Scientific Abstract
Proposal No. IBD-0001
Principal Investigator: Giamila Fantuzzi, Ph.D.
Applicant Organization: University of Colorado (Denver, U.S.A.)
Project Title: The leptin receptor: Role in inflammatory bowel disease
Period of Award: January 1, 2002 - February 29, 2004
The goal of this project is to investigate the role of leptin and the long form of its receptor (OB-Rb) in the susceptibility to intestinal inflammation in mice. In addition to acting as a regulator of food intake, leptin also modulates the immune and inflammatory response. Preliminary data indicate that leptin-deficient (ob/ob) and OB-Rb-receptor deficient (db/db) mice are resistant to colitis induced by chronic administration of dextran sodium sulphate (DSS).
The hypothesis of this proposal is that leptin, acting through OB-Rb, modulates responsivity to intestinal inflammation. In specific aim #1, the mechanism(s) by which leptin influences disease development in the chronic model of DSS-induced colitis will be investigated. In section a) of specific aim #1, we will try to identify the immune abnormalities which may account for the resistance of db/db mice to DSS-induced colitis. Lymphocyte activation markers, subpopulations of T cells, cytokine production, apoptosis and cell proliferation will be studied in mesenteric lymph nodes, lamina propria lymphocytes and intraepithelial lymphocytes of WT and db/db mice receiving chronic DSS. In section b), by generating bone marrow chimeras for OB-Rb, we will investigate whether expression of OB-Rb on leukocytes is necessary for DSS to induce colitis. In specific aim #2, the role of OB-Rb in intestinal inflammation induced by transfer of CD4+ CD45RBhigh cells will be investigated by comparing the effect of transferring WT or db/db CD4+ CD45RBhigh cells into scid recipients. Furthermore, the role of OB-Rb in the protective effect of CD4+ CD45RBlow cells on the development of intestinal inflammation induced by transfer of CD4+ CD45RBhigh cells will be investigated. If differences between WT and db/db cells in the ability to induce and/or protect from colitis are observed, we will investigate the possible mechanism underlying this difference.
These studies should help to better understand the complex network regulating IBD pathogenesis and the role of leptin and its receptor in immune regulation and in IBD. The information may lead to novel preventive and therapeutic approaches to IBD.