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Oncology, Hematology, Immunology and Pulmonology

Disorders of the Iron Metabolism


Muckenthaler Research Group


I.  Research areas

Our research investigates the regulatory mechanisms of iron homeostasis and their impairment in common disorders of the iron metabolism. Millions of patients worldwide suffer from either iron overload or iron deficiency. There are still large gaps in our understanding of the molecular mechanisms at the root of these disorders; consequently, effective treatment strategies are scarce. In our research we focus on the regulatory mechanisms of systemic iron homeostasis, which is controlled by the iron-regulating hormone hepcidin and its receptor ferroportin. In order to successfully treat disorders of the iron metabolism, we must prevent both excessive hepcidin expression, which causes iron deficiency anemia, and hepcidin deficiency, which leads to common iron overload disorders. To understand the regulation of hepcidin expression, we use system/network-based analyses and integrate data from transcription and protein analyses with examinations of the mouse model, as well as genome-wide functional RNAi screens. We expect our studies to contribute to clinical progress through such methods as drug repurposing or the identification of biomarkers with diagnostic and prognostic relevance.

Another priority of our research is to understand how the iron export is regulated. The process is controlled by the export protein ferroportin, a membrane protein which binds to hepcidin and is subsequently broken down. We perform genome-wide RNAi screens to identify new factors that determine the makeup and functioning of ferroportin. We have recently succeeded in creating a knock-in mouse that serves as a model for "ferroportin disease": we engineered a mutation in the mouse's ferroportin gene that impairs the bond between hepcidin and ferroportin. With this mouse model, we hope to gain new insights into the (patho)physiological effects of uncontrolled iron export. We will examine how a diminished ferroportin function causes organ-specific imbalances in the iron balance of various cell types (e.g. macrophages and brain cells), and how this contributes to the development of common disorders such as atherosclerosis or neurodegenerative diseases.

II.  Staff

Opens internal link in current windowMartina Muckenthaler

Opens internal link in current windowMuckenthaler group


III.  Publications

D'Alessio F, Hentze MW, Muckenthaler MU: The hemochromatosis proteins hfe, tfr2, and hjv form a membrane-associated protein complex for hepcidin regulation. Opens external link in new windowJ Hepatol 2012, 57(5):1052-60

Castoldi M, Vujic Spasic M, Altamura S, Elmen J, Lindow M, Kiss J, Stolte J, Sparla R, D'Alessandro LA, Klingmuller U, Fleming RE, Longerich T, Grone HJ, Benes V, Kauppinen S, Hentze MW, Muckenthaler MU: The liver-specific microrna mir-122 controls systemic iron homeostasis in mice.Opens external link in new window J Clin Invest 2011;121:1386-1396

Hentze MW, Muckenthaler MU, Galy B, Camaschella C: Two to tango: regulation of Mammalian iron metabolism. Opens external link in new windowCell 2010, 142(1):24-38

Muckenthaler MU: Fine tuning of hepcidin expression by positive and negative regulators. Opens external link in new windowCell Metab 2008, 8(1):1-3.

Ludwiczek S, Theurl I, Muckenthaler MU, Jakab M, Mair SM, Theurl M, Kiss J, Paulmichl M, Hentze MW, Ritter M, Weiss G: Ca2+ channel blockers reverse iron overload by a new mechanism via divalent metal transporter-1. Opens external link in new windowNat Med 2007, 13(4):448-454.

Roy CN, Custodio AO, de Graaf J, Schneider S, Akpan I, Montross LK, Sanchez M, Gaudino A, Hentze MW, Andrews NC, Muckenthaler MU: An Hfe-dependent pathway mediates hyposideremia in response to lipopolysaccharide-induced inflammation in mice. Opens external link in new windowNat Genet 2004, 36(5):481-485.

Muckenthaler M, Roy CN, Custodio AO, Minana B, deGraaf J, Montross LK, Andrews NC, Hentze MW: Regulatory defects in liver and intestine implicate abnormal hepcidin and Cybrd1 expression in mouse hemochromatosis. Opens external link in new windowNat Genet 2003, 34(1):102-107.

 

 

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