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Choroid Plexus a Target in Metal-Induced Neurotoxicity

Choroid Plexus a Target in Metal-Induced Neurotoxicity
脉络丛是金属引起的神经毒性的目标
批准号:
6696883
负责人:
WEI ZHENG
金额:
$24.97万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
1998
资助国家:
美国
项目状态:
已结题
起止时间:
1998-03-01 至 2005-11-30

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中文摘要
翻译
描述(申请人提供):最近添加了锰 含锰抗爆剂甲基环戊二烯三羰基锰(MMT) 美国汽油供应引起了人们对健康风险的极大关注 与锰的环境水平的潜在增加有关。两 环境和职业暴露(锰)导致神经退行性病变 类似帕金森病的症状然而,Mn的潜在机制 神经毒性仍然未知。我们最近的研究结果表明,在体内和体外, 暴露于锰改变系统和亚细胞铁状态。而前者 促进铁从血液循环流入脑脊髓 液体(CSF),后者促进细胞Fe过载。我们还发现 锰在脉络丛中的积累,脉络丛是血-CSF屏障 存在,增强转铁蛋白受体(TfR)mRNA的密度,其具有3'端, 结合IRE(铁响应元件)环接受[4Fe-4S] 含簇铁调节蛋白-1(IRP-1,或胞质乌头酸酶)。 这些发现使我们提出,锰引起 铁代谢异常可能是通过其与IRP-1的相互作用, 随后TfR过表达。这些事件反过来又加速了铁的运输, 脑屏障系统,加重神经细胞内铁的蓄积。 因此,我们假设在这个提议中,脉络膜中锰的积累 神经丛改变血-CSF屏障中的Fe调节机制, 干扰CSF中的Fe稳态,这可能有助于Mn诱导的 神经退行性帕金森症我们的研究目标是更好地了解 锰诱发帕金森病的机制,并在这样做的识别和预防 神经退行性疾病的环境原因。我们的具体目标是(1) 为了检验锰暴露改变铁调节的工作假设, 在脉络丛的机制,导致一个扭曲的铁状态的CSF。 我们将确定锰暴露和铁的剂量和时间反应关系, 脑脊液、血液和脉络丛,检测IRP-1活性,并确定 TfR在血-CSF屏障和选定脑区的表达;(2) 测试的工作假设,锰促进运输铁在 血-CSF屏障直接朝向CSF,并且在数量上更多 比通过血脑屏障运输更重要。我们将在体外使用 运输模型,以确定铁通量的方向和幅度在两个 主要的脑屏障,并调查是否阻断细胞运输的 TfR拮抗Mn增强的Fe单向转运;和(3)测试 锰对细胞铁调节的改变 在mRNA表达水平,而不是在转录水平, 基因组DNA的调节。我们将确定Mn对RNA结合的影响 IRP-1的能力和TfR的相关表达,检测Mn是否抑制 TfR mRNA的降解,并研究两种屏障中的细胞铁蛋白状态。 此外,我们将研究Mn对RNA结合能力的影响, 新发现的IRP调节[Fe-S]亚基的合成, 复合体I
英文摘要
DESCRIPTION (provided by applicant): The recent addition of a manganese (Mn)-containing antiknock compound methylcyclo-pentadienyl Mn tricarbonyl (MMT) to the US gasoline supply has raised a great concern about the health risks associated with a potential increase in the environmental levels of Mn. Both environmental and occupational exposures to (Mn) result in neurodegenerative symptoms resembling Parkinson's disease. However, the mechanisms underlying Mn neurotoxicity remain unknown. Our recent results show that in vivo and in vitro exposures to Mn alter both systemic and subcellular Fe status. While the former facilitates influx of Fe from the blood circulation to the cerebral spinal fluid (CSF), the latter promotes cellular Fe overload. We also found that accumulation of Mn in the choroid plexus, a tissue where blood-CSF barrier resides, enhances the density of transferrin receptor (TfR) mRNA, which has 3' binding IRE (iron responsive element) loops receptive to [4Fe-4S] cluster-containing iron regulatory protein-1 (IRP-1, or cytosolic aconitase). These findings have led us to propose that the mechanism by which Mn causes abnormal Fe metabolism is likely via its interaction with IRP-1 and the subsequent overexpression of TfR. The events, in turn, expedite Fe transport at the brain barrier systems and aggravate Fe accumulation in neuronal cells. Thus, we hypothesize in this proposal that accumulation of Mn in the choroid plexus alters Fe regulatory mechanisms in the blood-CSF barrier and thereby disturbs Fe homeostasis in the CSF, which may contribute to Mn-induced neurodegenerative Parkinsonism. Our research goals are to better understand the mechanism of Mn-induced Parkinsonism and in so doing identify and prevent environmental causes of neurodegenerative diseases. Our specific aims are (1) to test the working hypothesis that Mn exposure alters the Fe regulatory mechanism in the choroid plexus, leading to a distorted Fe status in the CSF. We will define the dose and time response relationship of Mn exposure and Fe in CSF, blood, and choroid plexus, examine the activity of IRP-1, and determine the expression of TfR in blood-CSF barrier and selected brain areas; (2) to test the working hypothesis that Mn-facilitated transport of Fe at the blood-CSF barrier is directed toward the CSF and quantitatively is more significant than transport by the blood-brain barrier. We will use in vitro transport models to determine the direction and magnitude of Fe fluxes at two major brain barriers and to investigate if blocking of cellular trafficking of TfR antagonizes Mn-augmented unidirectional transport of Fe; and (3) to test the working hypothesis that alteration by Mn of cellular Fe regulation takes place at the level of mRNA expression, but not at the level of transcriptional modulation of genomic DNA. We will deterrnine the effect of Mn on RNA binding capability of IRP-1 and pertinent expression of TfR, examine if Mn inhibits degradation of TfR mRNA, and study cellular ferritin status in both barriers. In addition, we will study the effect of Mn on the RNA binding capability of a newly discovered IRP which regulates the synthesis of an [Fe-S] subunit of Complex-I.
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Xi'an International Neurotoxicology Conference
  • 批准号:
    8130124
  • 项目类别:
  • 资助金额:
    $1.3万
  • 财政年份:
    2011
  • 负责人:
    WEI ZHENG
  • 依托单位:
Beta-Amyloid Clearance by Mammalian Choroid Plexus: Effect of Lead Exposure
  • 批准号:
    7848592
  • 项目类别:
  • 资助金额:
    $3.57万
  • 财政年份:
    2009
  • 负责人:
    WEI ZHENG
  • 依托单位:
Beta-Amyloid Clearance by Mammalian Choroid Plexus: Effect of Lead Exposure
  • 批准号:
    7777835
  • 项目类别:
  • 资助金额:
    $18.39万
  • 财政年份:
    2009
  • 负责人:
    WEI ZHENG
  • 依托单位:
Beta-Amyloid Clearance by Mammalian Choroid Plexus: Effect of Lead Exposure
  • 批准号:
    7568091
  • 项目类别:
  • 资助金额:
    $23.71万
  • 财政年份:
    2009
  • 负责人:
    WEI ZHENG
  • 依托单位:
海外基金