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鉴定决定个体在缺铁期间对脑铁缺乏的相对易感性的基因。我们的第一个具体目标是确定30只BXD/TyJ重组近交（Rl）小鼠对脑铁缺乏的易感性！将给小鼠喂食低铁或对照饮食，然后测量脑铁浓度，以确定脑中铁损失程度是否存在遗传差异。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）。QTL分析将使用WebQTL软件进行。QTL将在基于B6 D2 F2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，以调查是否与基因表达的差异相关的菌株之间的VMB铁缺乏的易感性的差异。如果是这样的话，我们的第四个具体目标是将QTL结果与微阵列分析的结果相结合，以选择我们观察到的QTL的候选基因。我们希望这种策略将导致选择强有力的候选基因与可检验的假设，并将增加了解如何个人，遗传为基础的差异影响脑铁调节。在这些R1小鼠品系中鉴定影响脑铁调节的基因将最终使我们更接近于鉴定人类中的同源遗传变体。反过来，这可能导致识别生物标志物和/或药物靶点，用于将来筛查和治疗易感个体。这项研究符合NIH的使命，因为缺铁是一个全球性的健康问题，患病率很高，并且已知在生物化学和行为水平上对大脑功能产生各种负面影响。此外，铁缺乏和脑铁失调一般已牵连在几个神经系统疾病。了解铁缺乏时脑铁调节的个体差异的遗传基础将有助于了解脑中的铁稳态。 与健康的相关性：据估计，全世界有10亿多人缺铁。有证据表明，基于遗传的个体差异存在于缺铁期间大脑中铁损失的易感性中。确定改变脑铁丢失易感性的基因与人类健康有关，因为缺铁对大脑功能的几个方面有负面影响，包括注意力，认知和运动缺陷，改变情绪调节以及神经水平的影响。

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.