Scientific Abstract

Proposal No.  IBD-0165R
Principal Investigator:  Efi G. Kokkotou, M.D., Ph.D.
Applicant Organization:  Beth Israel Deaconess Medical Center (Boston, Massachusetts, U.S.A.)
Project Title:  Targeting melanin concentrating hormone as a novel treatment for inflammatory bowel disease
Award Period:  January 1, 2006 - December 31, 2007

Melanin concentrating hormone (MCH) is a hypothalamic neuropeptide involved in the regulation of food intake and energy balance.  Injection of MCH into the rat brain increases food intake acutely and genetic ablation of MCH results in a relatively lean phenotype in mice, attributed to reduced food consumption combined with increased energy expenditure.  In contrast, transgenic mice engineered to overexpress MCH are prone to obesity and develop a diabetic phenotype.  In humans, two G protein-coupled MCH receptors have been identified, MCHR1 and MCHR2; rodents express only MCHR1.  MCH receptors are mainly localized in the brain, with lower levels in peripheral tissues, including the intestine.  However, the peripheral actions of MCH are largely unknown.  Based on reports describing a proinflammatory role of several neuropeptides in intestinal inflammation, we hypothesized that MCH might also be implicated in this process.  Our preliminary studies demonstrate that MCH and its receptors are upregulated several fold in the inflamed human and mouse intestine.  More importantly, MCH deficient mice had significantly lower colonic inflammation in the TNBS-induced mouse model of experimental colitis, while administration of an antibody to MCH to wild type mice resulted in similar protective responses and in a five-fold survival advantage.  Furthermore, exposure of human colonic epithelial cells to MCH stimulated IL-8 expression, which might be a potential mechanism for the MCH induced pathogenesis in intestinal inflammation. 

We will examine the hypothesis that MCH acts as a proinflammatory mediator in IBD.  Aim 1 will compare expression and cellular localization of MCH and its receptors in the intestine of control and inflammatory bowel disease (IBD) patients, as well as serum MCH levels and correlate these with disease activity.  Aim 2 will examine the therapeutic effects of blocking MCH, using an antibody or an antagonist, in TNBS- induced experimental colitis and in IL-10 ^-/- mice that develop spontaneous colitis.  Aim 3 will investigate the molecular mechanisms of MCH proinflammatory signaling.  Since several MCH antagonists have been developed so far for the treatment of obesity, our studies, in addition to shedding light on IBD pathogenesis, might provide a scientific basis for testing such compounds in IBD treatment in the near future.