Novel Approaches to Curing Short Bowel Syndrome
Faculty Profile: Brad Warner and Christopher Erwin, Pediatric Surgery
What causes intestinal tissue to grow back after part of the bowel has been removed? And how can scientists use that knowledge to give newborns hope for a normal life?
Those are the questions being studied by Brad Warner, MD, and his colleague Christopher Erwin, PhD, in the Cincinnati Children's Division of Pediatric General and Thoracic Surgery. Their research focuses on short bowel syndrome, most often the result of a large portion of the intestine being removed to treat necrotizing enterocolitis in preterm infants. The remnant bowel tries to grow back in length and girth to compensate for the missing portion -- a process known as the intestinal adaptation response. If the intestine grows back fully, the child can tolerate oral feedings completely. However, if the response is incomplete, the child will need nutrition by vein, which eventually can result in chronic liver failure.
Since 1994, Drs. Warner and Erwin have researched how various growth factors, particularly epidermal growth factor (EGF), can enhance the intestinal adaptation response. They have established that the EGF receptor in the intestine is critical, through studies in mice that both inhibited and increased the amount of EGF, thus correspondingly suppressing or amplifying the adaptation response. Their laboratory also pioneered small bowel resection procedures in mice.
Two recent National Institutes of Health grants are funding research into the causes of cell growth and death in the bowel after surgery. Drs. Warner and Erwin have determined that the P21 gene is required to induce cell proliferation in the remaining bowel. Now they are looking for the signaling pathways that turn on the gene, causing new cells to grow.
Approaching the problem from a different perspective, the researchers also are studying how EGF signaling works to decrease the rate of cell death, theorizing this may be a novel way to preserve remaining bowel tissue after surgery. After identifying the gene critical in inducing cell death, they are studying how EGF influences the rate of death by regulating the gene. Drs. Warner and Erwin also have developed a unique in vitro model to learn how factors circulating in the blood after intestinal removal may induce cell growth by triggering EGF receptors.
In addition, a collaboration with the University of Cincinnati's Division of Endocrinology and Metabolism is looking at new strategies to regrow the bowel by stimulating smooth muscle cells -- a departure from the traditional approach that focuses on the cells lining the bowel.
