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
基本信息
- 批准号:10350851
- 负责人:
- 金额:$ 44.28万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-09-01 至 2025-02-28
- 项目状态:未结题
- 来源:
- 关键词:AffectAgeAnimal ModelAnimalsApplications GrantsAstrocytesAutopsyBloodBlood-Retinal BarrierBrainBrain DiseasesC57BL/6 MouseCell DeathCell membraneCellsCerebrumChronicClinicalClinical TrialsCommunicable DiseasesCreutzfeldt-Jakob SyndromeDataDementiaDiagnostic testsDiseaseDisease ProgressionDoseDown-RegulationEvaluationExposure toFerritinHamstersHarvestHomeostasisHumanInterleukin-1 betaInterleukin-6IntestinesIronIron OverloadKnock-outLaboratoriesLethal Dose 50LiverMediatingMessenger RNAMicrogliaMusNatureNerve DegenerationNeuronsOxidation-ReductionPathogenesisPeptidesPlasmaPrPPrPSc ProteinsPrion DiseasesProcessProductionProtein Export PathwayProtein IsoformsProteinsPublishingReactive Oxygen SpeciesRegulationRetinaRetinal DegenerationRetinal Ganglion CellsRoleScrapieSerumSignal TransductionStabilizing AgentsTestingTherapeuticThickTissuesToxic effectTranscription CoactivatorTransferrinUp-Regulationbasebeta pleated sheetbrain tissuecytokinecytotoxicityend stage diseasehepcidinholotransferrinmetal transporting protein 1neuroblastoma cellneuroinflammationneuron lossneurotoxicityparacrinepre-clinicalretinal imagingretinal nerve fiber layeruptake
项目摘要
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.
朊病毒疾病是感染性的,并且总是致命的神经退行性疾病,与朊病毒的积累有关。
PrP-scrapie(PrPSc),一种在人脑和视网膜中的正常朊蛋白(PrPC)的β折叠丰富的同种型
和某些动物物种。散发性克雅氏病(sCJD)是人类最常见的朊病毒
疾病和PrPSc感染的动物模型用于了解感染性和毒性的机制。
神经炎症和铁积累是这些疾病的一致特征,后者有助于
铁催化活性氧(ROS)的神经毒性。然而,铁积累的原因有
仍然难以捉摸我实验室的最新数据表明,马槟榔碱介导的铁调素上调
是由星形胶质细胞合成的铁调素通过下调膜铁转运蛋白(Fpn)来调节铁,
唯一已知的铁输出蛋白。在正常情况下,铁调素是上调时,铁饱和度
转铁蛋白(Tf-Fe)低。然而,细胞因子的上调取代了来自Tf-Fe的信号。很可能
星形胶质细胞介导的铁调素上调是铁神经元积累的原因,
Fpn的细胞膜上,和ROS的毒性。为了支持这一假设,sCJD脑匀浆
显示铁调素mRNA和蛋白上调、Fpn下调和铁蛋白增加。同样,大脑
来自PrPSc感染的小鼠的匀浆显示铁调素mRNA的上调,来自PrPSc的视网膜切片显示铁调素mRNA的上调。
感染的仓鼠在疾病期间铁蛋白上调之前或同时显示小胶质细胞活化
进展基于这些观察结果,我们假设sCJD和PrPSc感染的
脑和视网膜的炎症是由精氨酸介导的局部铁调素上调引起的。提出了两个具体目标
来验证这个假设在目标1中,将检查额外的sCJD脑和视网膜组织中铁调素的增加
mRNA和铁的积累,并与神经元和视网膜神经节细胞(RGC)的死亡,
免疫染色切片。此外,将在疾病期间检查PrPSc感染小鼠的大脑和视网膜。
进展以探索细胞因子的增加是否先于铁调素和铁积累的上调,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的临床诊断测试。在aim 2中,hepcidin在脑和视网膜铁蓄积中的作用将进一步得到研究
使用接种PrPSc的铁调素敲除(hepc-/-)和同窝小鼠(hepc+/+)对照小鼠进行探索。一
与hepc+/+对照组相比,hepc-/-小鼠中的铁积累显著降低,尽管
细胞因子和PrPSc负荷与疾病进展的关系表明局部铁调素是铁积累的原因。
此外,在hepc-/-小鼠中神经元和RGC死亡的显著减少将表明铁在以下方面的重要作用:
诱导神经毒性,并证明使用铁调素拮抗剂和Fpn稳定剂可以减少神经毒性
铁作为治疗选择。在hepc-/-小鼠中铁水平的变化不会反驳我们的假设,
表明铁是疾病过程的附带现象。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Neena Singh其他文献
Neena Singh的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
$ 44.28万 - 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:
$ 44.28万 - 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:
$ 44.28万 - 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:
$ 44.28万 - 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:
$ 44.28万 - 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:
$ 44.28万 - 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:
$ 44.28万 - 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:
$ 44.28万 - 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:
8287667 - 财政年份:2010
- 资助金额:
$ 44.28万 - 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:
$ 44.28万 - 项目类别:
相似国自然基金
靶向递送一氧化碳调控AGE-RAGE级联反应促进糖尿病创面愈合研究
- 批准号:JCZRQN202500010
- 批准年份:2025
- 资助金额:0.0 万元
- 项目类别:省市级项目
对香豆酸抑制AGE-RAGE-Ang-1通路改善海马血管生成障碍发挥抗阿尔兹海默病作用
- 批准号:2025JJ70209
- 批准年份:2025
- 资助金额:0.0 万元
- 项目类别:省市级项目
AGE-RAGE通路调控慢性胰腺炎纤维化进程的作用及分子机制
- 批准号:
- 批准年份:2024
- 资助金额:0 万元
- 项目类别:面上项目
甜茶抑制AGE-RAGE通路增强突触可塑性改善小鼠抑郁样行为
- 批准号:2023JJ50274
- 批准年份:2023
- 资助金额:0.0 万元
- 项目类别:省市级项目
蒙药额尔敦-乌日勒基础方调控AGE-RAGE信号通路改善术后认知功能障碍研究
- 批准号:
- 批准年份:2022
- 资助金额:33 万元
- 项目类别:地区科学基金项目
补肾健脾祛瘀方调控AGE/RAGE信号通路在再生障碍性贫血骨髓间充质干细胞功能受损的作用与机制研究
- 批准号:
- 批准年份:2022
- 资助金额:52 万元
- 项目类别:面上项目
LncRNA GAS5在2型糖尿病动脉粥样硬化中对AGE-RAGE 信号通路上相关基因的调控作用及机制研究
- 批准号:n/a
- 批准年份:2022
- 资助金额:10.0 万元
- 项目类别:省市级项目
围绕GLP1-Arginine-AGE/RAGE轴构建探针组学方法探索大柴胡汤异病同治的效应机制
- 批准号:81973577
- 批准年份:2019
- 资助金额:55.0 万元
- 项目类别:面上项目
AGE/RAGE通路microRNA编码基因多态性与2型糖尿病并发冠心病的关联研究
- 批准号:81602908
- 批准年份:2016
- 资助金额:18.0 万元
- 项目类别:青年科学基金项目
高血糖激活滑膜AGE-RAGE-PKC轴致骨关节炎易感的机制研究
- 批准号:81501928
- 批准年份:2015
- 资助金额:18.0 万元
- 项目类别:青年科学基金项目
相似海外基金
Effect of tea flavonoids and low dose estrogen on bone metabolism in an animal model for age-related bone loss
茶黄酮和低剂量雌激素对年龄相关性骨质流失动物模型骨代谢的影响
- 批准号:
488140-2016 - 财政年份:2018
- 资助金额:
$ 44.28万 - 项目类别:
Postdoctoral Fellowships
The Structural and Metabolic Changes Associated with Ependymal Layer Disruption in the Age Continuum of Hydrocephalus - A Human and Animal Model Study
脑积水年龄连续体中与室管膜层破坏相关的结构和代谢变化 - 人类和动物模型研究
- 批准号:
376678 - 财政年份:2017
- 资助金额:
$ 44.28万 - 项目类别:
Studentship Programs
Effect of tea flavonoids and low dose estrogen on bone metabolism in an animal model for age-related bone loss
茶黄酮和低剂量雌激素对年龄相关性骨质流失动物模型骨代谢的影响
- 批准号:
488140-2016 - 财政年份:2017
- 资助金额:
$ 44.28万 - 项目类别:
Postdoctoral Fellowships
Effect of tea flavonoids and low dose estrogen on bone metabolism in an animal model for age-related bone loss
茶黄酮和低剂量雌激素对年龄相关性骨质流失动物模型骨代谢的影响
- 批准号:
488140-2016 - 财政年份:2016
- 资助金额:
$ 44.28万 - 项目类别:
Postdoctoral Fellowships
Animal model of impaired autoregulation for study of age related vascular cognitive impairment
用于研究年龄相关血管认知障碍的自动调节受损动物模型
- 批准号:
9197938 - 财政年份:2016
- 资助金额:
$ 44.28万 - 项目类别:
The domestic cat as an animal model for age-related neurofibrillary tangles
家猫作为年龄相关神经原纤维缠结的动物模型
- 批准号:
24780283 - 财政年份:2012
- 资助金额:
$ 44.28万 - 项目类别:
Grant-in-Aid for Young Scientists (B)
Identification of candidate genes responsible for an increased susceptibility of age-related macular degeneration using an animal model and its application to gene diagnosis.
使用动物模型鉴定导致年龄相关性黄斑变性易感性增加的候选基因及其在基因诊断中的应用。
- 批准号:
22591939 - 财政年份:2010
- 资助金额:
$ 44.28万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
MT1-MMP-based Animal Model of Age-related Macular Degeneration (AMD)
基于 MT1-MMP 的年龄相关性黄斑变性 (AMD) 动物模型
- 批准号:
8101435 - 财政年份:2008
- 资助金额:
$ 44.28万 - 项目类别:
MT1-MMP-based Animal Model of Age-related Macular Degeneration (AMD)
基于 MT1-MMP 的年龄相关性黄斑变性 (AMD) 动物模型
- 批准号:
7481783 - 财政年份:2008
- 资助金额:
$ 44.28万 - 项目类别:
A novel molecular paradigm of age-related macular degeneration in view of the social trend in nocturnal: An approach using an animal model
鉴于夜间活动的社会趋势,年龄相关性黄斑变性的新分子范式:使用动物模型的方法
- 批准号:
20791248 - 财政年份:2008
- 资助金额:
$ 44.28万 - 项目类别:
Grant-in-Aid for Young Scientists (B)