Lay Summary

Proposal No. IBD-0012R
Principal Investigator:  Lee A. Denson, M.D.
Current Applicant Organization:  Cincinnati Children's Hospital Medical Center (Ohio, U.S.A.)
Original Applicant Organization:  Yale University (New Haven, Connecticut, U.S.A.)
Project Title:  Mechanisms of growth hormone resistance in experimental colitis
Period of Award:  October 1, 2002 – March 31, 2006

Despite improved medical and nutritional management, patients with Inflammatory Bowel Disease (IBD) often experience poor growth, strength and defective intestinal healing.  This may be due to a combination of chronic inflammation and inadequate nutrition.  Normal growth and intestinal healing are dependent upon the actions of growth hormone (GH).  Prior studies have demonstrated that patients with IBD may be GH resistant; in other words, they produce enough GH, but are unable to respond to it.  Recent studies in our laboratory have indicated that inflammatory proteins that are produced in IBD, particularly tumor necrosis factor (TNF) and interleukin-6 (IL-6), can directly block the beneficial actions of GH.  This is, in turn, associated with poor growth and intestinal injury in mice with experimental colitis.

Most current IBD research and therapies are based on identifying and blocking specific aspects of the intestinal inflammatory process.  This has led to the development of a new class of medications, called biological therapies, which have proven to be quite effective.  An alternate approach, which is the focus of this project, is to identify ways to restore normal intestinal response to GH, and thereby enhance both growth and intestinal healing.

We will examine the manner in which inflammation and inadequate nutrition combine to block GH action in a mouse model of IBD.  In this model, mice develop chronic intestinal inflammation and progressive growth failure that resembles Crohn’s disease.  The effect of specific inflammatory proteins, including TNF and IL-6, upon GH action will be determined.  We will then use data from these initial studies to test the ability of new biological therapies targeted against inflammatory proteins to restore GH signaling.  It is hoped that these studies will lead to the identification of novel strategies that will both ameliorate intestinal inflammation, and optimize growth and intestinal healing, in patients with IBD.