DYNAMICS OF CELLULAR IRON MANAGEMENT IN BRAIN

Project: Research project

Project Details

Description

DESCRIPTION: Iron is essential for oxidative metabolism. The brain, which
has a higher rate of oxidative activity than any other organ, has a high
iron requirement. Although the brain requires a ready access to iron, it
resides behind a barrier which limits its access to plasma iron. Presumably
to compensate for the limited access to iron, there are iron rich areas in
the brain and an iron rich population of cells (oligodendrocytes). The
accumulation of iron must be stringently managed, however, as iron is a
potent inducer of free radicals and hence oxidative damage. Oxidative
damage and iron dysregulation have been proposed as part of the pathogenesis
in a number of common neurological disorders including Alzheimer's and
Parkinson's disease and Multiple Sclerosis. The focus of this research
program is to understand the mechanism(s) of iron management in the brain
with the ultimate goals of elucidating the effect of iron management and
mismanagement on neurological function. In this proposal the investigators
specifically focus on two proteins of the iron management system:
transferrin and ferritin. In aim 1, they propose to determine the role of
transferrin in oligodendrocyte physiology and the role of oligodendrocytes
in iron regulation in the brain using a naturally occurring mouse mutant
which does not make transferrin. In aim 2, because ferritin consists of
differing ratios of functionally distinct subunits they will determine the
cellular distribution of ferritin subunits in the developing brain to
elucidate iron utilization among different cell types. In the white matter,
ferritin is expressed in select oligodendrocytes and they will use
retroviral labeling to determine whether the expression of ferritin in those
cells is genetically or epigenetically regulated. Their preliminary
developmental analysis also revealed that the H subunit of ferritin (the one
capable or rapid detoxification of iron) is localized in neuronal nuclei.
Thus in aim 3, they will determine whether ferritin is present in the
nucleus to protect nuclear contents from iron induced oxidative damage or if
it acts in a sequence specific manner. In aim 4 we pursue the novel
observation of a ferritin receptor in brain which may be found predominantly
on oligodendrocytes. Finally, as it is becoming clear the H-ferritin may
have a major role in the normal development of the nervous system and a
continual role as a cytoprotectant we propose in aim 5 to study the in vivo
function of H-ferritin in a mutant mouse in which the H-ferritin gene has
been deleted. The brain clearly has an elegant system for iron management.
Our research program seeks to continue to define the components of this
system. The fine line between iron availability for normal neurological
function versus iron availability for induction of oxidative damage can only
be understood by elucidation of the mechanisms by which iron is regulated.
StatusFinished
Effective start/end date1/1/906/30/01

Funding

  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke
  • National Institute of Neurological Disorders and Stroke

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