BRAIN IRON--MOBILIZATION, FUNCTION, REGULATION

Project: Research project

Project Details

Description

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.
StatusFinished
Effective start/end date1/1/9712/31/97

Funding

  • National Institute of Neurological Disorders and Stroke

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