Modifiers of Iron Loading in Mice

小鼠铁负荷的调节剂

基本信息

批准号：
7345457
负责人：
NANCY CATHERINE ANDREWS
金额：
$ 41.98万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2004
资助国家：
美国
起止时间：
2004-02-01 至 2009-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7345457
关键词：
Abbreviations Accounting Affect Age Alleles Animals Backcrossings C57BL/10 Mouse Chromosomes Chromosomes, Human, Pair 1 Chromosomes, Human, Pair 13 Chromosomes, Human, Pair 9 Chronic Clinical Congenic Mice Congenic Strain Cytochromes b Data Deposition Elements Gene-Modified Generations Genes Genetic Genetic Polymorphism Genotype Glossary Goals Heart Heme Hemochromatosis Hereditary hemochromatosis Heterozygote Homozygote Human Inbred Strains Mice Individual Intestines Iron Iron-Regulatory Proteins Laboratories Lactoferrin Life Liver Localized Lod Score Major Histocompatibility Complex Maps Mus Mutant Strains Mice Mutation Names Nomenclature Nucleic Acids Organ Oxygenases Pancreas Patients Phenotype Principal Investigator Probability Proteins Quantitative Trait Loci Reading Risk SLC11A2 gene SWR Mouse Severity of illness Spleen Standards of Weights and Measures TFRC gene Text Tissues Title Toxic effect Transferrin Transferrin Receptor absorption base congenic genetic linkage human HFE protein human WNT2 protein in vivo iron metabolism lymphocyte transforming factor metal transporting protein 1 mouse model mutant programs simple sequence length polymorphism

项目摘要

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.

描述（由申请人提供）：血色素瘤病的特征是肠道吸收的慢性增加，导致铁，心脏，胰腺和其他器官的铁沉积过多。纯合为HFE基因突变或FPN基因突变的杂合子的患者处于这些并发症的危险中，但疾病严重程度的差异。这对HFE血色素肿瘤病的研究尤其很好。有些人在生命的第三个十年中患有严重的并发症，而其他人几乎没有或根本没有铁毒性的证据。该疾病的严重程度与组织铁负荷的程度相关。该提案的目的是确定改变铁载表型的基因。这将使用小鼠进行，因为在铁代谢中与人类相似，并且在实验室中可以使用HFE血色素沉着病和FPN血色素沉着症的小鼠模型。初步研究表明，两种近交小鼠菌株C57BL/10和SWR在其组织铁载表型中明显不同。 C57BL/10小鼠在肝脏和脾脏中积聚了很少的铁，而SWR小鼠在两组组织中都会累积大铁负担。定量肝脏和脾铁负载数据用于定量性状基因座（QTL）分析，以识别具有很高可能考虑两种菌株之间铁载的差异的染色体区域。在分析这些菌株之间的十字架的96个N2反向交叉动物中，确定了至少4个QTL（LOD评分2.9-4.0）用于肝铁负荷，并确定了一个QTL（LOD 8.3）以用于脾铁负载。本提案中描述的目的是（1）识别负责这些QTL的基因，（2）确定铁负荷的这些和其他潜在的潜在修饰剂是否还可以修饰患有HFE和FPN血流量的小鼠的表型。