Modifiers of Iron Loading in Mice

描述（由申请人提供）：血色病的特征是肠铁吸收的慢性增加，导致肝脏、心脏、胰腺和其他器官中过量的铁沉积。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。对于HFE血色素沉着症，这一点已经得到了很好的研究;一些人在生命的第三个十年中有严重的并发症，而另一些人在年老时几乎没有或没有铁毒性的证据。疾病的严重程度与组织铁负荷的程度相关。这项建议的目标是确定修改铁负载表型的基因。这将使用小鼠完成，因为小鼠在铁代谢方面与人类相似，并且实验室中可获得HFE血色病和FPN血色病的小鼠模型。初步研究表明，两个近交系小鼠品系，C57 BL/10和SWR，在其组织铁负荷表型显着不同。C57 BL/10小鼠在肝脏和脾脏中积累很少的铁，而SWR小鼠在这两种组织中积累大量的铁负荷。定量肝和脾铁负荷数据中使用的数量性状基因座（QTL）分析，以确定染色体区域，占两个菌株之间的铁负荷的差异具有很高的概率。在对96只来自这些品系之间杂交的N2回交动物的分析中，至少鉴定了4个QTL（LOD得分2.9 - 4.0）用于肝脏铁负荷，并且鉴定了1个QTL（LOD 8.3）用于脾脏铁负荷。本提案中描述的目的是（1）鉴定负责这些QTL的基因，以及（2）确定这些和其他铁负荷的潜在修饰剂是否也修饰患有Hfe和Fpn血色素沉着症的小鼠的表型。

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.