Grant: Operating Grant

Iron is essential for life, but in some individuals genetic diseases cause an accumulation of too much iron. Also, some kinds of anemias require repeated blood transfusions that lead to progressive iron overload in sensitive tissues. In these circumstances, drugs called chelators are used to control the effects of excess iron. With the identification of new proteins and regulatory pathways, we know much more about iron physiology and toxicity than we did a decade ago. Iron reacts with oxygen in the body to create chemical forms of oxygen that are damaging to cells. We now know that iron can also have additional effects on how cells express their genes, that are unrelated to direct effects of these forms of oxygen. Our current research is directed to distinguishing these different effects, using endpoints of toxicity linked to clinical disease. One aspect of this work is to understand how iron interacts with the energy-producing unit of the cell called the mitochondrion. We have also found that a protein intimately involved in iron metabolism, called IRP-1, binds and reacts with the cell's energy-carrying molecule, ATP. This provides a link between cellular iron levels and energy production, and we are studying the underlying chemistry of this sensing mechanism. Our ultimate objectives are to gain a deeper understanding of how iron causes organ damage, particularly to the heart and liver, and thus to provide additional insight into the design and implementation of therapies with iron chelators.