The IL-6 Induced Retinal Iron Sequestration Response
The IL-6 Induced Retinal Iron Sequestration Response
批准号:
10281696
负责人:
JOSHUA L DUNAIEF
金额:
$40.6万
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-06-01 至 2024-05-31
关键词:
AffectAgeAge related macular degenerationAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAlzheimer&aposs disease modelAlzheimer&aposs disease patientAstrocytesBacteriaBrainCellsChronicDataDeferoxamineDiseaseEnzyme-Linked Immunosorbent AssayEyeForeign BodiesGene ProteinsGenotypeGoalsGrowthHereditary DiseaseHumanIL6 geneIL6ST geneInductively Coupled Plasma Mass SpectrometryInflammationInheritedInjectionsInterleukin-6IronIron Chelating AgentsIron ChelationIron OverloadL-ferritinLeadLifeMessenger RNAModelingMusNerve DegenerationOrganOxidative StressPaperParkinson DiseasePathogenesisPathway interactionsPatientsPatternPhase II Clinical TrialsPhenotypeProteinsPublishingRegulationRetinaRetinal DegenerationRoleSignal TransductionStainsSystemic TherapyTFRC geneTechniquesTestingToxic effectTransgenic MiceUp-RegulationWorkabeta depositionbrain cellcatalasecell typecytokineextracellularhepcidinintraperitonealiron chelation therapymetal transporting protein 1mouse modelneuroinflammationnew therapeutic targetnovel therapeuticsoverexpressionoxidative damageparent grantpathogenprotein transportreceptorresponseretinal damagesuperoxide dismutase 1targeted treatmentuptake
中文摘要
项目概要/摘要
所提出的研究的目标是定义IL 6触发的细胞铁螯合反应(CISR)。
在阿尔茨海默病(AD)的小鼠模型中。铁是所有生命形式生长和生存所必需的,
所以细胞铁的摄取和螯合是限制细胞外细菌生长的机制。
然而,当CISR被慢性神经炎症不适应地激活时,
蓄积可能对CNS有毒。有毒的铁积累和失调已经牵连
正在进行的2期临床试验正在评估铁螯合剂在AD患者中的作用
(NCT03234686)。然而,了解导致铁失调的机制,
受影响的细胞类型可能导致比铁螯合更有针对性的治疗。的证据涉及
IL 6诱导的CISR在AD发病机制中包括:1)AD脑具有铁失调,
2)AD脑在斑块附近具有升高的IL 6水平。
过表达
升高
神经变性
大脑
作为
在
3)转基因小鼠
星形胶质细胞中的IL 6具有脑铁蓄积作用。4)AD的5XFAD小鼠模型具有
脑铁水平和CISR激活。5)铁螯合剂去铁胺能改善
AD表型
模式l App/Ps1,另一个由Aβ沉积驱动的模式。六、
铁失调也与帕金森病和遗传性疾病有关,
脑铁超载(NBIA)
了解IL 6诱导的CISR的作用
因此,AD发病机制可能导致患有这种疾病的患者的新疗法。
英文摘要
PROJECT SUMMARY/ABSTRACT
The goal of the proposed studies is to define an IL6 triggered cellular iron sequestration response (CISR)
in a mouse model of Alzheimer's Disease (AD). Iron is necessary for growth and survival for all life forms,
so cellular iron uptake and sequestration is a mechanism that limits the growth of extracellular bacteria.
However, when the CISR is maladaptively activated by chronic neuroinflammation, the resulting iron
accumulation can be toxic to the CNS. Toxic iron accumulation and dysregulation have been implicated
in AD pathogenesis, and an ongoing phase 2 clinical trial is evaluating an iron chelator in AD patients
(NCT03234686). However, understanding the mechanisms leading to iron dysregulation, and the brain
cell types affected is likely to lead to a more targeted therapy than iron chelation. Evidence implicating
an IL6 induced CISR in AD pathogenesis includes: 1)AD brains have iron dysregulation, with iron
accumulation in plaques 2) AD brains have elevated IL6 levels near plaques.
overexpressing
elevated
neurodegeneration
Brain
as
in
3)A transgenic mouse
IL6 i n astrocytes has brain iron accumulation. 4)The 5XFAD mouse model of AD has
brain iron levels and CISR activation. 5) The iron chelator deferoxamine can ameliorate the
phenotype of the AD
mode l App/Ps1, another model driven by Aβ deposition. 6)
iron dysregulation is also associated with Parkinson's Disease and t he hereditary diseases classified
Neurodegenerations with Brain Iron Overload (NBIA).
Understanding the role of the IL6 induced CISR
AD pathogenesis is thus likely to lead to novel therapeutics for patients suffering from this disease.
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The IL-6 Induced Retinal Iron Sequestration Response
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