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My laboratory is focused on elucidating the molecular and cellular mechanisms involved in iron homeostasis.
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My laboratory is focused on elucidating the molecular and cellular mechanisms involved in iron homeostasis. Our ultimate goal is to identify new treatment strategies for disorders of iron homeostasis, such as the anemia of chronic disease (including the anemia of chronic kidney disease) and the iron overload disorder hemochromatosis.
Based on its ability to donate and accept electrons, iron is essential for many biological reactions important for living organisms including oxygen transport, cellular respiration, and DNA synthesis. However, this same property makes excess iron toxic by generating free radicals that can damage lipid membranes, proteins, and nucleic acids leading to cell death. As a result, iron levels must be tightly regulated both on a cellular level and systemically.
We have discovered that the bone morphogenetic protein (BMP)-SMAD signaling pathway plays an important role in systemic iron balance by modulating expression of the main iron regulatory hormone hepcidin. A soluble protein secreted by the liver, hepcidin works by blocking the iron channel ferroportin, preventing iron release into the bloodstream from dietary sources and from iron storage cells. Hepcidin expression is induced by inflammation, which is thought to be part of the host defense mechanism to fight infection and cancer by limiting iron availablity. However, in chronic inflammatory states, this leads to a deficiency of iron available for red blood cell production, which is a major contributing factor to the anemia of chronic disease. In contrast, hepcidin deficiency, which causes excessive dietary iron absorption and progressive tissue iron deposition and dysfunction, is the common pathogenic mechanism underlying the iron overload disorder hereditary hemochromatosis.
Our lab has shown that 1) mutations in either the BMP co-receptor hemojuvelin or the ligand BMP6 each lead to hepcidin deficiency and severe hemochromatosis; 2) iron regulates BMP6 ligand expression and SMAD signal transduction in the liver; and 3) modulation of the BMP-SMAD signaling pathway in vivo regulates hepcidin expression and systemic iron balance. Our current focus is working to understand the molecular and cellular mechanisms by which body iron levels are sensed and how this signal is transduced to modulate hepcidin expression and maintain systemic iron balance. We are also testing BMP-hepcidin pathway modulators as new treatment strategies for anemia of chronic disease and hemochromatosis.
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