P152 EVALUATING THE EFFICACY OF GLUTAMATE CARBOXYPEPTIDASE II (GCPII) INHIBITORS IN “WILD-TYPE” MICE: LESSONS LEARNED FROM THE DEDICATOR OF CYTOKINESIS 2 MUTANT MOUSE

Abstract

Glutamate carboxypeptidase II (GCPII) is highly upregulated in human IBD and is a therapeutic target under active investigation by our laboratory. We recently published that a spontaneously occurring loss-of-function mutation in dedicator of cytokinesis 2 (Dock2Hsd) that was present in commercially-purchased “wild-type” C57Bl6/NHsd mice increased their sensitivity to DSS-colitis and caused them to closely resemble human IBD with respect to GCPII. The DSS-exposed Dock2Hsd mice had significantly elevated colon GCPII activities and were sensitive to treatment with the GCPII inhibitor, 2-PMPA. We hypothesized that if colitis of the same severity were to be induced in Dock2WT mice, that they would also exhibit heightened colon GCPII activity and would be equally sensitive to 2-PMPA treatment.