Inflammatory bowel disease is a debilitating chronic illness with a relatively high prevalence in North America and Europe (45-200 people affected per 100,000). Our long-term objectives are the elucidation of the contributions of the nervous system to this important disease: this application focuses on the role of a neurokinin, substance P, one of the most abundant neurotransmitters in the gut, in the development and persistence of this disease. Using a unique murine model of inflammatory bowel disease that shares many features in common with human inflammatory bowel disease, including, importantly, the upregulation of substance P binding sites over lymphoid aggregates, the proposed studies will determine: 1) whether the substance P binding sites seen over lymphoid aggregates in this murine model of inflammatory bowel disease represent substance P receptors, as they do in human inflammatory bowel disease, using in situ hybridization, immunohistochemistry and quantitative competitive RT-PCR. 2) what cell type within the lymphoid aggregates expresses substance P binding sites in this murine model of inflammatory bowel disease, using flow cytometry and RT- PCR. 3) the effects of a substance P antagonist on the development or resolution of inflammatory bowel disease-like lesions, and adhesion molecule expression in this murine model of IBD. 4) whether substance P release is increased in the central nervous system of mice with inflammatory bowel-like lesions, using in situ hybridization, immunohistochemistry and quantitative competitive RT-PCR. The proposed studies will yield valuable information about the role of substance P in the development a of inflammation in this important disease, and will open the door to new therapeutic modalities.
