Project Grant R01DK136071

REGULATION OF INTESTINAL IMMUNITY AND REPAIR BY INTEGRINS - PROJECT SUMMARY ULCERATIVE COLITIS (UC) IS A CHRONIC INFLAMMATORY BOWEL DISEASE (IBD) OF THE COLON THAT AFFECTS ROUGHLY ONE MILLION AMERICANS. UC IS GENERALLY NONFATAL AND OFTEN OCCURS IN THE PRIME OF LIFE, POTENTIALLY RESULTING IN DECADES OF SUFFERING, DISABILITY AND LOST PRODUCTIVITY. THE UNDERLYING MECHANISMS THAT LEAD TO DISEASE ARE POORLY UNDERSTOOD, AND THERE ARE NO CURRENT MEDICATIONS THAT CAN 'CURE' UC. RECENTLY ALMOST ALL PATIENTS WITH UC (BUT ALMOST NONE WITH CROHN'S DISEASE OR NO IBD) HAVE BEEN FOUND TO MAKE HIGH TITER ANTIBODIES TO THE INTEGRIN AVB6. FURTHERMORE, ANTI-AVB6 AUTOANTIBODIES PRECEDED CLINICAL DIAGNOSIS OF UC BY UPTO 10 YEARS, AND WERE ASSOCIATED WITH INCREASED ADVERSE OUTCOMES, SUGGESTING THEY MAY REPRESENT A FUNDAMENTAL PREREQUISITE OR CAUSE OF THE PATHOGENESIS OF UC. A MAJOR ROLE FOR AVB6 IS THE ACTIVATION OF THE CYTOKINE TGF-B, A MAJOR REGULATOR OF INTESTINAL BARRIER FUNCTION AND MUCOSAL IMMUNE RESPONSES. WE HAVE SPENT MANY YEARS INVESTIGATING THE ROLE OF AV INTEGRINS IN ACTIVATING TGF-B TO PROMOTE INTESTINAL IMMUNITY AND MAINTAIN HOMEOSTASIS, AND WE HAVE FOUND THAT MICE IN WHICH AVB6 IS SELECTIVELY DELETED IN THE INTESTINAL EPITHELIUM DEVELOP MORE SEVERE INTESTINAL INFLAMMATION IN A COLITIS MODEL, AND THIS IS ASSOCIATED WITH CHANGES IN EPITHELIAL CELL GENE EXPRESSION SIMILAR TO THOSE SEEN IN UC. BASED ON THESE DATA WE HYPOTHESIZE THAT INTESTINAL EPITHELIAL AVB6 ACTIVATES TGF-B FOR AUTOCRINE AND PARACRINE SIGNALING TO PROMOTE INTESTINAL IMMUNE HOMEOSTASIS, AND THAT DISRUPTION OF AVB6 FUNCTION RESULTS IN 'PRE-CLINICAL' UC IN MICE AND HUMANS. IN THIS PROJECT, WE WILL MAKE USE OF UNIQUE MOUSE MODELS, HUMAN EPITHELIAL CELL AND ORGANOID CULTURES, AND UC PATIENT SAMPLES TO TEST THESE HYPOTHESES AND DETERMINE THE ROLE OF AVB6 AUTOANTIBODIES IN IBD. SUCCESSFUL COMPLETION OF THESE EXPERIMENTS WILL DEFINE A ROLE FOR EPITHELIAL CELLS AS A NEXUS FOR REGULATION OF TGF- B ACTIVATION IN THE INTESTINE, AND PROVIDE A CRITICAL UNDERSTANDING OF THE REGULATION OF THIS CYTOKINE IN HEALTH AND DISEASE.