A novel role for Reelin therapeutics in inflammatory bowel disease

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.Project Narrative
Chronic inflammation contributes in a substantial way to the pathology observed in multiple chronic degenera-
tive diseases, including and inflammatory bowel disease (IBD). In this application, we explore the feasibility of
targeting a novel pro-inflammatory system, based on the interaction of Reelin with Apolipoprotein-ER2, to
decrease disease progression in a mouse model of human IBD.
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