Issues in Metal Homeostasis

Our lab is interested in multiple issues relating to iron metabolism in animals and humans. From the practical viewpoint, iron is an important nutrient, but its ability to act in the ferrous and ferric state also makes it toxic. Thus iron deficiency is the most frequent disorder in the world and hereditary hemochromatosis (HH) is the most common Mendelian disorder in the USA.

The research is related to differentiation on the fundamental level and to genetic and acquired diseases on the applied level. Recently new vistas have opened for the anemia of chronic diseases for example, leading to re-examination of how microbes and their hosts (us) fight for iron. We approach these issues by working on rodent models and focus now on the Belgrade rat plus a series of genetically engineered mice. The rat has a hypochromic, microcytic anemia inherited as an autosomal recessive. The defect is in an iron transporter called DMT1 (previously Nramp2 or DCT1) that is responsible for iron uptake by enterocytes and immature red blood cells and is also responsible for iron exiting endosomes in the transferrin cycle. The rats appear to have a severe iron deficiency. Although dietary iron and iron injection increase the number of RBCs, they do not restore the RBCs nor the rat itself to a normal phenotype. Past students have worked on the nature of the anemia, on the response to iron supplementation, on gastrointestinal iron uptake or on the serum levels of iron and iron binding capacity, on the levels of iron regulatory proteins (IRPs) in tissues.

Recent discoveries show that DMT1 is ubiquitous and responsible for transport of multiple other metals such as Mn and Ni. It occurs in the kidney, brain and lung at even higher levels than in the GI tract or in erythroid cells. It also has multiple isoforms and we have cloned them and developed cell lines that express high levels of particular isoforms. We have specific antibodies to the isoforms and assays for each of the mRNAs too. Future projects in this lab will continue to address whether DMT1 is dysregulated in HH, tackle how DMT1 functions in neurons, pneumocytes and other tissues, look at isoforms of DMT1 under circumstances where we suspect that they must have different functions from one another, and examine DMT1's relevance to iron metabolism and human disease. Because we recently cloned the gene and identified the mutation, a number of molecular and cellular approaches can now be used. As evidence indicates that metal ion homeostasis fails in Huntington's Disease, Alzheimer's Disease and Parkinson's Disease, research on DMT1 has opened new vistas for these disorders too.

• Only after a mutual agreement after an interview for admission to the lab will a student receive a list of several review papers and 1 or 2 research papers to read. Assimilating such papers is a real challenge for undergraduate researchers. After the student does so, they will receive a list of projects from which to choose. After the choice, more reviews or papers may be available depending on the choice. Access to posters by prior students on earlier work on the project could also develop.

Biochemistry