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Modulation of brain iron by local hepcidin in prion disorders

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
负责人:
Neena Singh
金额:
$44.28万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
未结题
起止时间:
2021-09-01 至 2025-02-28

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中文摘要
翻译
Prion疾病是一种传染性的,总是致命的神经退行性疾病,与积聚的 PrP-scrapie(PrPSc),人脑和视网膜中的一种富含β-Sheet的正常蛋白亚型 以及某些动物物种。散发性克雅氏病(SCJD)是人类最常见的病毒 无序性和PrPSc感染动物模型被用来理解感染性和毒性的机制。 神经炎症和铁蓄积是这些疾病的一贯特征,后者导致 铁催化的活性氧(ROS)的神经毒性。然而,铁积累的原因有 仍然难以捉摸。来自我的实验室的最新数据表明细胞因子介导的海普西丁上调 由星形胶质细胞合成,这是一个重要的原因。海普西丁通过下调铁门蛋白(FPN)来调节铁, 唯一已知的铁出口蛋白质。在正常情况下,当铁饱和时,海普西丁上调 转铁蛋白(Tf-Fe)含量低。然而,细胞因子的上调取代了Tf-Fe的信号。很可能是 细胞因子介导的星形胶质细胞对海普西丁的上调是铁神经元聚集的原因 质膜上的FPN和ROS的毒性。为了支持这一假设,sCJD大脑匀浆 表现为海普西丁mRNA和蛋白表达上调,FPN表达下调,铁蛋白表达增加。同样,大脑也是如此 从PrPSc感染的小鼠的匀浆中显示出Hepsidin mRNA的上调,而PrPSc感染的小鼠的视网膜切片显示。 感染的仓鼠在发病期间铁蛋白上调之前或伴随着铁蛋白上调而出现小胶质细胞的激活 进步。基于这些观察结果,我们推测在sCJD和PrPSc感染中铁积累 大脑和视网膜是细胞因子介导的局部海普西丁上调的结果。提出了两个具体目标 来检验这一假设。在目标1中,将检查更多的sCJD大脑和视网膜组织中是否存在海普西丁的增加 大鼠视网膜神经节细胞(RGC)死亡与铁的表达和蓄积的关系 免疫组织化学染色切片。此外,感染PrPSc的小鼠的大脑和视网膜将在疾病期间进行检查 进一步探索细胞因子的增加是否先于海普西丁和铁积累的上调,以及 视网膜变性是否先于神经变性。这将为视网膜成像铺平道路。 SCJD的临床诊断试验。在目标2中,海普西丁在大脑和视网膜铁蓄积中的作用将进一步 用基因敲除的海普西丁(HepC-/-)和产仔鼠(HepC/)作为对照,分别接种PrPSc。一个 与HepC/对照组相比,HepC-/-小鼠体内的铁蓄积显著减少,尽管在 随着疾病进展,细胞因子和PrPSc负荷将提示局部海普西丁是铁蓄积的原因。 此外,在HepC-/-小鼠中,神经元和RGC死亡的显著减少将表明铁在 诱导神经毒性,并证明使用海普西丁拮抗剂和FPN稳定剂来减少 累积的铁作为治疗选择。HepC-/-小鼠体内铁水平的变化不会反驳我们的假设,并且 提示铁是疾病过程中的一种附带现象。
英文摘要
Prion disorders are infectious and invariably fatal neurodegenerative conditions associated with accumulation of PrP-scrapie (PrPSc), a β-sheet rich isoform of the normal prion protein (PrPC), in the brain and retina of humans and certain animal species. Sporadic Creutzfeldt-Jakob-disease (sCJD) is the most common human prion disorder, and PrPSc-infected animal models are used to understand the mechanism of infectivity and toxicity. Neuroinflammation and iron accumulation are consistent features of these disorders, the latter contributing to neurotoxicity by iron-catalyzed reactive oxygen species (ROS). The cause of iron accumulation, however, has remained elusive. Recent data from my laboratory suggest cytokine-mediated upregulation of hepcidin synthesized by astrocytes as a significant cause. Hepcidin regulates iron by downregulating ferroportin (Fpn), the only known iron export protein. Under normal conditions, hepcidin is upregulated when iron saturation of transferrin (Tf-Fe) is low. Upregulation by cytokines, however, supersedes the signal from Tf-Fe. It is likely that cytokine-mediated upregulation of hepcidin by astrocytes is the cause of iron neuronal accumulation that express Fpn on their plasma membrane, and toxicity by ROS. In support of this hypothesis, sCJD brain homogenates show upregulation of hepcidin mRNA and protein, downregulation of Fpn, and increase in ferritin. Likewise, brain homogenates from PrPSc-infected mice show upregulation of hepcidin mRNA, and retinal sections from PrPSc- infected hamsters show activation of microglia before or concomitant with upregulation of ferritin during disease progression. Based on these observations, we hypothesize that iron accumulation in sCJD and PrPSc-infected brains and retina results from cytokine-mediated upregulation of local hepcidin. Two specific aims are proposed to test this hypothesis. In aim 1, additional sCJD brain and retinal tissue will be checked for increase in hepcidin mRNA and accumulation of iron, and correlated with neuronal and retinal ganglion cell (RGC) death in immunostained sections. In addition, the brain and retina of PrPSc-infected mice will be examined during disease progression to explore if increase in cytokines precedes upregulation of hepcidin and iron accumulation, and whether retinal degeneration precedes neurodegeneration. This will pave the way for retinal imaging a pre- clinical diagnostic test for sCJD. In aim 2, the role of hepcidin in brain and retinal iron accumulation will be further explored using hepcidin knock-out (hepc-/-) and littermate (hepc+/+) control mice inoculated with PrPSc. A significant decrease in iron accumulation in hepc-/- mice relative to hepc+/+ controls despite similar increase in cytokines and PrPSc load with disease progression will suggest local hepcidin as the cause of iron accumulation. Moreover, a marked reduction in neuronal and RGC death in hepc-/- mice will suggest a significant role of iron in inducing neurotoxicity, and justify the use of hepcidin antagonists and Fpn stabilizing agents to reduce accumulated iron as therapeutic options. No change in iron levels in hepc-/- mice will refute our hypothesis, and suggest iron as an epiphenomenon of the disease process.
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Local hepcidin in the anterior segment: Physiological and pathological implications
  • 批准号:
    10546487
  • 项目类别:
  • 资助金额:
    $24.15万
  • 财政年份:
    2022
  • 负责人:
    Neena Singh
  • 依托单位:
Local hepcidin in the anterior segment: Physiological and pathological implications
  • 批准号:
    10370658
  • 项目类别:
  • 资助金额:
    $20.13万
  • 财政年份:
    2022
  • 负责人:
    Neena Singh
  • 依托单位:
Molecular Basis of Iron Imbalance in sCJD Brain and CSF
  • 批准号:
    8417651
  • 项目类别:
  • 资助金额:
    $22.73万
  • 财政年份:
    2012
  • 负责人:
    Neena Singh
  • 依托单位:
Molecular Basis of Iron Imbalance in sCJD Brain and CSF
  • 批准号:
    8302810
  • 项目类别:
  • 资助金额:
    $19.63万
  • 财政年份:
    2012
  • 负责人:
    Neena Singh
  • 依托单位:
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