Genes that modify Iron loading in mice

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重要的基因，总体目标是了解人类铁失调。我们使用遗传性缺铁性贫血的动物模型来确定铁运输途径的关键成分。我们还在患有遗传性铁疾病的人类患者中发现了基因缺陷。在这项资助的第一个周期，我们将注意力转向发现在铁生物学中发挥更微妙作用的新基因，理由是小鼠遗传学不仅可以用作发现铁运输和调节途径的主要成分的工具，而且还可以用作铁状态的重要修饰剂的次要成分。然而，我们仍然缺乏一个完整的了解遗传因素导致变异的临床表现在人类患者铁失调。在过去的五年中，进行修饰基因定位实验的技术已经得到了改进，允许采用新的方法来解决这个问题。本提案描述了两个基因发现实验，这将有助于鉴定额外的候选基因。我们的总体假设是，改变老鼠体内铁储存的基因也会改变人类铁紊乱的临床表达。为此，我们将(1)在具有可变组织铁含量的高级杂交小鼠系中确定负责数量性状位点的基因；(2)使用缺乏铁调节激素hepcidin产生的关键抑制剂Tmprss6的小鼠，对涉及铁稳态的新基因进行遗传筛选。这些互补的方法应该增强我们对铁稳态的理解，重要的是，为决定铁疾病发病率和严重程度的临床变异性的基因提供新的候选基因。公共卫生相关性：铁超载和铁缺乏症在人群中很常见。有强有力的证据表明，遗传因素影响到受影响最严重的个体。该应用程序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铁代谢的惊人相似性。这项工作的完成将有助于我们预测哪些患者需要积极治疗，哪些患者可以保守治疗

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