Timely and adequate iron acquisition by the brain is a key component of normal neurological function. However, the mechanisms underlying region specific acquisition of iron into brain are unknown despite clear evidence that some regions of the brain are iron rich. The global objective of this line of research is to elucidate the mechanism(s) for brain iron uptake, redistribution and efflux. This objective will be addressed using four experimental paradigms: normal development, dietary iron deficiency, hypotransferrinemia and compromised intracellular ability to store iron. The latter two conditions will use mouse mutants; one has a splicing defect in transferrin and the other is an H-ferritin null mutant. We propose to examine: 1) expression of the iron regulatory protein (IRP) in the brain because it is the physiological indicator of intracellular iron levels. Two IRPs exist which we hypothesize are developmentally regulated and functionally distinct. 2) the hypothesis that transferrin (protein and transcript) expression in brain is responsive to changes in iron availability in iron specific and age dependent manner. 3) the hypothesis that brain Tf is required for redistribution of iron within the brain and efffux of iron from the brain but is only one of three up take mechanisms 4) the distribution and response of a recently discovered ferritin receptor and compare the findings to those for the transferrin receptor. The distribution of the ferritin receptor in brain is directly opposite that of the transferrin receptor suggesting cell specific iron uptake mechanisms. 5) the hypothesis that iron can be delivered to brain via iron-citrate and H- ferritin in addition to Tf. We further hypothesize that the different systems for brain iron delivery can compensate for each other during development but not after receptor expression has reached adult levels. 6) mitochondrial iron dependent enzymes as universal parameters of iron metabolism to determine the effect of the different experimental paradigms on the regional activities of these enzymes. The expected results will demonstrate regional dynamics of the iron acquisition and regulatory systems in brain, reveal novel mechanisms for brain iron mobility, and establish animal models in which the brain iron regulatory system can be manipulated. The significance of the projected findings lie in our ability to predict windows of opportunity or iron repletion therapy for perinatal and postnatal iron deficiency and provide insight into the mechanism by which brain iron mobility may diminish with age and in a number of neurodegenerative diseases.
Showing the most recent 10 out of 21 publications
