Iron is required for the function of many proteins that are needed for biological processes, including electron transfer, oxygen transport and DNA synthesis. Iron is toxic to organisms due to its ability to generate free radicals that oxidize macromolecules. The accumulation of excess iron can result in cirrhosis, cardiomyopathy, diabetes mellitus, neurodegeneration, and increased risk of cancer, while iron deficiency can result in permanent neurocognitive and motor impairment in children. Because of the deleterious yet beneficial effects of iron, mammalian cells have developed highly regulated mechanisms to sense, acquire and store iron. Our goal is to determine the mechanisms by which the iron-regulatory proteins 1 and 2 (IRP1 and IRP2) control iron homeostasis. IRP1 and IRP2 bind to iron-responsive elements (IREs) in mRNAs encoding proteins involved in uptake, sequestration and utilization of iron, and regulate their translation and degradation. Although IRP1 and IRP2 have similar sequences, they differ with respect to their binding affinities for individual mRNA's and the mechanism by which their activity is regulated by iron. Furthermore, Irp2-/- mice develop neurodegenerative disease, while Irp1-/- mice display no obvious abnormalities. We plan to determine the distinct roles of IRP1 and IRP2 and the mechanisms by which they regulate cellular iron metabolism.
Our specific aims are: 1) to determine specific roles of IRP1 and IRP2 in iron homeostasis, we will study mice in which endogenous coding sequences of the mouse Irp2 gene are deleted and replaced with those of Irp1. Our goal is to use these mice to determine if the replacement of IRP2 coding sequences with those of IRP1 can rescue abnormalities in Irp2-/- mice, 2) to determine the mechanism that signals IRP2 for iron-mediated degradation, and 3) to determine the physiological significance of IRP2 phosphorylation.
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