Project Grant R43AR081762

A NOVEL ROLE FOR REELIN THERAPEUTICS IN RHEUMATOID ARTHRITIS - ABSTRACT CHRONIC INFLAMMATORY PATHOLOGY OF CARTILAGE AND BONE REPRESENTS A MAJOR SOURCE OF DAMAGE TO THE SYNOVIAL JOINTS OBSERVED IN RHEUMATOID ARTHRITIS (RA). ALTHOUGH THE PRECISE ETIOLOGY OF THESE DISEASES IS OFTEN UNKNOWN, EXCESSIVE LEUKOCYTE EXTRAVASATION IS A SUBSTANTIAL CONTRIBUTOR TO THE TISSUE DAMAGE/INFLAMMATION AND OUR RECENT DATA SHOW A PROMINENT ROLE OF THE PLASMA PROTEIN, REELIN IN THIS PROCESS. FURTHERMORE, WE HAVE NOW SHOWN THAT IT IS POSSIBLE, USING ANTI-REELIN MONOCLONAL ANTIBODIES, TO DEPLETE THE PLASMA OF REELIN, WHICH RESULTS IN A SIGNIFICANT REDUCTION OF A WIDE RANGE OF VASCULAR ADHESION MOLECULE EXPRESSION. THUS, IN CONTRAST TO THE CURRENT METHODS OF DEPLETING INDIVIDUAL ADHESION MOLECULES OR IMMUNE RECEPTORS, OUR ANTI-REELIN APPROACH SYSTEMATICALLY DOWNREGULATES ALL MAJOR INFLAMMATION-DRIVEN ADHESION PROTEINS ON THE VASCULAR ENDOTHELIUM. THE PURPOSE OF THIS PROPOSAL IS TO DEMONSTRATE THE ROLE OF REELIN IN RA BY 1) IDENTIFYING HIGH AFFINITY REELIN ANTIBODIES AND 2) VALIDATING THE THERAPEUTIC POTENTIAL OF MITIGATING CHRONIC INFLAMMATORY MILIEU WITH AN ANTI-REELIN ANTIBODY IN AN RA MOUSE MODEL.