Regulation of systemic iron homeostasis by microRNA-122

• Applicant: Professorin Dr. Martina Muckenthaler
• Subject Area: Pediatric and Adolescent Medicine
• Term: from 2010 to 2013
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 164848204

Systemic Iron homeostasis must be precisely balanced to prevent diseases of iron deficiency and Iron overload, which belong to the most frequent disorders worldwide. The hepatic peptide hormone hepcidin maintains plasma Iron concentrations by controlling duodenal Iron absorption and macrophage Iron release. Hepcidin transcription Is regulated transcriptionally by the hereditary hemochromatosis associated proteins [Hfe, TfR2 and Hfe2 (hemojuvelin)], high erythropoietic activity and Inflammatory cytokines. For the first time we now show that systemic Iron metabolism is also controlled by a non-coding microRNA, miR- 122, which Is abundantly expressed in the liver: efficient and specific depletion of miR-122 In the mouse causes microcytosis, reduced serosal and liver iron levels as well as Increased mRNA expression of hepcidin, HFE and HFE2.The alms of this research proposal are (1) to identify mlR-122 target mRNAs that explain the physiological changes observed in miR-122 depleted mice by applying transcriptomic and proteomic experimental approaches; (2) to test whether miR-122 depletion can be applied to revert murine Iron overload and (3) to study the role of additional miRNAs differentially expressed In response to murine iron overload In maintaining systemic Iron metabolism. We expect to gain fundamental Insights into the regulation of iron homeostasis by miRNAs and the therapeutic potential miRNAs may have in reversing iron overload in a hereditary hemochromatosis disease model.

• DFG Programme: Research Grants