The role of local iron homeostasis in inflammatory bowel disease

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PROJECT ABSTRACT Anemia is the most common complication of inflammatory bowel disease (IBD). IBD-associated anemia is often refractory to treatment, and the role of dysregulated iron homeostasis in IBD pathology is unknown. Accordingly, a better understanding of intestinal iron homeostasis may facilitate new therapeutic strategies for IBD and IBD-associated anemia. Anemia and inflammation are directly linked by the hormone hepcidin, which critically inhibits iron release from intracellular stores via the iron transporter ferroportin. In new data, I've identified that hepcidin produced by dendritic cells (DCs) is critical for tissue healing after intestinal inflammation, and that hepcidin is highly expressed by DCs in inflamed tissues of pediatric Crohn's disease (CD) patients. Moreover, hepcidin promoted healing by limiting iron availability to tissue-associated bacteria via iron sequestration in intestinal myeloid cells. The focus of this research proposal is to investigate the hypothesis that intestinal iron homeostasis is regulated by hepcidin in chronic intestinal inflammation and in pediatric Crohn's patients to promote tissue healing. In Aim 1, I will interrogate the role of hepcidin and ferroportin in chronic intestinal inflammation, iron homeostasis, and myeloid cell biology. In Aim 2, I will define the regulation of hepcidin and ferroportin expression in humans, and I will probe correlations between this axis, iron homeostasis, and TNF blockers in pediatric Crohn's disease. I will employ innovative technical approaches to characterize anatomical iron levels in mice and IBD patient samples, and I will develop new genetic tools to study the role of hepcidin and ferroportin in myeloid cells. Collectively, results from these studies will define the regulation and functional significance of intestinal iron homeostasis in IBD, with the potential to define novel therapeutic strategies for pediatric CD patients.