Jerry Kaplan, M.D.
Assistant Vice President for Basic Science
30 North 1900 East RM 5R472
CAMPUS
(801) 581-7427
Email: jerry.kaplan@path.utah.edu
Jerry Kaplan's Lab
Read More About Dr. Kaplan
Our research is focused on understanding how defects in iron metabolism result in human disease. Iron is an essential element for almost all organisms. It is used as a catalytic group on enzymes and as a substrate for heme. While iron is essential, high levels of iron can be toxic. Consequently, all organisms tightly control iron acquisition, as malregulation or iron uptake leads to disease. Too little iron results in anemia and cognitive defects. Too much iron leads to iron overload disease. A genetic form of iron overload disease, HFE Hereditary Hemochromatosis is the most common genetic disease of Caucasian males. We have taken two different approaches to understand iron metabolism. The first approach is to identify genes required for iron acquisition and for the regulation of iron acquisition. To this end we have taken advantage of yeast to identify genes required for iron metabolism. Yeast has tractable genetics and many of the same genes that are in humans are present in yeast. We have identified yeast genes that encode iron transporters and using those genes we have found both human and plant counterparts. One of the human counterparts we discovered was responsible for iron storage. In particular in this past year we discovered a new pathway for the regulation of iron metabolism genes in yeast. We determined that heme affects the expression of genes that encode iron transporters and that in the absence of heme iron and copper transporters are not synthesized.
Our second approach is to directly look at those genes that are not expressed in yeast. Those genes encode proteins that both transport iron between cells and regulate that transport. In the past two years we have identified a regulatory circuit that underlies iron homeostatis in humans. In response to inflammation the liver secretes a hormone hepcidin, which regulates iron entry into plasma. Chronic inflammation leads to anemia due to lack of iron. The seminal work characterizing this disorder (the Anemia of Chronic Disease) was perfomed by Drs. Wintrobe and Cartwright over 50 years ago at the University of Utah. We discovered that the hormone hepcidin binds to an iron transporter (ferroportin) and leads to its degradation. Thus, high levels of hormone result in low levels of iron transport. Our finding provides a molecular explanation for the result from a lack of hepcidin. This past year we described how mutations in the iron exporter Ferroportin result in a genetic iron overload disease Hereditary Hemochromatosis Type IV.