multi-organ failure in mouse research models.

“IAIP appears to calm down the body,” she said. “In babies with NEC, their bodies are trying to protect themselves, but they are not mature enough to differentiate between what is bad and what is good, so their immune system basically kills all the cells, and their organs begin to fail. Giving IAIP appears to be a way to quiet down the body’s inflammation.”

Rapid diagnostic tool

Chaaban and fellow OU College of Medicine neonatologist Birju Shah, M.D., are working with a company called ProThera Biologics to test a rapid diagnostic tool that can be used at the bedside to measure levels of IAIP. Results would be available within 10 minutes, allowing doctors to act quickly. After Phase 1 and 2 clinical trials testing the device, it appears promising.

Because Oklahoma Children’s Hospital OU Health offers the highest level of neonatal intensive care and around-the-clock surgical coverage, it treats most babies in the state with NEC. Complementing that expertise with research will improve the care that babies receive.

“I love taking care of patients and families and having those individual relationships, but science gives us the opportunity to have a wider impact and maybe even make a positive change for an entire population of patients. Research is incredibly important,” Hunter said.