Genes that modify Iron loading in mice

改变小鼠铁负荷的基因

基本信息

批准号：
8098082
负责人：
NANCY CATHERINE ANDREWS
金额：
$ 36.69万
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 2013-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Our laboratory has focused on discovering genes that are important for regulating iron homeostasis, with the overall goal of understanding human iron disorders. We have used animal models with inherited iron deficiency anemia to identify key components of iron transport pathways. We have also identified genes defective in human patients with inherited iron disorders. In the first cycle of this grant, we turned our attention to the discovery of novel genes that play more subtle roles in iron biology, reasoning that mouse genetics could be used as a tool not only to discover major components of iron transport and regulatory pathways, but also minor components that become important as modifiers of iron status. However, we still lack a complete understanding of genetic factors leading to variability in clinical presentations among human patients with iron disorders. The technology to carry out modifier gene mapping experiments has improved over the past five years, allowing novel approaches to this problem. This proposal describes two gene discovery experiments that will aid in the identification of additional candidate genes. Our overall hypothesis is that genes that modify iron stores in mice also modify the clinical expression of iron disorders in humans. Towards this end, we will (1) identify genes responsible for quantitative trait loci apparent in advanced intercross mouse lines with variable tissue iron content and (2) carry out genetic screens for novel genes involved in iron homeostasis using mice lacking Tmprss6, a key inhibitor of production of the iron regulatory hormone hepcidin. These complementary approaches should enhance our understanding of iron homeostasis and, importantly, yield new candidates for genes that determine clinical variability in the incidence and severity of iron disorders. PUBLIC HEALTH RELEVANCE: Iron overload and iron deficiency disorders are common in human populations. There is strong evidence that genetic factors influence which individuals are most severely affected. This application proposes two complementary approaches to identify those genetic factors, taking advantage of striking similarities in iron metabolism between humans and mice. Completion of this work should aid us in predicting which patients will need aggressive therapy and which can be managed conservatively

描述（由申请人提供）：我们的实验室专注于发现对调节铁稳态至关重要的基因，其总体目标是了解人类铁疾病。我们已经使用具有遗传铁缺乏贫血的动物模型来识别铁运输途径的关键组成部分。我们还确定了遗传性铁疾病的人类患者中有缺陷的基因。在这笔赠款的第一个周期中，我们将注意力转向了在铁生物学中发挥更微妙作用的新基因的发现，认为小鼠遗传学不仅可以用作发现铁运输和调节途径的主要组成部分，而且还可以作为铁状态的修改器变得重要。但是，我们仍然缺乏对遗传因素的完全了解，从而导致人类铁疾病患者的临床表现差异。在过去的五年中，进行修饰符基因映射实验的技术有所改进，从而允许解决这个问题的新方法。该建议描述了两个基因发现实验，这些实验将有助于鉴定其他候选基因。我们的总体假设是，修改小鼠铁储存的基因还改变了人类铁疾病的临床表达。为此，我们将（1）确定在具有可变组织铁含量的高级间折叠小鼠系中显而易见的定量性状基因座的基因，并且（2）使用缺乏TMPRSS6的小鼠进行遗传筛选，用于使用TMPRSS6的小鼠，这是铁调节性激素Hepcidin的关键抑制剂。这些互补方法应增强我们对铁稳态的理解，重要的是，为确定铁疾病发病率和严重程度的临床变异性的基因提供了新的候选。公共卫生相关性：人群中的铁超载和铁缺乏症很常见。有强有力的证据表明，遗传因素会影响哪些人受到最严重影响。该应用提出了两种互补的方法来识别这些遗传因素，利用人类和小鼠之间的铁代谢相似之处。这项工作的完成应有助于我们预测哪些患者需要积极的治疗，哪些可以保守管理