Analysis of Genetic Variation in Brain Iron Regulation during Iron Deficiency

描述（由申请人提供）：本研究的长期目标是确定在缺铁期间决定个体对脑铁缺陷相对易感性的基因。我们的第一个具体目标是确定30个BXD/TyJ重组近交系小鼠对脑铁缺陷的易感性！研究人员将给小鼠喂食低铁或控制饮食，然后测量脑铁浓度，以观察大脑中铁流失程度是否存在基于基因的差异。我们的第二个具体目标是确定与脑铁缺乏易感性差异相关的数量性状位点（QTL）。使用WebQTL软件进行QTL分析。QTL将在基于B6D2F2标记的选择实验中进行独立确认。我们的第三个具体目标是使用微阵列分析来研究菌株之间对VMB铁缺陷的易感性差异是否与基因表达差异有关。如果是这样的话，我们的第四个具体目标是将QTL结果与微阵列分析结果结合起来，为我们观察到的QTL选择候选基因。我们期望这一策略将导致具有可测试假设的强候选基因的选择，并将增加对个体遗传差异如何影响脑铁调节的理解。在这些小鼠的Rl品系中识别影响脑铁调节的基因将最终使我们更接近于识别人类的同源遗传变异。反过来，这可能会导致未来筛选和治疗易感个体的生物标志物和/或药物靶点的鉴定。缺铁是全球普遍存在的健康问题，在生化和行为层面对大脑功能产生各种负面影响，因此此次研究符合NIH的使命。此外，铁缺乏和脑铁调节失调通常与几种神经系统疾病有关。了解缺铁期间脑铁调节个体差异的遗传基础将有助于理解脑铁稳态。

DESCRIPTION (provided by applicant): 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.