Divalent Metal-ion Transporter 1 as a Therapeutic Target to Optimize Intestinal Iron Transport

二价金属离子转运蛋白 1 作为优化肠道铁转运的治疗靶点

基本信息

  • 批准号:
    9314563
  • 负责人:
  • 金额:
    $ 51.35万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2016
  • 资助国家:
    美国
  • 起止时间:
    2016-07-15 至 2021-04-30
  • 项目状态:
    已结题

项目摘要

Project Summary Iron is an essential nutrient for humans, yet excess iron is toxic. As such, iron overload and iron deficiency result in severe homeostatic perturbations. Iron overload is most frequently associated with hereditary hemochromatosis (HH), which afflicts ~1:250 adults in the U.S. Tissue iron accumulation in patients with HH leads to arthritis, osteoporosis, liver damage and cancer, cardiomyopathy, diabetes mellitus, and impotence. HH results from impaired production of the iron-regulatory hormone hepcidin (HEPC) or as a result of mutations in the HAMP gene (encoding HEPC). HEPC limits intestinal iron absorption. Moreover, reduced HEPC synthesis underlies the iron loading that typifies disorders of ineffective erythropoiesis (e.g. β- thalassemia intermedia [βTI]). In HH and βTI, intestinal iron absorption is thus excessive. This leads to pathological iron overload since humans cannot excrete excess iron. Regulation of intestinal iron absorption is thus critical to properly control body iron levels. Dietary iron exists primarily as inorganic (or nonheme) iron. Ferric (Fe3+) nonheme iron is first reduced to Fe2+, imported into duodenal enterocytes by divalent metal-ion transporter 1 (DMT1), exported by ferroportin 1 (FPN1) and oxidized for binding to transferrin. DMT1 is the primary intestinal iron importer under basal conditions, but the relative contribution of DMT1 to iron accumulation in HH and βTI is unknown. In Aim 1, we will thus test the hypothesis that DMT1 is required for iron loading in mouse models of HH (HEPC KO) and βTI (Hbbd3th; with a mutated β major globin [Hbb- b1]) gene. We will thus generate HEPC and Hbb-b1 KO mice that are also lacking intestinal DMT1. We further hypothesize that decreasing DMT1 expression will prevent iron loading in HH and βTI. Accordingly, we have developed ginger nanoparticle-derived lipid vectors (GNLVs) which can deliver functional DMT1 siRNA to the mouse duodenum in vivo (~40% reduction in DMT1 expression). In Aim 2, this GNLV delivery system will be tested for its ability to prevent iron loading in rodent models of HH and βTI. Furthermore, iron deficiency (ID) is also common in the U.S., afflicting ~8 million young women, and 700,000 infants. ID frequently occurs when absorption of dietary iron does not meet the body’s demand. ID most commonly occurs as a consequence of rapid growth, pregnancy, menstrual blood loss, malabsorptive disorders, gastric bypass surgery and chronic inflammation. ID symptoms include anemia, impaired cognition, decreased immune response, and fatigue. During ID, DMT1 increases Cu transport into duodenal enterocytes and emerging data demonstrates that copper is critical to support iron repletion during states of deficiency. The mechanism that transforms DMT1 into a copper transporter is, however, unknown. Aim 3 will thus test the hypothesis that the DMT1 protein is post-translationally modified during iron deficiency, allowing Cu transport. Plausible alternative hypotheses may also be considered. Overall, this DMT1-focused investigation is likely to potentiate the development of novel therapeutic and nutritional approaches to modulate intestinal iron absorption in at-risk individuals.
项目总结

项目成果

期刊论文数量(0)
专著数量(0)
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会议论文数量(0)
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James F. Collins其他文献

<span class="small-caps">dl</span>-2-[3,4-<sup>3</sup>H]Amino-4-phosphonobutyrate binding sites in the rat hippocampus: distribution and possible physiological role
  • DOI:
    10.1016/0006-8993(87)90596-8
  • 发表时间:
    1987-09-01
  • 期刊:
  • 影响因子:
  • 作者:
    Steven P. Butcher;Peter J. Roberts;James F. Collins
  • 通讯作者:
    James F. Collins
Independence of sensitivity on different foveal areas
ACELL November 46/5
ACELL 十一月 46/5
  • DOI:
  • 发表时间:
    1999
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Y. Guner;P. Kiela;XU Hua;James F. Collins;F. Ghishan
  • 通讯作者:
    F. Ghishan
Aminoacyltransferase II from Rat Liver: I. PURIFICATION AND ENZYMATIC PROPERTIES
  • DOI:
    10.1016/s0021-9258(18)62428-7
  • 发表时间:
    1971-02-25
  • 期刊:
  • 影响因子:
  • 作者:
    Samuel Raeburn;James F. Collins;Hong Mo Moon;Elizabeth S. Maxwell
  • 通讯作者:
    Elizabeth S. Maxwell
Molecular cloning, promoter characterization, and gene structure of murine intestinal type IIB sodium-phosphate cotransporter gene
  • DOI:
    10.1016/s0016-5085(00)80270-x
  • 发表时间:
    2000-04-01
  • 期刊:
  • 影响因子:
  • 作者:
    Kayo Arima;James F. Collins;Eric R. Hines;Liqun Bai;Fayez K. Ghishan
  • 通讯作者:
    Fayez K. Ghishan

James F. Collins的其他文献

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{{ truncateString('James F. Collins', 18)}}的其他基金

Iron Pathobiology in β-thalassemia Pregnancy
妊娠β地中海贫血中的铁病理学
  • 批准号:
    10923418
  • 财政年份:
    2023
  • 资助金额:
    $ 51.35万
  • 项目类别:
Mechanisms of Heme and Non-heme Iron Absorption in Murine Models of Iron Overload
铁过载小鼠模型中血红素和非血红素铁吸收的机制
  • 批准号:
    10701227
  • 财政年份:
    2022
  • 资助金额:
    $ 51.35万
  • 项目类别:
Divalent Metal-ion Transporter 1 as a Therapeutic Target to Optimize Intestinal Iron Transport
二价金属离子转运蛋白 1 作为优化肠道铁转运的治疗靶点
  • 批准号:
    9920132
  • 财政年份:
    2016
  • 资助金额:
    $ 51.35万
  • 项目类别:
Molecular Mechanisms of Intestinal Metal Ion Transport During Iron Deficiency
缺铁期间肠道金属离子转运的分子机制
  • 批准号:
    8506803
  • 财政年份:
    2007
  • 资助金额:
    $ 51.35万
  • 项目类别:
Molecular Mechanisms of Intestinal Metal Ion Transport During Iron Deficiency
缺铁期间肠道金属离子转运的分子机制
  • 批准号:
    9919534
  • 财政年份:
    2007
  • 资助金额:
    $ 51.35万
  • 项目类别:
Molecular Mechanisms of Intestinal Metal Ion Transport During Iron Deficiency
缺铁期间肠道金属离子转运的分子机制
  • 批准号:
    8813554
  • 财政年份:
    2007
  • 资助金额:
    $ 51.35万
  • 项目类别:
Molecular Mechanisms of Intestinal Metal Ion Transport During Iron-Deficiency
缺铁期间肠道金属离子转运的分子机制
  • 批准号:
    7706543
  • 财政年份:
    2007
  • 资助金额:
    $ 51.35万
  • 项目类别:
Molecular Mechanisms of Intestinal Metal Ion Transport During Iron-Deficiency
缺铁期间肠道金属离子转运的分子机制
  • 批准号:
    7636746
  • 财政年份:
    2007
  • 资助金额:
    $ 51.35万
  • 项目类别:
Molecular Mechanisms of Intestinal Metal Ion Transport During Iron-Deficiency
缺铁期间肠道金属离子转运的分子机制
  • 批准号:
    7587761
  • 财政年份:
    2007
  • 资助金额:
    $ 51.35万
  • 项目类别:
Molecular Mechanisms of Intestinal Metal Ion Transport During Iron-Deficiency
缺铁期间肠道金属离子转运的分子机制
  • 批准号:
    8098833
  • 财政年份:
    2007
  • 资助金额:
    $ 51.35万
  • 项目类别:

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