Medical Student Research Fellowship for Summer 2007

Mentor: Zhi-Ping Liu
Department: Internal Medicine-Cardiology
Room number: NB10.222
Mail Code: 8573
Phone number: 214 648-1485
E-mail: liu@arnie.swmed.edu
Project title: Role of FoxO4 in Inflammatory Bowel Disease

Human subjects IRB approved project number (where applicable):

Animal subjects IRB approved project number (where applicable): 1068-06-02-1

Project Type (patient-based research, animal-based research, or basic research; this characterization is only to permit a general classification for grouping similar types of projects) Animal-based and basic research

Brief Description of Project:

The etiology of inflammatory bowel disease (IBD) remains unknown. However, it is well established that the lesions and symptoms are associated with over-production of pro-inflammatory cytokines. Recent studies in mouse models of IBD suggest that a combination of genetic characteristics and enteric environment contribute to the susceptibility, initiation and progression of IBD in both man and mouse. Several genetic loci have been shown to be associated with the pathogenesis of IBD. However, the transcriptional regulation of these genes in the development of IBD remains elusive. During ongoing studies of the functions of FoxO4, we have found that mice lacking Foxo4 are more prone to die after intracolonic administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS), a chemical known to induce chronic colitis with both T helper cell 1 and 2-type responses, characteristics found in Crohn's disease and Ulcerative Colitis in human, respectively. We have further observed that FoxO4 is expressed in the mucosa of intestinal tract and its expression is upregulated after treatment with TNBS. FoxO4 is a member of the forkhead transcription factor O subfamily that also includes FoxO1, FoxO3, and FoxO6. FoxO3 has been shown to regulate T help cell activation by inhibiting NF-?B activity in aged mouse. We have found that FoxO4, like FoxO3, has similar immunoregulatory activity in vitro. Since hyperactivation of T helper cells with excessive production of IL-2 and IFN? is the hallmark of TNBS-induced colitis, we hypothesize that FoxO4 may play a protective role against IBD by inhibiting NF-?B mediated cytokine production. The experiments in this project are designed to test this hypothesis with two specific aims: (1) To investigate the role of FoxO4 in protecting against TNBS-induced colitis and (2) To investigate the mechanisms that activate the transcription of Foxo4.

Previous Research Activities or Publications with Medical Students:

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