Attenuation of neuroinflammation and Alzheimer’s disease pathology by disrupting LXRα phosphorylation
通过破坏 LXRα 磷酸化来减轻神经炎症和阿尔茨海默病病理学
基本信息
- 批准号:10285124
- 负责人:
- 金额:$ 25.43万
- 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:2021-08-15 至 2023-04-30
- 项目状态:已结题
- 来源:
- 关键词:APP-PS1Alzheimer&aposs DiseaseAlzheimer&aposs disease brainAlzheimer&aposs disease modelAlzheimer&aposs disease pathologyAlzheimer&aposs disease riskAmyloidAnti-Inflammatory AgentsApolipoprotein EAttenuatedBrainCardiometabolic DiseaseCell LineCholesterol HomeostasisChronicCognitiveDataDevelopmentDiseaseDisease ProgressionEtiologyExhibitsFoundationsFundingGene ExpressionGenesGeneticGoalsHematologic NeoplasmsHumanInflammationInflammatoryInflammatory ResponseInnate Immune ResponseInterventionKnock-inKnock-in MouseLXRalpha proteinLigandsLinkLipidsLiver X ReceptorMeasuresMetabolicMetabolic DiseasesMetabolismMicrogliaMusNuclear ReceptorsPathway interactionsPatientsPhagocytesPhagocytosisPharmacologyPhosphorylationPilot ProjectsPlayPreventiveProcessProtein IsoformsPublishingReceptor SignalingReportingResearchResearch PersonnelRoleSenile PlaquesSerineStimulusTestingTherapeuticTherapeutic InterventionTransgenic MiceUnited States National Institutes of HealthWorkamyloid peptideattenuationbehavioral studycasein kinase IIgenome wide association studyimmunoregulationinhibitor/antagonistmacrophagemouse modelneuroinflammationnovel strategiesrisk variantsmall moleculetargeted treatmenttranscriptometranscriptome sequencingupstream kinase
项目摘要
PROJECT SUMMARY
The goal of this proposal is to determine if LXRα phosphorylation at serine 196 (S196) is a possible target for
therapeutic intervention in Alzheimer's disease (AD). Our previous published studies demonstrated both in
cultured macrophages cell lines and in mouse models of cardiometabolic diseases that the non-phosphorylated
form of LXRα S196A reprograms the LXR-modulated transcriptome and produces a more anti-inflammatory
response. In addition, previous studies from others have shown that LXRα is a potential target for reducing
neuroinflammation, and AD pathology because genetic loss of LXRα in the APP/PS1 transgenic mouse model
of AD increased the number of amyloid plaques, while its activation attenuated the inflammatory response of
primary glial cultures to fibrillar amyloid peptide. As a majority of AD risk loci are in genes expressed most highly
in microglia, and that LXRα is expressed in both mouse and human microglia, we hypothesize that reducing
LXRα phosphorylation in microglia would restrain inflammation and diminish AD progression.
To test this we will develop a mouse model that harbors a microglia-specific LXRα S196A knockin in the context
of an AD-prone mouse (APP/PS1), and compare the number of AD plaques with those in wild-type littermate
controls. To examine effects of LXR
α S196 phosphorylation on the inflammatory gene expression, we will
generate primary glial cultures from wild-type and microglia-specific LXR
α S196A mice and measure their ability
to inhibit the inflammatory response to
fibrillar amyloid peptide. We will also perform RNA-seq of primary
microglia generated from WT and LXRα S196A mice in the absence and presence of fibrillar amyloid peptide to
reveal genes and pathways modulated by LXR
α S196 phosphorylation
that can be manipulated for preventive
and therapeutic purposes. Given that the LXRα inflammatory responses can be controlled by phosphorylation
we will also test whether pharmacological interventions that promote the non-phosphorylated form of the wild
type LXRα can protect APP/PS1 mice from AD pathology. Successful completion the aims will determine
whether LXRα phosphorylation represents a tractable target for the treatment of AD due to its ability to reduce
inflammatory gene expression in the brain.
项目概要
该提案的目标是确定 LXRα 丝氨酸 196 (S196) 磷酸化是否是一个可能的目标
阿尔茨海默病(AD)的治疗干预。我们之前发表的研究表明
在培养的巨噬细胞系和心脏代谢疾病的小鼠模型中,非磷酸化
LXRα S196A 的形式重新编程 LXR 调节的转录组并产生更具抗炎作用的
回复。此外,其他人之前的研究表明,LXRα是减少
APP/PS1 转基因小鼠模型中 LXRα 遗传缺失导致神经炎症和 AD 病理学
AD 增加了淀粉样斑块的数量,而其激活则减弱了淀粉样斑块的炎症反应
原代神经胶质细胞培养为纤维状淀粉样肽。由于大多数 AD 风险位点位于表达最高的基因中
在小胶质细胞中,并且 LXRα 在小鼠和人类小胶质细胞中都有表达,我们假设减少
小胶质细胞中的 LXRα 磷酸化会抑制炎症并减缓 AD 的进展。
为了测试这一点,我们将开发一个小鼠模型,该模型在环境中含有小胶质细胞特异性 LXRα S196A 敲入
易患 AD 的小鼠 (APP/PS1) 的 AD 斑块数量与野生型同窝小鼠的 AD 斑块数量进行比较
控制。检查 LXR 的效果
αS196磷酸化对炎症基因表达的影响,我们将
从野生型和小胶质细胞特异性 LXR 生成原代胶质细胞培养物
α S196A小鼠并测量其能力
以抑制炎症反应
纤维状淀粉样肽。我们还将进行初级RNA-seq
在纤维状淀粉样肽不存在和存在的情况下,WT 和 LXRα S196A 小鼠产生的小胶质细胞
揭示 LXR 调节的基因和途径
α S196 磷酸化
可以被操纵以进行预防
和治疗目的。鉴于 LXRα 炎症反应可以通过磷酸化来控制
我们还将测试是否可以促进野生非磷酸化形式的药物干预
LXRα 型可以保护 APP/PS1 小鼠免受 AD 病理的影响。成功完成目标将决定
LXRα 磷酸化是否代表了治疗 AD 的一个易于处理的靶点,因为它能够减少
大脑中炎症基因的表达。
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)
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MOSES VICTOR CHAO其他文献
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{{ truncateString('MOSES VICTOR CHAO', 18)}}的其他基金
Attenuation of neuroinflammation and Alzheimer’s disease pathology by disrupting LXRα phosphorylation
通过破坏 LXRα 磷酸化来减轻神经炎症和阿尔茨海默病病理学
- 批准号:
10460595 - 财政年份:2021
- 资助金额:
$ 25.43万 - 项目类别:
Diverse Neuroscientists: Doctoral Training Series (DeNDriTeS)
多元化的神经科学家:博士培训系列 (DeNDriTeS)
- 批准号:
10447210 - 财政年份:2018
- 资助金额:
$ 25.43万 - 项目类别:
Diverse Neuroscientists: Doctoral Training Series (DeNDriTeS)
多元化的神经科学家:博士培训系列 (DeNDriTeS)
- 批准号:
10199068 - 财政年份:2018
- 资助金额:
$ 25.43万 - 项目类别:
The role of neuroimmune interactions in the pathogenesis of chronic pain
神经免疫相互作用在慢性疼痛发病机制中的作用
- 批准号:
10451784 - 财政年份:2018
- 资助金额:
$ 25.43万 - 项目类别:














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