Scientific Abstract

Proposal No. IBD-0176R
Principal Investigator:  Huabao Xiong, Ph.D.
Applicant Organization:  Mount Sinai School of Medicine (New York, New York, U.S.A.)
Project Title:   Blocking TLR signaling pathway by TLR peptides in the treatment of colitis
Period of Award:  March 15, 2006 – March 14, 2008

Toll-like receptors (TLR) are essential for host defense against pathogens. However, inappropriate activation of TLR leads to excessive release of Th1 cytokines IL-12, IL-18, TNFα, and unregulated inflammation characteristic of Crohn’s disease (CD). IL-12 secretion, triggered by an innate immune response to enteric bacteria, is pivotal to CD pathology. Colitis in animal model of CD is ameliorated under germ-free conditions and anti-IL-12 therapy is effective in both animal models of CD and in human disease. We have synthesized peptides that mimic the TLR4 and TLR2 juxtamembrane cytoplasmic regions. These peptides inhibit TLR signal activation and cytokine production in vitro and block LPS-induced septic shock and death in vivo. To study the feasibility of using the TLR4 and TLR2 peptides in the treatment of CD, we propose the following aims: 1) We will test the ability of TLR4 and TLR2 peptides to alter the course of disease in the IL-10 knock out and trinitrobenzene sulfonic acid (TNBS)-induced murine models of CD and oxazolone-induced murine model of human ulcerative colitis (UC). 2) We will determine the molecular mechanism underlining the effects of TLR4 and TLR2 peptides on inflammation by examining TLR complex formation with MyD88 and IRAK. We will also test the effects of TLR4 and TLR2 peptides on dendritic cell maturation. These studies should confirm the feasibility of therapy to treat CD with cell-permeable peptides targeting the TLR signal pathway.