My laboratory is primarily interested in investigating how mammals acquire and utilize iron. In mammals, erythrocytes typically contain greater than 70% of the organism’s iron in the form of heme in hemoglobin. Over the past several years, many of the transporter and accessory proteins involved in intercellular iron metabolism have been described. However, many proteins involved in intracellular iron metabolism beyond the basic components of the transferrin cycle remain elusive. Furthermore, the enzymatic components of heme biosynthesis are well characterized, but accessory transporters and other proteins required to shuttle heme precursors between mitochondria and the cytoplasm are unknown. To investigate these areas, we are taking two general approaches. First, we are using modern genetic techniques to identify and characterize the genes underlying mouse and human hereditary defects in erythroid iron and heme metabolism that lead to congenital forms of anemia. Second, using targeted mutagenesis in the mouse, we are studying proteins implicated in systemic, intracellular, and erythroid iron homeostasis. In particular, we are interested in the pathogenesis in a group of bone marrow disorders known as sideroblastic anemias, in which erythroid precursors develop pathologic mitochondrial iron deposits. At present, we are working on three ongoing projects:

1) Congenital sideroblastic anemia (CSA): We have developed a growing repository of >250 CSA probands and are using positional cloning and next generation sequencing to define new disease genes. We have identified five novel disease genes and are now modeling these and other previously characterized phenotypes in mouse models.
2) In a multi-institutional collaborative RC2 grant we are systematically evaluating the genetics and genomics of inherited and acquired bone marrow failure disorders, including aplastic anemia, congenital cytopenias, and myelodysplastic syndromes in children.
3) The ubiquitin-proteasome system (UPS) in erythropoiesis: in collaboration with Dr. Dan Finley at Harvard Medical School, we are discovering the targets of UPS components in developing red blood cells.