Abstract Factors that contribute to the onset of inflammatory bowel disease (IBD) remain incompletely understood. Although specific genetic factors may increase risk, most IBD cannot be readily explained based on genetics. Dysbiosis in intestinal microbiomes also has been implicated. Once IBD is established, chronic inflammation is a central hallmark and also a major target for therapy. Both forms of IBD, Crohn’s Disease (CD) and Ulcerative Colitis (UC), are typically characterized by periods of remission and flares. The flares can be serious and difficult to reverse, contributing to irreversible tissue damage. Existing therapies for IBD are insufficient and identification of new targets represents an important goal. We have identified a novel system that controls inflammation. Reelin, a plasma protein, binds to endothelial cell ApoER2, increasing expression of diverse endothelial cell receptors involved in transporting inflammatory cells into regions of inflammation. The major goal of this proposal is to test our hypothesis that targeting the Reelin/ApoER2 system therapeutically may be efficacious in IBD. In preliminary studies, we have shown that we can deplete the plasma of Reelin in a stable manner using anti- Reelin monoclonal antibodies. We also have available mice in which Reelin is deleted. In Specific Aim 1, we will test the hypothesis that Reelin deletion will decrease the severity of colitis that develops in response to dextran sodium sulfate (DSS). In Aim 2, we will test the efficacy of anti-Reelin antibody at attenuating the response to DSS. These proof of principle experiments will provide pre-clinical evidence in support of our goal to target the Reelin/ApoER2 system therapeutically in clinical trials in IBD patients.