Lay Summary

Proposal No.  IBD-0272R 
Principal Investigator:  Jerrold Turner, M.D., Ph.D. 
Applicant Organization:  The University of Chicago (Illinois, U.S.A.)
Project Title:  Epithelial myosin light chain kinase trafficking: a therapeutic target in inflammatory bowel disease
Period of Award:  May 1, 2009 – October 31, 2010

The intestinal epithelial cells, which line the inner surface of the intestine, form a barrier that prevents free mixing of noxious and potentially infectious luminal material with the protected internal milieu. However, this barrier function is compromised in patients with Crohn’s disease (CD) and the barrier dysfunction may precede disease re-activation in patients during remission. Moreover, a subset of healthy first-degree relatives of CD patients have barrier defects, which suggests that that barrier dysfunction is a fundamental mechanism that contributes to development of CD. We have shown that a key physiological regulator of the intestinal epithelial barrier, the enzyme myosin light chain kinase (MLCK), is associated with immune-mediated barrier dysfunction and is activated in human and experimental inflammatory bowel disease (IBD). Furthermore, our preliminary data suggest that correction MLCK-dependent barrier defects delays onset and lessens severity of experimental IBD. While we have developed a highly-specific inhibitor of MLCK, the domain against which this agent is targeted is present in all smooth muscle and non-muscle MLCK isoforms, suggesting a significant risk of systemic toxicity. Thus, for MLCK to be a viable therapeutic target in IBD, an alternative, non-enzymatic approach to MLCK inhibition is needed. We have now developed first-generation, drug-like molecules that are able to prevent MLCK from moving to the intracellular sites required for the enzyme to cause barrier loss. Importantly, these drug-like molecules are able to prevent acute barrier loss and diarrhea in vitro and in vivo without inhibiting MLCK enzymatic activity.

The aims of this proposal are to determine whether this new class of drugs is able to delay or prevent progression of experimental IBD in vivo. These studies are expected to accelerate development of a novel class of non-immunosuppressive agents that may, as part of multi-agent therapy, maintain remission with significantly less toxicity than current approaches.