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Molecular Medicine Program
Researchers in the Program in Molecular Medicine seek to understand mechanisms of disease through analysis of mouse models and studies of human patients. Abnormalities of metal homeostasis are under investigation, including the role of iron misregulation in the pathogenesis of neurodegeneration and refractory anemias and the role of copper transport abnormalities in Menkes disease and related conditions.
Stephen Kaler’s Unit on Pediatric Genetics investigates the copper transport disorders Menkes disease and its allelic variant, occipital horn syndrome—in particular the effects of early diagnosis and treatment. In an ongoing clinical trial, the Unit evaluates patient materials with cellular and molecular bench methods. Recently, the Unit published a study demonstrating that initiation of copper replacement therapy in neonatal Menkes disease patients shortly after birth greatly improves neurological outcomes. In a separate project, the Unit documented skewed X-chromosome inactivation in the family of a female child with PHACES syndrome—a disorder manifesting midline developmental abnormalities. In conjunction with the pronounced female gender bias in this condition, the results suggest inheritance of the syndrome as an X-linked lethal trait. With regard to the platelet glycoprotein adhesion complex GPIbalpha-GPIbbeta-GPIX, the Unit continues its efforts to express and purify the platelet glycoprotein GP1b beta for crystallography and for generating neutralizing antibodies that might modulate the platelet adhesion response in patients at risk for thromboembolic events.
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. The Section also focuses on mammalian ironsulfur cluster assembly because of its relevance to IRP1 regulation. Researchers characterized numerous mammalian genes involved in iron-sulfur cluster synthesis and developed in vitro and in vivo methods to assess cluster biogenesis. The Section’s discoveries may promote understanding and treatment of neurodegenerative diseases, especially Parkinson’s disease and Friedreich ataxia and hematologic disorders such as refractory anemias and erythropoietic protoporphyria. The Section recently discovered that use of Tempol, a stable nitroxide, prevents neurodegeneration in a mouse model.