The Leibold Lab is interested in how eukaryotic cells sense and respond to iron and how dysregulation of iron metabolism leads to disease. Iron is essential due to its presence in proteins involved oxygen transport, DNA synthesis and respiration. Regulation of cellular iron content is critical as excess iron catalyzes the generation of free radicals while iron deficiency causes cell cycle arrest and reduces cell proliferation. Dysregulation of iron homeostasis caused by iron deficiency or iron excess leads to common hematological, neurodegenerative and metabolic diseases. All organisms have thus developed specialized mechanism to sense, acquire and store iron.
Vertebrate cellular iron metabolism is controlled post-transcriptionally by iron regulatory proteins 1 and 2 (IRP1 and IRP2). IRPs bind to RNA stem-loop structures in the mRNAs of proteins involved in iron uptake, sequestration and export and regulate either the translation or stability of the mRNA. Our research is specifically focused on understanding the mechanism by which IRP2 senses iron and how IRP2 deficiency causes disease. IRP2 is regulated by iron-dependent proteolysis and iron-dependent phosphorylation during the cell cycle.
Our goal is to understand how IRP2 affects cell cycle progression and cellular proliferation. We are interested in understanding the mechanisms by which IRP2 deficiency leads to disease. Mice with a targeted deletion of the Irp2 gene develop anemia, neurological disease associated with altered brain iron and diabetes. Our current project is focused on determining the mechanism responsible for diabetes in IRP2 deficient mice. Another research area is using genetic approaches in Caenorhabditis elegans to identify novel iron-regulated genes and pathways that are conserved in mammals.