The long term objective of this study is to identify genes that determine an individual's relative susceptibility to brain iron deficits during iron deficiency. Our first specific aim is to determine the susceptibility to brain iron deficits for 30 BXD/TyJ recombinant inbred (Rl) strains of mice! Mice will be fed a low-iron or control diet, then brain iron concentrations will be measured to see if genetically-based differences exist in the extent of iron loss in the brain. Our second specific aim is to identify quantitative trait loci (QTL) associated with differences in susceptibility to brain iron deficits. QTL analysis will be conducted using WebQTL software. QTL will be subjected to independent confirmation in a B6D2F2 marker-based selection experiment. Our third specific aim is to use microarray analysis to investigate whether differences in the susceptibility to VMB iron deficits between strains are associated with differences in gene expression. If this is the case, our fourth specific aim is to combine the QTL results with results of the microarray analysis to select candidate genes for the QTL we observed. We expect that this strategy will lead to the selection of strong candidate genes with testable hypotheses and will increase the understanding of how individual, genetically based differences influence brain iron regulation. Identifying genes that influence brain iron regulation in these Rl strains of mice will ultimately bring us closer to identifying homologous genetic variants in humans. This, in turn, may lead to the identification of biomarkers and/or drug targets for the screening and treatment of susceptible individuals in the future. This research is in line with the mission of the NIH as iron deficiency is a global health problem with high prevalence and is known to exert a variety of negative effects on brain functioning at the biochemical and behavioral levels. Moreover, iron deficiency and brain iron misregulation in general have been implicated in several neurological diseases. Understanding the genetic basis for individual differences in brain iron regulation during iron deficiency will aid in understanding iron homeostasis in the brain. ? ? Relevance to Health: More than one billion people worldwide are estimated to be iron deficient. Evidence suggests that genetic-based, individual differences exist in the susceptibility to iron loss in the brain during iron deficiency. Determining genes that alter susceptibility to brain iron loss is relevant to human health as iron deficiency has negative effects on several aspects of brain functioning, including attentional, cognitive, and motor deficits, altered emotional regulation, and effects at the neural level. ? ? ?
| Jellen, L C; Lu, L; Wang, X et al. (2013) Iron deficiency alters expression of dopamine-related genes in the ventral midbrain in mice. Neuroscience 252:13-23 |
| Yin, Lina; Unger, Erica L; Jellen, Leslie C et al. (2012) Systems genetic analysis of multivariate response to iron deficiency in mice. Am J Physiol Regul Integr Comp Physiol 302:R1282-96 |
| Jellen, Leslie C; Unger, Erica L; Lu, Lu et al. (2012) Systems genetic analysis of the effects of iron deficiency in mouse brain. Neurogenetics 13:147-57 |
| Jellen, Leslie C; Beard, John L; Jones, Byron C (2009) Systems genetics analysis of iron regulation in the brain. Biochimie 91:1255-9 |
