Marianne Wessling-Resnick

Department of Genetics and Complex Diseases
Harvard School of Public Health
Division of Biological Sciences
Building 2, Room 205
665 Huntington Avenue
Boston, MA 02115
Tel: (617) 432-3267
Fax: (617) 432-5236
Email: wessling@hsph.harvard.edu
5 postdoctoral fellows, 1 graduate student

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. Our laboratory studies how the iron exporter ferroportin-1 (Fpn1) plays a role in this process. Mutations in Fpn1 have been described to promote an iron overload disorder called "ferroportin disease" and our current investigations are examining how known human mutations affect Fpn1 function during the erythrophagocytic cycle.

Other studies in our laboratory have recently characterized a rather unique pattern of ligand uptake and delivery to multivesicular bodies by transferrin receptor 2 (TfR2). We have also found that protein levels of TfR 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, we have 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 genetic defects in the transferrin receptor-2 gene are associated with iron overload disorders. We continue to explore the regulation and function of this interesting receptor.

Another area of research in our laboratory employs chemical genetics to identify iron transport inhibitors. These efforts have led to the discovery of ten novel small molecule inhibitors of non-transferrin bound iron uptake. Ongoing efforts focus on characterizing the activity of these compounds, as well as developing new approaches and strategies to use small molecule probes to study iron transport and its regulation.

References:

• Brown, J.X., Buckett, P.D., and Wessling-Resnick, M. (2004) Identification of small molecule inhibitors that distinguish between non-transferrin bound iron uptake and transferrin-mediated iron transport. Chem. Biol. 11: 407-416.
• Robb, A.D., Ericsson, M., and Wessling-Resnick, M. (2004) Transferrin receptor-2 mediates a biphasic pattern of transferrin uptake associated with ligand delivery to multivesicular bodies. Am. J. Physiol. Cell Physiol. 287: C1769-75.
• Robb, A.D., and Wessling-Resnick, M. (2004) Regulation of transferrin receptor 2 protein levels by transferrin. Blood 104: 4294-9
• Knutson, M., Oukka, M., Koss, L.M., Aydemir, F., and Wessling-Resnick, M. (2005) Iron release from macrophages after erythrophagocytosis is up-regulated by ferroportin 1 overexpression and down-regulated by hepcidin. Proc. Natl. Acad. Sci. U.S.A. 102:1324-8