Genes that modify Iron loading in mice

描述(申请人提供)：我们的实验室致力于发现对调节铁稳态非常重要的基因，总体目标是了解人类铁代谢紊乱。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。我们还在人类遗传性铁代谢障碍患者中发现了缺陷基因。在这笔赠款的第一个周期中，我们将注意力转向在铁生物学中发挥更微妙作用的新基因的发现，理由是老鼠的遗传学不仅可以作为工具来发现铁运输和调控途径的主要成分，而且还可以作为铁状态修饰物的次要成分。然而，我们仍然缺乏对导致人类铁紊乱患者临床表现多样性的遗传因素的完全了解。进行修饰基因图谱实验的技术在过去五年中得到了改进，允许采用新的方法来解决这个问题。这项提案描述了两个基因发现实验，它们将有助于识别更多的候选基因。我们的总体假设是，改变小鼠体内铁储存的基因也改变了人类铁紊乱的临床表现。为此，我们将(1)识别与组织铁含量可变的高级交叉小鼠品系中明显的数量性状基因座有关的基因，以及(2)利用缺乏Tmprss 6的小鼠对涉及铁稳态的新基因进行遗传筛选，Tmprss 6是铁调节激素海普西丁产生的关键抑制物。这些互补的方法应该会增强我们对铁稳态的理解，重要的是，产生新的候选基因，这些基因决定了铁紊乱的发生率和严重程度的临床变异性。公共卫生相关性：铁超载和铁缺乏症在人类人群中很常见。有强有力的证据表明，遗传因素会影响哪些人受到的影响最严重。这项申请提出了两种互补的方法来识别这些遗传因素，利用了人类和老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