Using mouse models and tissue culture, Tracey Rouault's Section on Human Iron Metabolism studies mammalian iron metabolism. Rouault previously identified and characterized two major cytosolic iron-regulatory proteins (IRP). Targeted deletion of each IRP in mice revealed that misregulation of iron metabolism due to loss of IRP2 causes functional iron deficiency, erythropoietic protoporphyria, anemia, and neurodegeneration, which adversely affects motor neurons in particular. The Section also focuses on mammalian iron sulfur cluster assembly because of its relevance to IRP1 regulation. Researchers in the Section characterized numerous mammalian genes involved in iron-sulfur cluster synthesis and developed in vitro and in vivo methods to assess iron sulfur cluster biogenesis. The Section's discoveries may promote understanding and treatment of neurodegenerative diseases, especially Parkinson's disease and Friedreich's ataxia and hematologic disorders such as refractory anemias and erythropoietic protoporphyria. The Section discovered that use of Tempol, a stable nitroxide, prevents neurodegeneration in a mouse deficient in IRP2. The Section is pursuing studies to elucidate the pathophysiology and develop treatments for three diseases caused by defects in iron sulfur cluster biogenesis, including Friedreich's ataxia, ISCU myopathy, and GLRX5 sideroblastic anemia as well as mutations in the NFU gene. The section is also working on cancers caused by mutations in succinate dehydrogenase and fumarate hydratase, with emphasis on understanding metabolic remodeling, including changes in iron metabolism that accompany the switch to aerobic glycolysis.
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