HEMOCHROMATOSIS: FROM GENES TO CLINICS AND BACK

Hemochromatosis (HH) is a genetic disorder due to mutations of different genes that decrease the activation of the hepatic peptide hepcidin, causing excessive iron absorption and iron overload. The molecular genetics is well known, but the treatment, still based on phlebotomy, is suboptimal since, abnormally suppressing hepcidin levels, it further increases iron absorption. Setting the hepcidin levels to normal would be a more pathophysiological approach to treat HH patients. Our project proposes to clarify the interactions of HH proteins in cell and animal models and to evaluate the hepcidin response to iron challenge in patients. More specifically we will study “in vitro”: a) the function of HJV, the most important hepcidin activator and its interactions with other proteins; b) the effect of HH protein isoforms on hepcidin activation/inhibition in analogy with the opposite effect demonstrated for membrane and soluble HJV; c) the potential protective effect of HJV and HH proteins from excessive iron uptake. For “in vivo” studies we will use: a) murine models of Tfr2 deficiency to better understand the molecular pathogenesis of this rare HH, important at young age and the potential function of a TfR2 isoform; b) zebrafish model to develop a new strategy for the study of iron defects, taking advantage of its fast developmental phase. Finally we will develop a clinical trial to understand the HH protein function in humans. The elucidation of the hepcidin regulatory pathways is crucial for their therapeutic manipulation. The results of this project may be relevant not only to develop innovative treatment strategies for HH patients, but also for secondary iron overload and anemia of chronic diseases, whose pathogenesis is hepcidin-related.