Scientific Abstract

Proposal No.   IBD-0199R
Principal Investigator:  Raja Fayad, M.D.
Current Applicant Organization:  South Carolina Research Foundation (Charlotte, North Carolina, U.S.A.)
Original Applicant Organization:  The Board of Trustees of the University of Illinois (Chicago, U.S.A.)
Project Title: Adipose tissue macrophages: role in the development of strictures in Crohn's disease
Period of Award:  October 1, 2007 - November 30, 2010

We will investigate the role played by adipose tissue macrophages (MΦ) in the development of strictures in Crohn’s disease (CD). Our central hypothesis is that adipose tissue MΦ could contribute to the inflammation and/or the development of strictures in CD. In Specific Aim 1, we will investigate the adipocytes, adipose tissue T cells and MΦ cytokine production near CD stricture, inflamed, and normal intestine. Furthermore, we will investigate what are the activation phenotypes of adipose tissue MΦ, in the presence of adipocyte/T cell conditioned medium, near the stricture of CD compared to those isolated from inflamed area. Furthermore, we will study the effect of lipid-derived messenger molecules, prostaglandin E1, E2 and leukotriene B4, on adipose tissue M activation phenotype and adipose tissue T cells, in terms of collagen formation and cytokine production respectively.

Specific Aim 2 will be devoted to study whether inhibiting fatty acid oxidation modulates arginase-I and iNOS expression in adipose tissue MΦ. Data obtained from the proposed studies will clarify the role of adipocyte tissue MΦ in modulating inflammation/fibrosis formation in CD and investigate for the first time the responsiveness of these MΦ to adipocyte/T cell conditioned medium. Our study will address this issue, which has not been investigated to date. It will also determine the M activation phenotype and which cytokines are involved in activation that could lead to future prevention/treatment of CD strictures. The long-term questions we will ask are:

1) Which are the cytokines produced by adipose tissue immune cells and what activation phenotype will adipose tissue MΦ have near the stricture lesion of CD? Are there differences in lipid-derived messenger molecule products in adipose tissue-associated cells near strictures of CD and what is the effect of these factors on these cells in the context of inflammation and collagen formation?

2) Does inhibiting fatty acid oxidation modulate arginase-I and iNOS expression in adipose tissue MΦ?