The iron modulatory function of prion protein and prion disorders

朊病毒蛋白和朊病毒疾病的铁调节功能

基本信息

  • 批准号:
    8287667
  • 负责人:
  • 金额:
    $ 32.25万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2010
  • 资助国家:
    美国
  • 起止时间:
    2010-05-15 至 2014-04-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Prion protein (PrPC) is a normal glycoprotein implicated in the pathogenesis of prion disorders, a group of fatal neurodegenerative conditions of humans and animals. A change in the conformation of PrPC to an aggregated, PrP-scrapie (PrPSc) form is believed to be the principal cause of neurotoxicity in these disorders. Recently, we demonstrated that PrPC plays a functional role in cellular iron uptake and transport, and selective deletion of PrPC in PrP knock-out (PrPKO) mice induces a state of systemic iron deficiency in these animals relative to wild-type (wt) controls. Specifically, PrPKO mice show impaired transport of orally introduced iron from the duodenum to the blood stream, and inefficient uptake of plasma iron by hematopoietic precursor cells and parenchymal cells of major organs. Together with our recent report demonstrating a phenotype of iron deficiency that correlates with PrPSc deposits in prion disease affected brains, these observations suggest that loss of normal function of PrPC due to aggregation to the PrPSc form may be responsible for brain iron dys- homeostasis in diseased brains. In this application, we will focus on the mechanism of iron modulation by PrPC, and hypothesize that PrPC is a novel iron uptake and transport protein, and modulates cellular iron metabolism either directly or by interacting with other iron transport protein(s). The proposed studies will test this hypothesis using two complementary approaches: 1) by evaluating the transport of different sources of iron that utilize distinct pathways of transport in the same tissue, and 2) by investigating the transport of same source of iron across tissues that utilize distinct pathways of uptake and transport. Mouse models that express no PrPC (PrPKO), wt levels (wt), and 10-fold higher than wt levels of PrPC (PrPOV) will be used for this analysis. This approach will allow identification of pathways of iron transport by PrPC, and the point where PrPC intersects with known pathways of iron metabolism. Three specific aims are proposed to accomplish these goals. In aim 1, the functional role of PrPC in brain iron metabolism will be evaluated in wt, PrPKO, and PrPOV mice, and the underlying mechanism will be investigated in neuroblastoma cells expressing normal and mutant forms of PrP defective in iron transport. In addition, the correlation between PrPC, PrPSc, and brain iron status will be assessed in scrapie infected wt and PrPOV mice. In aim 2, the transport of different sources of iron will be checked in hematopoietic and reticuloendothelial cells isolated from wt, PrPKO, and PrPOV mice, and the underlying mechanism will be investigated in K562 erythroleukemia cells transfected with normal and mutant PrP forms. In aim 3, the uptake and transport of different sources of iron across the intestinal epithelium will be checked in wt, PrPKO, and PrPOV mice, and compared with aim 2 above. Based on in vivo results, polarized Caco-2 cells transfected to express PrPC or mutant PrP forms will be used as models of absorptive enterocytes to understand the mechanism of iron transport by PrPC. Successful completion of these studies will uncover novel pathway(s) of iron modulation by PrPC, and improve our understanding of the mechanism(s) underlying brain iron imbalance and associated neurotoxicity in prion disorders. PUBLIC HEALTH RELEVANCE: The long term goal of this application is to understand the role of prion protein (PrPC) in iron uptake, transport, and utilization. Preliminary data from my laboratory demonstrate that PrPC is involved in iron uptake and transport, and loss of this function contributes to brain iron dyshomeostasis in prion disorders. Successful completion of the proposed studies will improve our understanding of the functional role of PrPC in iron metabolism, and the underlying cause of brain iron imbalance in prion disorders.
描述(由申请人提供):朊蛋白(PrPC)是一种正常的糖蛋白,与朊病毒疾病的发病机制有关,朊病毒疾病是人类和动物的一组致命的神经退行性疾病。PrPC的构象改变为聚集的prp -瘙痒(PrPSc)形式被认为是这些疾病中神经毒性的主要原因。最近,我们证明了PrPC在细胞铁摄取和运输中起着功能性作用,PrP敲除(PrPKO)小鼠中PrPC的选择性缺失导致这些动物相对于野生型(wt)对照出现系统性铁缺乏状态。具体来说,PrPKO小鼠表现出口服铁从十二指肠到血流的运输受损,造血前细胞和主要器官实质细胞对血浆铁的吸收效率低下。再加上我们最近的报告表明,朊病毒疾病影响的大脑中存在与PrPSc沉积相关的缺铁表型,这些观察结果表明,PrPC因聚集到PrPSc形式而丧失正常功能可能是患病大脑中脑铁稳态的原因。在本应用中,我们将重点研究PrPC对铁的调节机制,并假设PrPC是一种新的铁摄取和转运蛋白,直接或通过与其他铁转运蛋白相互作用来调节细胞铁代谢。拟议的研究将使用两种互补的方法来验证这一假设:1)通过评估不同来源的铁在同一组织中的运输,利用不同的运输途径;2)通过研究相同来源的铁在不同组织中的运输,利用不同的摄取和运输途径。不表达PrPC (PrPKO)、wt水平(wt)和10倍于wt水平的PrPC (PrPOV)小鼠模型将用于本分析。这种方法将允许鉴定PrPC的铁运输途径,以及PrPC与已知铁代谢途径相交的点。为实现这些目标,提出了三个具体目标。在目的1中,将在wt、PrPKO和PrPOV小鼠中评估PrPC在脑铁代谢中的功能作用,并在表达正常和突变形式的铁运输缺陷PrP的神经母细胞瘤细胞中研究其潜在机制。此外,将在瘙痒病感染的wt和PrPOV小鼠中评估PrPC、PrPSc和脑铁状态之间的相关性。在目的2中,将在wt、PrPKO和PrPOV小鼠分离的造血细胞和网状内皮细胞中检查不同来源的铁的运输,并在转染正常和突变PrP形式的K562红白血病细胞中研究其潜在机制。在目的3中,将在wt、PrPKO和PrPOV小鼠中检查肠上皮对不同来源铁的摄取和运输,并与上述目的2进行比较。基于体内实验结果,我们将利用转染表达PrPC或突变PrP形式的极化Caco-2细胞作为吸收性肠细胞模型,以了解PrPC转运铁的机制。这些研究的成功完成将揭示PrPC调节铁的新途径,并提高我们对朊病毒疾病中脑铁失衡和相关神经毒性机制的理解。

项目成果

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Neena Singh其他文献

Neena Singh的其他文献

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{{ truncateString('Neena Singh', 18)}}的其他基金

Local hepcidin in the anterior segment: Physiological and pathological implications
眼前节局部铁调素:生理和病理学意义
  • 批准号:
    10370658
  • 财政年份:
    2022
  • 资助金额:
    $ 32.25万
  • 项目类别:
Local hepcidin in the anterior segment: Physiological and pathological implications
眼前节局部铁调素:生理和病理学意义
  • 批准号:
    10546487
  • 财政年份:
    2022
  • 资助金额:
    $ 32.25万
  • 项目类别:
Modulation of brain iron by local hepcidin in prion disorders
朊病毒病中局部铁调素对脑铁的调节
  • 批准号:
    10350851
  • 财政年份:
    2021
  • 资助金额:
    $ 32.25万
  • 项目类别:
Molecular Basis of Iron Imbalance in sCJD Brain and CSF
sCJD 脑和脑脊液中铁失衡的分子基础
  • 批准号:
    8417651
  • 财政年份:
    2012
  • 资助金额:
    $ 32.25万
  • 项目类别:
Molecular Basis of Iron Imbalance in sCJD Brain and CSF
sCJD 脑和脑脊液中铁失衡的分子基础
  • 批准号:
    8302810
  • 财政年份:
    2012
  • 资助金额:
    $ 32.25万
  • 项目类别:
Role of Brain Ferroxidases in AD and sCJD Pathogenesis
脑铁氧化酶在 AD 和 sCJD 发病机制中的作用
  • 批准号:
    8338829
  • 财政年份:
    2011
  • 资助金额:
    $ 32.25万
  • 项目类别:
Role of Brain Ferroxidases in AD and sCJD Pathogenesis
脑铁氧化酶在 AD 和 sCJD 发病机制中的作用
  • 批准号:
    8243115
  • 财政年份:
    2011
  • 资助金额:
    $ 32.25万
  • 项目类别:
The iron modulatory function of prion protein and prion disorders
朊病毒蛋白和朊病毒疾病的铁调节功能
  • 批准号:
    7906472
  • 财政年份:
    2010
  • 资助金额:
    $ 32.25万
  • 项目类别:
The iron modulatory function of prion protein and prion disorders
朊病毒蛋白和朊病毒疾病的铁调节功能
  • 批准号:
    8541551
  • 财政年份:
    2010
  • 资助金额:
    $ 32.25万
  • 项目类别:
The iron modulatory function of prion protein and prion disorders
朊病毒蛋白和朊病毒疾病的铁调节功能
  • 批准号:
    8466314
  • 财政年份:
    2010
  • 资助金额:
    $ 32.25万
  • 项目类别:

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