PPAR- GAMMA LIGANDS IN ULCERATIVE COLITIS
Principal Investigator: James Lewis
Abstract: Ulcerative colitis (UC) is a chronic inflammatory disease involving all or a portion of the colon. Currently, there are few effective medical therapies for UC. Furthermore, because of the potential toxicity of the currently available agents, there is a great need for alternative therapies to treat patients with UC refractory to therapy with 5-ASA agents. Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of transcription factors whose activities are regulated by high affinity binding of small lipophilic ligands such as steroid hormones. A new class of diabetic drugs, the thiazolidinediones, has been developed to bind to the gamma subtype of the PPARs. Colonic epithelial cells express high levels of PPARgamma protein and have the ability to produce inflammatory cytokines that may contribute to the inflammatory process in UC. We have previously demonstrated that PPARgamma ligands significantly attenuate cytokine gene expression in colon cancer cell lines by inhibiting the activation of Nuclear Factor KappaB via an IkappaB dependent mechanism. Furthermore, we have demonstrated that thiazolidinedione ligands for PPARgamma markedly reduce colonic inflammation in a mouse model of ulcerative colitis. As such, we believe that PPARgamma ligands represent a potentially novel class of medications with therapeutic activity in ulcerative colitis. The proposed study is designed to test the feasibility of therapy with the PPARgamma ligand, troglitazone in mild to moderate ulcerative colitis. Fifteen patients with mild to moderate ulcerative colitis will be treated in a open labeled study with 600 mg troglitazone daily for 6 weeks. The main clinical outcome to be studied is the induction of remission of the UC as measured by the Sutherland Disease Activity Index. Additionally, patients will be monitored for any evidence that troglitazone therapy may worsen the severity of their UC. We will also determine the ability of this medication to modify colonic gene expression. We will use the techniques of immunohistochemistry and RNA analysis to detect expression of PPARgamma receptors in human colon tissue and to determine whether exposure to PPARgamma ligands results in altered expression of colonic gene products related to the inflammatory cascade. Specifically, we will localize expression of PPARgamma protein in inflamed colonic mucosa of patients with ulcerative colitis. Similarly, we will compare expression of target genes in inflamed colonic tissue prior to and following exposure to troglitazone. It is expected that in the final 6 months of this project, the investigators will organize a multicenter randomized controlled trial of troglitazone in the treatment of mild to moderate ulcerative colitis.
Funding Period: 2000-03-01 - 2003-02-28
more information: NIH RePORT