Because iron is an essential component of oxidative metabolism and a potent toxin, an exquisite system for regulating the availability of iron has been developed. The regulation of iron includes insuring its timely delivery, and sequestering it in a rapidly retrievable form. The brain is highly susceptible to iron induced oxidant damage because of its high iron content (equal to that of liver on a per weight basis), high rate of oxidative metabolism and the high phospholipid content of white matter. Our ultimate goal is to determine (1) the mechanism(s) by which iron homeostasis is maintained in the brain and (2) the specific role(s) for iron in brain metabolism. Our research indicates neuroglial cells are primarily responsible for maintenance of iron homeostasis in brain. Normal expression of the iron mobilization protein, transferrin, its mRNA, and receptor are all dependent upon a normal oligodendrocyte population. Iron itself is found predominantly in oligodendrocytes. This proposal has two components with the common goal of determining the role of glial cells in establishing and maintaining iron homeostasis in the brain. The first component using an in vivo approach will characterize 1) the establishment of normal iron homeostasis during development, 2) the effect of a compromised oligodendrocyte population on establishing iron homeostasis, and 3) the effect of trauma on iron homeostasis. This line of research will test the hypothesis that each glial cell subtype can be recruited to regulate iron access to the brain (neurons). In both trauma and in the absence of oligodendrocytes astrogliosis occurs. We predict astrocytes become involved in regulating iron access to brain following invasive gliosis, but not in the absence of an invasive injury. In both cases, microglial cells are predicted to increase iron-uptake, ferritin synthesis, etc. The second phase of this proposal uses an in vitro approach to: 1) characterize the parameters associated with iron metabolism such as iron-uptake and transferrin and ferritin synthesis and secretion in neuroglia, 2) identify feedback mechanisms for iron regulation in neuroglia and identify factors which regulate parameters of iron metabolism in glial cells. The hypothesis for this component is that iron metabolism in neuroglial cells is responsive to changes in the milieu. We will focus on iron/transferrin levels, but will eventually examine the effects of hormones, growth factors, cytotoxins, etc. The predicted results are that iron metabolism in each glial cell type will be altered in a manner specific to that cell type. These results would indicate iron has a unique role in the metabolism of each neuroglial cell and that each neuroglial cell has a unique role in attempting to establish iron balance in the neural environment. This line of research is relevant to a number of neurodegenerative disorders including Alzheimer's, Parkinson's, and Multiple Sclerosis and a broad spectrum of neurobiology covering trophic factors, neuronal and glial cell metabolism, oxidative stress, metal neurotoxicity, myelination and possibly immune functions of neuroglia.
