Modifiers of Iron Loading in Mice

描述（由申请人提供）：血色素沉着症的特点是肠道铁吸收慢性增加，导致肝脏、心脏、胰腺等器官铁沉积过多。HFE基因突变纯合子或FPN基因突变杂合子的患者有发生这些并发症的风险，但疾病严重程度存在差异。这在HFE血色素沉着症中已经得到了很好的研究；有些人在生命的第三个十年出现严重的并发症，而另一些人在老年时很少或没有铁中毒的证据。疾病的严重程度与组织铁负荷的程度有关。这一建议的目标是确定基因修改铁负载表型。这将在小鼠身上完成，因为小鼠的铁代谢与人类相似，并且HFE血色素沉着症和FPN血色素沉着症的小鼠模型在实验室中都是可用的。初步研究表明，两种近交系小鼠C57BL/10和SWR在组织铁负荷表型上存在显著差异。C57BL/10小鼠在肝脏和脾脏中积累的铁很少，而SWR小鼠在这两个组织中积累的铁量很大。定量肝脏和脾脏铁负荷数据被用于定量性状位点（QTL）分析，以确定染色体区域有高概率解释两株之间铁负荷差异。在对96只N2回交动物的分析中，至少鉴定出4个与肝脏铁负荷相关的QTL (LOD评分2.9 ~ 4.0)，1个与脾脏铁负荷相关的QTL （LOD评分8.3）。本提案的目的是：(1)鉴定这些qtl的基因，(2)确定这些和其他潜在的铁负载修饰因子是否也能修饰Hfe和Fpn血色素沉着症小鼠的表型。

DESCRIPTION (provided by applicant): Hemochromatosis is characterized by a chronic increase in intestinal iron absorption, leading to excessive iron deposition in the liver, heart, pancreas and other organs. Patients who are homozygous for mutations in the HFE gene or heterozygous for mutations in the FPN gene are at risk for these complications, but there is variability in disease severity. This has been particularly well studied for HFE hemochromatosis; some individuals have severe complications in the third decade of life, whereas others reach old age with little or no evidence of iron toxicity. The severity of the disease correlates with the extent of tissue iron loading. The goal of this proposal is to identify genes that modify iron-loading phenotypes. This will be done using mice, because mice are similar to humans in their iron metabolism, and mouse models of both HFE hemochromatosis and FPN hemochromatosis are available in the laboratory. Preliminary studies show that two inbred mouse strains, C57BL/10 and SWR, differ markedly in their tissue iron loading phenotypes. C57BL/10 mice accumulate little iron in the liver and spleen, while SWR mice accumulate large iron burdens in both tissues. Quantitative liver and spleen iron loading data were used in a quantitative trait locus (QTL) analysis to identify chromosomal regions that have a high probability of accounting for differences in iron loading between the two strains. In the analysis of 96 N2 backcross animals from a cross between these strains, at least 4 QTLs (LOD scores 2.9 - 4.0) were identified for liver iron loading, and one QTL (LOD 8.3) was identified for spleen iron loading. The aims described in this proposal are (1) to identify the genes responsible for these QTLs, and (2) to determine whether these and other potential modifiers of iron loading also modify the phenotypes of mice with Hfe and Fpn hemochromatosis.