Modifiers of Iron Loading in Mice

描述(由申请人提供)：回应通知的申请编号：NOT-OD-09-058通知标题：NIH宣布可为竞争性修订申请提供恢复法案资金。我们的实验室一直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。在父母资助的第一个周期中，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。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。正在进行的父母拨款的竞争性续签申请包括两种基因发现方法，以确定直接或间接调节组织铁在肝脏和脾中积累的其他候选基因。在这份补充资料中，我们建议用假说指导的研究来补充这些研究，研究两个已知基因-DMT1和TFR1-在另一个组织中的作用，这在铁稳态中是重要的。我们将使用我们实验室已经开发的新的、未发表的小鼠模型来研究改变肠道中DMT1和TFR1表达的动态平衡含义。这些互补的方法应该增强我们对铁稳态的理解，重要的是，扩大我们对铁紊乱发生率和严重程度的临床变异性的理解。) 公共卫生相关性：铁超载和铁缺乏症在人类人群中很常见。在这份竞争性补充资料中描述的项目集中在对铁稳态调节中重要的基因进行转基因的新的小鼠模型的特征。这项工作的完成将提供有关铁调节基因的更多知识。这些信息将有助于确定治疗人类铁紊乱的可能治疗靶点。

DESCRIPTION (provided by applicant): Application in response to Notice Number: NOT-OD-09-058 Notice Title: NIH Announces the Availability of Recovery Act Funds for Competitive Revision Applications. 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 the parent 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. The technology to carry out modifier gene mapping experiments has improved over the past five years, allowing novel approaches to this problem. A pending competing renewal application for the parent grant covers two gene discovery approaches to identify additional candidate genes that directly or indirectly modulate tissue iron accumulation in the liver and spleen. In this Supplement, we propose to complement those studies with hypothesis-directed studies of the roles of two known genes - DMT1 and TFR1 - in another tissue that is important in iron homeostasis. We will use novel, unpublished mouse models, already developed in our laboratory, to investigate the homeostatic implications of altering DMT1 and TFR1 expression in the intestine. These complementary approaches should enhance our understanding of iron homeostasis and, importantly, expand our understanding of clinical variability in the incidence and severity of iron disorders. ) PUBLIC HEALTH RELEVANCE: Iron overload and iron deficiency disorders are common in human populations. The projects described in this competitive supplement focus on the characterization of novel mouse models transgenic for genes important in the regulation of iron homeostasis. Completion of this work will provide additional knowledge regarding genes involved in iron regulation. This information will help identify possible therapeutic targets for the treatment of iron disorders in humans.