Divalent Metal Transporter: Role in Manganese Toxicity

二价金属转运蛋白:在锰毒性中的作用

基本信息

项目摘要

DESCRIPTION (provided by applicant): Chronic exposure to the divalent heavy metals, lead, manganese (Mn) and chromium, has all been linked to development of severe and irreversible neurological disorders as well as increased risk to develop Parkinson disease. Although the mechanisms by which these metals induce neuronal cell death are not well defined, neurotoxicity is regulated by a number of factors, one of which is the transport of these metals across the blood brain barrier and their subsequent uptake within targeted neuron. Once inside the neuron these heavy metals provoke a series of biochemical and molecular events leading to cell death induced by apoptosis and/or necrosis. In the case of Mn, chronic high level exposure provokes a syndrome resembling Parkinson?s disease, which at the latter stages consists of severe extrapyramidal dysfunction. Recent studies have indicated that Mn toxicity is integrally linked to transport and disposition of iron. Mn is predominantly taken up into cells via the same transporter responsible for iron uptake, i.e. the divalent metal transporter, DMT1. This transporter has a very broad specificity and is responsible for the cellular uptake of other divalent cations as well, including Cd+2, Zn+2, Co+2, Ni+2, Cu+2 and Pb+2. One of the two forms of DMT1, the form containing the iron-response element (+IRE) in the 3?-noncoding region of the message, is negatively regulated by iron status such that if iron levels are low, DMT1 expression is elevated resulting in increased transport and the potential for enhanced metal toxicity. The other form (-IRE) presumably is not regulated in this fashion. Recent studies have demonstrated that the two isoforms of DMT1 (+/-IRE) are distributed in different subcellular compartments with the -IRE species selectively present in the nucleus of neuronal and neuronal-like cells. However, the function and structure of this nuclear-based form of DMT1 have not been determined. Accordingly, we propose to examine the function of both the +IRE and -IRE forms of DMT1 and their contribution to the cellular uptake and subcellular distribution of Mn and their role in supporting heavy metal neurotoxicity. We have a unique ability to study the function of DMT1 in regulating Mn and other heavy metal toxicity since Dr. Michael Garrick, a coinvestigator in this grant, has an animal model, the Belgrade rat, with a mutation in DMT1 making it functionally inactive. Accordingly, the following studies are proposed: 1) determine the contribution of the +/-IRE forms of DMT1 in supporting iron and Mn transport and toxicity, 2) characterize factors regulating expression of +/-IRE forms of DMT1, 3) determine the structural features promoting nuclear localization of the -IRE form of DMT1, 4) determine the function of nuclear DMT1 and its contribution to Mn-induced toxicity, and 5) localization of the +/-IRE isoforms in rat brain.
描述(申请人提供):长期接触二价重金属 铅、锰和铬等金属都与发育有关。 严重和不可逆转的神经疾病以及增加的风险 患上帕金森氏症。尽管这些金属诱导的机制 神经细胞死亡没有很好的定义,神经毒性是由一个 许多因素,其中之一是这些金属的运输 血脑屏障及其随后在靶神经元内的摄取。一次 在神经元内部,这些重金属引发了一系列的生化和 通过细胞凋亡和/或坏死导致细胞死亡的分子事件。在……里面 锰,慢性高水平暴露会引发一种类似于 帕金森?S病,在后期由严重的 锥体外系功能障碍。最近的研究表明,锰的毒性是 与铁的运输和处置密不可分。锰的主要成分是 通过负责铁摄取的同一转运体进入细胞,即 二价金属转运蛋白DMT1。这辆运输车有一个非常宽广的 特异性,并负责细胞摄取其他二价体 还有阳离子,包括Cd+2,Zn+2,Co+2,Ni+2,Cu+2和Pb+2。 DMT1的两种形式,即包含铁响应元件(+ire)的形式 3?--信息的非编码区,受铁状态等负调控 如果铁水平低,DMT1的表达就会升高,从而导致 运输和增强金属毒性的可能性。另一种形式(-ire) 大概不会以这种方式受到监管。最近的研究表明 DMT1(+/-ire)的两种异构体分布于不同的亚细胞 带有-ire物种的隔室选择性地出现在 神经元和神经元样细胞。然而,它的功能和结构 核基形式的DMT1尚未确定。因此,我们建议 检查DMT1的+ire和-ire形式的功能及其 对细胞吸收和亚细胞分布的贡献 它们在支持重金属神经毒性方面的作用。我们有一种独特的能力 DMT1在调节锰等重金属毒性中的作用 由于迈克尔·加里克博士是这笔拨款的合作研究员,他有一个动物模型, 贝尔格莱德大鼠,DMT1基因突变使其功能不活跃。 据此,提出了以下研究建议:1)确定贡献率 DMT1的+/-IRE形式在支持铁和锰的运输和毒性方面, 2)表征调节DMT1+/-IRE形式表达的因素,3) 确定促进-IRE核局部化的结构特征 DMT1的形式,4)决定核DMT1的功能及其对 5)+/-IRE异构体在大鼠脑内的定位。

项目成果

期刊论文数量(5)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Manganese-induced toxicity in normal and human B lymphocyte cell lines containing a homozygous mutation in parkin.
锰对含有 Parkin 纯合突变的正常和人 B 淋巴细胞系产生的毒性。
Expression and localization of different forms of DMT1 in normal and tumor astroglial cells.
  • DOI:
    10.1016/j.molbrainres.2003.11.023
  • 发表时间:
    2004-03
  • 期刊:
  • 影响因子:
    0
  • 作者:
    A. Lis;T. Barone;Prasad N. Paradkar;R. Plunkett;J. Roth
  • 通讯作者:
    A. Lis;T. Barone;Prasad N. Paradkar;R. Plunkett;J. Roth
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JEROME Allan ROTH其他文献

JEROME Allan ROTH的其他文献

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{{ truncateString('JEROME Allan ROTH', 18)}}的其他基金

Occupational exposure to manganese and noise potentiate hearing loss
职业接触锰和噪音会加剧听力损失
  • 批准号:
    8721345
  • 财政年份:
    2012
  • 资助金额:
    $ 26.86万
  • 项目类别:
Occupational exposure to manganese and noise potentiate hearing loss
职业接触锰和噪音会加剧听力损失
  • 批准号:
    8270945
  • 财政年份:
    2012
  • 资助金额:
    $ 26.86万
  • 项目类别:
Role of Parkin in Regulating Manganese Toxicity
Parkin 在调节锰毒性中的作用
  • 批准号:
    7814314
  • 财政年份:
    2009
  • 资助金额:
    $ 26.86万
  • 项目类别:
Role of Parkin in Regulating Manganese Toxicity
Parkin 在调节锰毒性中的作用
  • 批准号:
    7939786
  • 财政年份:
    2009
  • 资助金额:
    $ 26.86万
  • 项目类别:
Mechanism and Treatment of Manganese Toxicity
锰中毒的机制及治疗
  • 批准号:
    7903624
  • 财政年份:
    2009
  • 资助金额:
    $ 26.86万
  • 项目类别:
Mechanism and Treatment of Manganese Toxicity
锰中毒的机制及治疗
  • 批准号:
    7586917
  • 财政年份:
    2008
  • 资助金额:
    $ 26.86万
  • 项目类别:
Mechanism and Treatment of Manganese Toxicity
锰中毒的机制及治疗
  • 批准号:
    7729078
  • 财政年份:
    2008
  • 资助金额:
    $ 26.86万
  • 项目类别:
Divalent Metal Transporter: Role in Manganese Toxicity
二价金属转运蛋白:在锰毒性中的作用
  • 批准号:
    6623748
  • 财政年份:
    2002
  • 资助金额:
    $ 26.86万
  • 项目类别:
Divalent Metal Transporter: Role in Manganese Toxicity
二价金属转运蛋白:在锰毒性中的作用
  • 批准号:
    6470013
  • 财政年份:
    2002
  • 资助金额:
    $ 26.86万
  • 项目类别:
EFFECT OF O3, NO2 ON LUNG MACROPHAGE PHAGOCYTOSIS
O3、NO2对肺巨噬细胞吞噬功能的影响
  • 批准号:
    3252290
  • 财政年份:
    1986
  • 资助金额:
    $ 26.86万
  • 项目类别:

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