IRON TRANSPORT IN A MURINE MODEL OF HEMOCHROMATOSIS

说明(改编自应用程序) 遗传性血色沉着症是一种常见的常染色体隐性遗传性疾病。 以饮食中铁的过度吸收为特征的铁代谢。HH是 由HFE突变引起，HFE是一种在稳定的环境中发现的MHC I类蛋白 十二指肠组织中β2-微球蛋白和转铁蛋白受体的相关性研究 隐窝细胞。HFe在调节膳食铁吸收中的重要作用 被我们的观察证实，HFe基因敲除小鼠表现出过多的铁 正在装车。HFe调节肠道铁吸收的机制是 未知。我们的工作假设是，HFE 1)的中断会降低 十二指肠隐窝细胞摄取和/或增加血浆铁的释放 从而2)减少隐窝细胞调节铁池，3)增加 铁转运蛋白DMT1在子代肠上皮细胞中的顶端表达 反过来，增加饮食中铁的摄取量。我们的总体目标是了解 高铁调节膳食铁转运的机制。我们将继续追查此事 通过使用两只新的小鼠检验工作假说的每一步来实现目标 一种是HFE基因被破坏，另一种是 被过度表达了。两个HFE等位基因正常的对照组将是 分析-一组缺铁，另一组铁充足。在建议的 HFE基因敲除和过表达小鼠(及正常对照)的研究 等位基因)我们有4个明确的目标： 1)通过以下方法测量转铁蛋白结合铁和离子铁的吸收和释放 十二指肠隐窝细胞。 2)量化十二指肠的铁反应元素结合活性 隐窝绒毛轴。 3)检测DMT1在十二指肠肠上皮细胞中的表达。 4)测定十二指肠铁摄取和转运。 这些研究应该通过以下方式提高我们对HH发病机制的理解 定义调节膳食铁吸收的分子事件和 HFE功能丧失的后果。我们希望这些发现能给我们带来新的启示。 预防HH和其他饮食过量疾病铁负荷的方法 铁吸收。

DESCRIPTION (adapted from the application) Hereditary hemochromatosis (HH) is a common autosomal recessive disorder of iron metabolism characterized by excess absorption of dietary iron. HH is caused by mutation of HFE, a MHC class I-like protein found in stable association with Beta-2-microglobulin and transferrin receptor in duodenal crypt cells. An essential role for HFE in regulating dietary iron absorption was confirmed by our observation that HFE knockout mice manifest excess iron loading. The mechanism by which HFE modulates intestinal iron absorption is unknown. Our working hypothesis is that disruption of HFE 1) decreases the uptake and/or increases the release of plasma iron by duodenal crypt cells, and thereby 2) decreases the crypt cell regulatory iron pool, which 3) increases apical expression of the iron transporter DMT1 in daughter enterocytes, which in turn, 4) increases dietary iron uptake. Our broad goal is to understand the mechanism by which HFE modulates dietary iron transport. We will pursue this goal by testing each step of the working hypothesis using two novel murine models-one in which the HFE gene has been disrupted, and the other in which it has been overexpressed. Two control groups with normal HFE alleles will be analyzed-one group iron-deficient and the other iron-replete. In the proposed studies on HFE knockout and overexpressing mice (and controls with normal alleles) we have 4 specific aims: 1) Measure the uptake and release of transferrin-bound and ionic iron by duodenal crypt cells. 2) Quantify iron-responsive element binding activity along the duodenal crypt-villus axis. 3) Characterize DMT1 mRNA and protein expression in duodenal enterocytes. 4) Measure duodenal iron uptake and transfer. These studies should improve our understanding of the pathogenesis of HH by defining the molecular events regulating dietary iron absorption and the consequences of functional loss of HFE. We hope the findings suggest novel approaches to prevent iron loading in HH and other diseases with excess dietary iron absorption.