Diane McVey Ward

My research has focused on two major areas.  First, I study membrane trafficking specifically looking at vesicle formation and molecules involved in endocytic/secretory vesicle homeostasis.  My lab, in collaboration with Dr. Ryan O’Connell (Pathology), has focused on identifying the mechanisms that regulate exosome formation, release and delivery in vivo and in vitro and how exosomes modulate immune response.  I have also focused my efforts on biochemically and genetically dissecting the mechanisms of vesicle fusion with lysosomes, specifically examining how the loss of the protein Lyst (mutant in Chediak Higashi Syndrome) affects lysosome size.   We have utilized yeast, mammalian cells and mouse models to understand lysosome biology and membrane trafficking.  Understanding lysosome biology has led to the study of how iron is stored in lysosomes and how it is transported out of lysosomes upon iron demand.  This research connects my membrane trafficking research and the second focus in my lab.

The second area of research I have focused on is iron metabolism. Iron is an element required by virtually all organisms. The transport of iron into cells and within cells requires appropriate membrane trafficking. Our studies on iron metabolism have focused primarily on the mechanisms that regulate iron import/export in the model organism Saccharomyces cerevisiae with the goal of identifying homologues in higher eukaryotes. Malregulation of iron metabolism in humans leads to anemia when iron uptake into the body is inadequate and iron overload disease when iron transport cannot be regulated. Work in the lab has led to a mechanistic understanding of both iron overload and the anemia of chronic disease. Mammalian iron metabolism is regulated by a hormone, termed hepcidin, which is secreted by the liver in response to inflammation and iron. We discovered that this hormone binds to the iron exporter Ferroportin and induces the internalization and degradation of Ferroportin resulting in retention of iron in cells. We have identified mitochondrial iron transporters Mitoferrin1 and Mitoferrin2 and partner proteins Abcb10 involved in mitochondrial iron homeostasis. We have generated conditional knockout mice for Mitoferrin1 and Mitoferrin2 and are determining their role in development, red blood cell formation and organ physiology.