Roles of Iron Transport Factor Genes In Iron Absorption

描述（由申请人提供）：铁是人体正常细胞功能所必需的，铁平衡的紊乱可导致危及生命的各种器官的关键表现。由于排出的铁很少，为了防止铁超载，体内的铁量是通过调节肠道铁的吸收来维持的。尽管我们对铁的细胞利用和储存有先进的了解，但铁在粘膜上的转运机制仍然不清楚。我们的长期研究目标是了解肠道铁吸收过程的细胞和分子机制及其对各种病理生理条件的调节反应。最近发现的两个基因hephaestin和ferroportinl （Iregl/MTP1）将有助于了解铁的吸收机制及其调控。虽然hephaestin被认为在铁穿过粘膜基底外膜的运输中起重要作用，但portinl被认为是铁的出口者。这些基因在肠道铁吸收过程中的确切功能目前尚不清楚。因此，本探索性R21提案的主要目标是了解和定义hephaestin和ferroportinl在肠道铁吸收过程中的功能。在这个R21项目中，我们将利用人类肠道细胞系来研究这两个基因的功能。我们将用编码人类hephaestin和ferroportinl的基因转染人肠道Caco-2细胞，以确定它们在肠道铁吸收过程中的作用。具体而言，这些研究将：(1)表征hephaestin和ferroportinl在人肠道细胞中的细胞位置和铁转运功能；(2)确定hephaestin和ferroportinl的关联，以及它们如何利用人肠道Caco-2细胞过表达hephaestin但缺乏ferroportinl（或hephaestin缺乏但过表达ferroportinl）来影响铁的转运。这项研究的结果将为理解调节肠道铁吸收的细胞和分子机制提供重要信息。这项R21研究的完成将是实现我们长期目标的关键一步。

DESCRIPTION (provided by applicant): Iron is essential for normal cellular functions in human body and the disturbances of iron homeostasis can cause life-threatening critical manifestations in various organs. Since very little iron is excreted, to prevent iron overload, the amount of iron in the body is tightly maintained by regulating intestinal iron absorption. Despite our advanced knowledge on the cellular utilization and storage of iron, the mechanism of iron transfer across the mucosa still remains unclear. The long-term goals of our research are to understand the cellular and molecular mechanism of the intestinal iron absorption processes and its regulation response to the various patho-physiological conditions. Recent discovery of two genes, hephaestin and ferroportinl (Iregl/MTP1), will help understand the mechanism of iron absorption and its regulation. While hephaestin was proposed to have an important role in iron transport across the basolateral membrane of mucosa, ferroportinl was expected to function as an iron exporter. The exact functions of these genes in the processes of intestinal iron absorption currently remain unknown. Thus, the primary goals of this exploratory R21 proposal are to understand and define functions of hephaestin and ferroportinl in the intestinal iron absorption processes. In this R21 project, we will utilize the human intestinal cell line to study the function of these two genes. We will transfect human intestinal Caco-2 cells with the genes encoding human hephaestin and ferroportinl to determine their roles in the processes of intestinal iron absorption. Specifically, these studies will: (1) characterize the cellular location and iron transport function of hephaestin and ferroportinl in human intestinal cell, and (2) determine the association of hephaestin with ferroportinl and how they might interact to affect the transfer of iron utilizing human intestinal Caco-2 cells overexpressing hephaestin but lacking ferroportinl (or hephaestin deficient but overexpressing ferroportinl). Results from this proposed study will provide critical information towards understanding the cellular and molecular mechanisms of regulating intestinal iron absorption. The completion of the proposed study in this R21 will be a critical step in achieving our long-term goals.