IL-1Beta-Induced Retinal Iron Accumulation in Age-Related Macular Degeneration
IL-1Beta-Induced Retinal Iron Accumulation in Age-Related Macular Degeneration
批准号:
10547817
负责人:
Jacob Khan Sterling
金额:
$1.81万
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:
已结题
起止时间:
2021-01-01 至 2023-05-15
关键词:
AcuteAgeAge related macular degenerationAnimalsAntibodiesAqueous HumorAstrocytesAutopsyBasic ScienceBlindnessBrainCASP1 geneCell FractionCell SeparationCellsCessation of lifeChronicClinical SciencesDNA Sequence AlterationDataDependovirusDevelopmentDoseDown-RegulationExposure toFDA approvedFluorescent in Situ HybridizationFosteringGenesGenetic TranscriptionGoalsGrantHepatocyteHomeostasisHumanIL1R1 geneImmunofluorescence ImmunologicIn VitroIndividualInflammationInflammatoryInterleukin-1 betaIronIron OverloadLinkLipopolysaccharidesMacrophageMagnetismMapsMeasuresMessenger RNAMicrodissectionMicrogliaMolecular Biology TechniquesMuller&aposs cellMusNerve DegenerationNeurogliaNormal CellOphthalmologistOphthalmologyOxidative StressPathogenesisPathway interactionsPatientsPhotoreceptorsPopulationProductionProtein Export PathwayProtein ImportProteinsProteomePublishingResearchRetinaRetinal DegenerationRetinal DiseasesRodSalineScientistSecondary toSerumSignal TransductionSignaling ProteinStarvationStimulusStructure of retinal pigment epitheliumSupporting CellTechnologyTestingTissuesToxinTrainingUnited StatesUp-RegulationVascular Endothelial CellWorkcell typecellular targetingcytokineepithelial injuryin vivoin vivo Modeliron chelation therapymaculamouse modelneuroinflammationneurosensorynovel therapeutic interventionoverexpressionpathogenphotoreceptor degenerationpreventproteostasisreceptorresponsesystemic inflammatory responsetranscriptome
中文摘要
项目摘要
视网膜相关性黄斑变性(AMD)是美国最常见的不可逆性失明的原因。
States. AMD的特征是光感受器及其支持细胞视网膜色素的死亡
上皮(RPE)。Dunaief实验室先前已经证明铁在光感受器中积累
与年龄匹配的对照组相比,AMD患者的RPE。随后的体外和体内工作
证明铁的积累足以导致视网膜变性。此外,铁螯合疗法
对各种毒素和基因突变引起的视网膜变性具有保护作用
与AMD有关。然而,AMD中铁积累的机制尚不清楚。在本提案中,我们
利用磁性细胞分选技术与分子生物学技术相结合,
组织来检验我们的假设:IL-1β触发视网膜铁在光感受器和RPE中的积累,
AMD.
在目的1中,我们将从AMD和正常视网膜分离细胞组分以确定哪种细胞类型产生IL-10。
1β以及表达IL-1β信号转导所必需的受体蛋白的细胞类型。我们还将
测量每个细胞组分中铁转运蛋白的mRNA和蛋白水平,以鉴定哪些转运蛋白
导致光感受器和RPE中的视网膜铁过载。在目标2中,我们将使用细胞分选来分离
来自慢性神经炎症小鼠模型的视网膜细胞组分。我们假设IL-1β和IL-1β
受体IL-1 R1是铁积累和继发于慢性炎症的铁转录组变化所必需的。
炎症刺激我们还假设,长期给予IL-1β,通过视网膜内注射,
腺相关病毒,将足以改变视网膜铁转录组和铁积累。
这些数据将共同确定(1)IL-1β信号传导是否可以作为视网膜铁积累的触发因素,
(2)IL-1β抑制剂是否可用于防止铁在光感受器和RPE中的积聚。
这笔补助金将为我成为一名有抱负的科学家-眼科医生提供不可或缺的支持,
我可以实现我的最终目标,融合临床和基础科学眼科学,
视网膜疾病的治疗。
英文摘要
PROJECT SUMMARY
Age-related macular degeneration (AMD) is the most common cause of irreversible blindness in the United
States. AMD is characterized by the death of photoreceptors and their supporting cells, the retinal pigment
epithelium (RPE). The Dunaief lab has previously demonstrated that iron accumulates in the photoreceptors
and RPE of AMD patients compared to age-matched controls. Subsequent in vitro and in vivo work
demonstrated that iron accumulation is sufficient for retinal degeneration. Furthermore, iron chelation therapy
is protective against retinal degeneration secondary to a diverse array of toxins and genetic mutations
associated with AMD. However, the mechanism of iron accumulation in AMD is not known. In this proposal, we
utilize magnetic cell sorting technology paired with molecular biology techniques in human and mouse retinal
tissue to test our hypothesis: IL-1β triggers retinal iron accumulation in photoreceptors and RPE, exacerbating
AMD.
In Aim 1, we will isolate cell fractions from AMD and normal retinas to determine which cell-types produce IL-
1β and which cell-types express the receptor proteins necessary for IL-1β signal transduction. We will also
measure mRNA and protein levels of iron transporters in each cell fraction to identify which transporters
contribute to retinal iron overload in the photoreceptors and RPE. In Aim 2, we will use cell sorting to isolate
retinal cell fractions from a mouse model of chronic neuroinflammation. We hypothesize that IL-1β and IL-1β
receptor, IL-1R1, are necessary for iron accumulation and iron transcriptome changes secondary to a chronic
inflammatory stimulus. We also hypothesize that chronic administration of IL-1β, delivered to retina using an
adeno-associated virus, will be sufficient for changes in the retinal iron transcriptome and iron accumulation.
Together these data will determine (1) if IL-1β signaling may serve as a trigger for retinal iron accumulation in
AMD and (2) whether IL-1β inhibition can be used to prevent iron accumulation in photoreceptors and RPE.
This grant will provide indispensable support towards my training as an aspiring scientist-ophthalmologist so
that I can achieve my ultimate goal of fusing clinical and basic science ophthalmology to create better
therapies for retinal disease.
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IL-1Beta-Induced Retinal Iron Accumulation in Age-Related Macular Degeneration
-
批准号:10452487
-
项目类别:
-
资助金额:$5.18万
-
财政年份:2021
-
负责人:Jacob Khan Sterling
-
依托单位:
国内基金
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