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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS034280-04
Application #
6139520
Study Section
Nutrition Study Section (NTN)
Program Officer
Nichols, Paul L
Project Start
1997-01-01
Project End
2001-12-31
Budget Start
2000-01-01
Budget End
2001-12-31
Support Year
4
Fiscal Year
2000
Total Cost
$277,477
Indirect Cost
Name
Pennsylvania State University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
129348186
City
Hershey
State
PA
Country
United States
Zip Code
17033
Connor, James R (2003) Iron transport proteins in the diseased brain. J Neurol Sci 207:112-3
Han, Jian; Day, Jonathan R; Connor, James R et al. (2003) Gene expression of transferrin and transferrin receptor in brains of control vs. iron-deficient rats. Nutr Neurosci 6:1-10
Siddappa, Asha Jyothi M; Rao, Raghavendra B; Wobken, Jane D et al. (2003) Iron deficiency alters iron regulatory protein and iron transport protein expression in the perinatal rat brain. Pediatr Res 53:800-7
Thompson, Khristy; Menzies, Sharon; Muckenthaler, Martina et al. (2003) Mouse brains deficient in H-ferritin have normal iron concentration but a protein profile of iron deficiency and increased evidence of oxidative stress. J Neurosci Res 71:46-63
Beard, John L; Wiesinger, Jason A; Connor, James R (2003) Pre- and postweaning iron deficiency alters myelination in Sprague-Dawley rats. Dev Neurosci 25:308-15
Beard, John (2003) Iron deficiency alters brain development and functioning. J Nutr 133:1468S-72S
Strube, Yi Ning J; Beard, John L; Ross, A Catharine (2002) Iron deficiency and marginal vitamin A deficiency affect growth, hematological indices and the regulation of iron metabolism genes in rats. J Nutr 132:3607-15
Malecki, Elise A; Cable, Edward E; Isom, Harriet C et al. (2002) The lipophilic iron compound TMH-ferrocene [(3,5,5-trimethylhexanoyl)ferrocene] increases iron concentrations, neuronal L-ferritin, and heme oxygenase in brains of BALB/c mice. Biol Trace Elem Res 86:73-84
Siddappa, Asha Jyothi M; Rao, Raghavendra B; Wobken, Jane D et al. (2002) Developmental changes in the expression of iron regulatory proteins and iron transport proteins in the perinatal rat brain. J Neurosci Res 68:761-75
Han, Jian; Day, Jonathan R; Connor, James R et al. (2002) H and L ferritin subunit mRNA expression differs in brains of control and iron-deficient rats. J Nutr 132:2769-74

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