Modifiers of Iron Loading in Mice

小鼠铁负荷的调节剂

基本信息

批准号：
7826407
负责人：
NANCY CATHERINE ANDREWS
金额：
$ 23.07万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-11-18 至 2010-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7826407
关键词：
Accounting Adult Affect Alleles Animal Model Attention Award Biology Budgets C57BL/10 Mouse Candidate Disease Gene Cells Chromosome Mapping Clinical Complement Development Disease Embryonic Development Enterocytes Epithelial Funding Gene-Modified Genes Genetic Genetic Polymorphism Genetic Screening Genetically Engineered Mouse Goals Grant Hemochromatosis Homeostasis Human Inbred Strain Incidence Induced Mutation Inherited Intestines Iron Iron Metabolism Disorders Iron Overload Iron deficiency anemia Knockout Mice Knowledge Laboratories Lead Liver Maps Methods Minor Modeling Mouse Strains Mus Mutation National Institute of Diabetes and Digestive and Kidney Diseases Occupations Pathway interactions Patients Phenotype Play Population Quantitative Trait Loci Recovery Refractory Regulation Regulatory Pathway Reporting Research Research Personnel Role SLC11A2 gene SWR Mouse Scientist Severities Spleen Stimulus Technology Testing Tissues Transferrin Receptor Transgenic Organisms United States National Institutes of Health Work absorption clinical phenotype crypt cell gene discovery hepcidin human TFRC protein improved in vitro Assay insight intestinal epithelium metal transporting protein 1 mouse model novel novel strategies overexpression parent grant public health relevance research study response therapeutic target tool uptake

项目摘要

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.

描述（由申请人提供）：响应通知号的申请：NOT-OD-09-058通知标题：NIH宣布为竞争性修订申请提供恢复ACT资金。我们的实验室专注于发现对于调节铁稳态至关重要的基因，其总体目的是了解人类铁疾病。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。在父母赠款的第一个周期中，我们将注意力转向了新的基因的发现，这些基因在铁生物学中起着更微妙的作用，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。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。对父母赠款的竞争续订申请的竞争性续签涵盖了两种基因发现方法，以识别直接或间接调节肝脏和脾脏组织铁的积累的其他候选基因。在这种补充中，我们建议将这些研究与假设指导的研究相互补充，以研究两个已知基因DMT1和TFR1的作用 - 在另一个在铁稳态中很重要的组织中。我们将使用已经在实验室中开发的新型，未发表的小鼠模型来研究改变肠中DMT1和TFR1表达的稳态含义。这些互补方法应增强我们对铁稳态的理解，并重要的是，我们对铁疾病的发病率和严重程度的临床变异性扩大。）公共卫生相关性：人群中的铁超载和铁缺乏症很常见。这种竞争性补充剂中描述的项目侧重于针对铁稳态调节重要基因的新型小鼠模型转基因的特征。这项工作的完成将提供有关铁调节所涉及的基因的更多知识。这些信息将有助于确定可能治疗人类铁疾病的可能治疗靶标。