Iron deficiency is a prevalent nutritional problem throughout the world and in the U.S. population, pregnant women and children are particularly at risk. At the same time, emerging information about human genetics associated with iron overload disorders has shed new light on the prevalence of hemochromatosis in our population.
To better understand how iron balance is maintained, Dr. Wessling-Resnick's research interests focus on elucidating the mechanisms regulating iron transport. Current research efforts include:
1) Ferroportin-1 function and regulation: Macrophages of the reticuloendothelial system (RES) play a major role in iron metabolism by recycling iron from red blood cells. Each day, the RES ingests ~ 360 billion senescent erythrocytes and recycles approximately 25 mg iron back into the circulation. Although this represents the largest flux of iron within the body, how iron is released from macrophages remains poorly defined. Dr. Wessling-Resnick's studies have documented a role for the iron exporter ferroportin-1 (FPN1) in this process. Mutations in FPN1 have been described to promote an iron overload disorder called "ferroportin disease" and current investigations are studying how the known human mutations affect FPN1 function.
2) Relationship between Copper and Iron Metabolism: Copper is also known to play a role in iron recycling from macrophages. For example, copper deficiency induces a microcytic hypochromic anemia that can not be resolved by iron administration and which is paradoxically associated with high levels of iron in the liver. A long-held dogma has been that copper is required for the function of ceruloplasmin, a plasma ferroxidase thought to be responsible for loading iron onto transferrin. However, Dr. Wessling-Resnick's laboratory has recently examined the influence of copper on FPN1 levels and found that high copper increases mRNA and protein. These effects correlate with increased iron efflux. Animal studies from her group have further shown that copper-deficient mice with microcytic hypochromic anemia fail to up-regulate FPN1 mRNA expression as expected. These combined data provide a substantial basis for the hypothesis that copper regulates expression of FPN1 mRNA and protein such that copper sufficiency is required for normal maintenance of iron export function. Thus, a new role for copper in the regulation of macrophage iron recycling has been suggested from Dr. Wessling-Resnick's investigations. Further research will examine the molecular mechanisms responsible for the induction of FPN1 gene expression and iron efflux by this metal.
3) Discovery of Small Molecule Inhibitors of Iron Uptake: One focus on the cellular uptake of iron by the Wessling-Resnick laboratory has been to develop pharmacological tools to help advance our molecular understanding of the pathways involved. Chemical genetics is an emerging field that takes advantage of small molecule libraries to dissect complex biological processes. Dr. Wessling-Resnick has established a cell-based screen that enables the rapid identification of iron transport inhibitors. From initial efforts, 10 small molecule inhibitors of transport have been identified, and ongoing studies focus on characterizing their mechanisms of inhibition.
4) Identification of Transferrin Receptor-2 as an Iron Sensor: Previous studies of a homolog of the transferrin receptor, transferrin receptor-2, suggested that it participated in transferrin-mediated iron uptake. However, human mutations in transferrin receptor-2 are found to promote hemochromatosis, a disorder of iron loading, and these clinical observations are inconsistent with the proposed function in iron uptake. Recent functional studies performed in the Wessling-Resnick laboratory have shown that this receptor displays a rather unique pattern of ligand uptake and delivery to multivesicular bodies that suggests an alternate role in iron metabolism. Dr. Wessling-Resnick has found that protein levels of transferrin receptor 2 are regulated by holo-transferrin in a time- and dose-responsive manner consistent with the iron saturation of the ligand. Using several different animal models of iron status (iron deficiency anemia, iron overload, b-thalassemia and hypotransferrinemia), the Wessling-Resnick established that protein levels of transferrin receptor-2 are regulated by transferrin saturation in vivo such that this receptor appears to sense iron status through interactions with its ligand. Loss of the iron sensor activity helps to explain why defects in the transferrin receptor-2 gene are associated with iron overload disorders.