Is their a role for endoplasmic reticulum aminopeptidase 1 in experimental colitis and inflammatory bowel disease?

Inflammatory Bowel Disease (IBD) is a chronic inflammatory disease of the intestine for which no
definitive cure exists. Searching for novel therapeutic targets, we identified a functional candidate
gene for IBD, called endoplasmic reticulum aminopeptidase 1 (ERAP1). This gene is located within a
risk locus identified in genome-wide association studies (5q15) and we showed a reduced
expression of ERAP1 in peripheral blood mononuclear cells and gut biopsies of IBD patients. In
addition, exonic sequencing of this gene in 15 familial IBD cases revealed 20 missense mutations.
ERAP1 is an aminopeptidase that trims peptides for MHC class I presentation to CD8+ T cells and its
reduced expression or activity may therefore contribute to overactive immune responses in the
intestinal mucosa of IBD patients. In addition, ERAP1 is able to cleave membrane-bound receptors
of pro-inflammatory cytokines TNF, IL1 and IL6, which may also represent important immune
regulatory functions involved in chronic intestinal inflammation.
Whether ERAP1-mediated production of misprocessed antigens or impaired receptor shedding
affects the disease course of IBD is unknown. Therefore, we will investigate the functional role of
ERAP1 by:
1. evaluation of the effect of ERAP1 in experimental colitis models using ERAP1 knockout mice and
ERAP1 inhibitors;
2. determining the enzymatic activity of ERAP1 in IBD patients who carry a mutation in ERAP1