PROGRAM IN MOLECULAR MEDICINE
Researchers in the Program in Molecular Medicine seek to understand mechanisms of disease through analysis of mouse models and research on human patients. Abnormalities of metal homeostasis are under investigation, particularly 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 works on three main projects: (1) copper transport disorders, including X-linked recessive Menkes’ disease and its allelic variant, occipital horn syndrome; (2) the PHACES syndrome of midline developmental abnormalities; and (3) the platelet glycoprotein adhesion complex GPIbalpha-GPIbbeta-GPIX. In the case of Menkes’ disease, the section has been investigating the effects of early diagnosis and treatment by conducting a clinical trial; the section evaluates patient materials using cellular and molecular bench methods. The investigators also studied a female child with PHACES syndrome and documented skewed X chromosome inactivation in the family. In conjunction with the pronounced female gender bias in this condition, the results suggest inheritance of the syndrome as an X-linked lethal trait. The group also continues to pursue characterization of the platelet glycoprotein GP1b beta, attempting to express and purify the protein for crystallographic confirmation of its proposed structure and for generation of neutralizing antibodies that may be active in modulating the platelet adhesion response in patients at risk for thromboembolic events.
Tracey Rouault’s Section on Human Iron Metabolism uses mouse models and tissue culture to study mammalian iron metabolism. Rouault previously identified and characterized two major cytosolic iron-regulatory proteins (IRPs). Targeted deletion of each IRP in mice revealed that misregulation of iron metabolism owing to loss of IRP2 causes functional iron deficiency, erythropoietic protoporphyria, anemia, and neurodegeneration in animals. The section also focuses on mammalian iron-sulfur 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.
