microRNA (miRNA) signaling in Alzheimer's disease(AD)
阿尔茨海默病 (AD) 中的 microRNA (miRNA) 信号传导
基本信息
- 批准号:9176078
- 负责人:
- 金额:$ 36.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2011
- 资助国家:美国
- 起止时间:2011-08-01 至 2021-04-30
- 项目状态:已结题
- 来源:
- 关键词:3&apos Untranslated RegionsAgeAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAmyloidAreaBioinformaticsBoxingBrainBrain DiseasesBrain StemBrain regionCell LineCellsCharacteristicsChronicClinical ManagementCoculture TechniquesDNADataDot ImmunoblottingDown SyndromeDown-RegulationEnzyme-Linked Immunosorbent AssayEpigenetic ProcessFactor AnalysisFamilyGelGene ChipsGene ExpressionGoalsHippocampus (Brain)HomeostasisHumanImpairmentIn VitroIndividualInflammationInflammatoryInterleukin-1 betaMapsMessenger RNAMicroRNAsMicrogliaMolecular GeneticsMusNF-kappa BNatural ImmunityNeocortexNeuronsPathologyPathway interactionsPeptidesPhagocytosisPhysiologicalProcessProteinsReactive Oxygen SpeciesRegulator GenesResearchSamplingSignal TransductionStagingStressSystemTNF geneTNFRSF5 geneThalamic structureTherapeuticTissuesTransgenic MiceTransgenic ModelTransgenic OrganismsUbiquitinUbiquitinationUp-RegulationWorkamyloidogenesisbasebrain cellcytokinedisorder controlgamma-Glutamyl Hydrolasein vivoindexinginhibitor/antagonistinternal controlmembermind controlmouse modelneuroinflammationneuropathologynovelnovel therapeutic interventionnovel therapeuticsoverexpressionp65receptorstressorsynaptogenesistau Proteinstransgenic model of alzheimer disease
项目摘要
microRNA (miRNA) signaling in Alzheimer's disease (AD)
Through extensive miRNA- and DNA-based expression array-, LED-Northern-, ELISA,
Western-, immunological and bioinformatics-based analysis we have discovered a highly
interactive network of NF-kB sensitive, up-regulated pro-inflammatory microRNAs (miRNAs)
and their down-regulated messenger RNA (mRNA) targets and the proteins these mRNAs
encode in sporadic Alzheimer's disease (AD) brain. The up-regulation of these pathogenic
miRNAs and their down-regulated mRNA targets has been further analyzed in stressed human
brain cells in primary culture and in 5xFAD amyloid over-expressing transgenic mouse lines.
Through miRNA and mRNA abundance analysis, miRNA-mRNA complementarity mapping,
association energy (EA) indexing, ELISA and Western analysis we can explain much of the
observed neuropathology characteristic of the AD process by analyzing significant disruptions in
selective miRNA-mRNA signaling. Our hypothesis is that there exists a small family of at least 6
critical pro-inflammatory miRNAs in AD brains responsible for targeting and down-regulating a
group of pathogenic messenger RNA (mRNA) targets responsible for amyloidogenesis, tau
pathology and neuroinflammation with accompanying deficits in synaptogenesis, innate-
immunity, phagocytosis and a progressive impairment in Aβ42 peptide clearance.
This renewal of our previous 5 year NIA R01 will investigate the integrated actions of this
group of 6 pro-inflammatory, pathogenic miRNAs up-regulated in sporadic AD brain, in stressed
human brain cells in primary culture in the brains of 5xFAD mice. The 6 up-regulated pro-
inflammatory microRNAs to be studied in detail are miRNA-7, miRNA-9, miRNA-34a, miRNA-125b,
miRNA-146a and miRNA-155. Stressors will be those encountered as are found in aging AD brain
– these include reactive oxygen species (ROS), the pro-inflammatory cytokines IL-1β and TNFα
and Aβ42 peptides. Specific Aim 1 will analyze the contribution of these factors in moderate-to-
advanced sporadic AD and Down's syndrome (DS) brain; Specific Aim 2 will analyze the
contribution of these factors in stressed human brain cells, i.e. in neuronal-glial primary cell co-
cultures; Specific Aim 3 will analyze the contribution of these factors in 5xFAD amyloid over-
expressing transgenic mouse lines. We will specifically accentuate the study of the most up-
regulated miRNAs: miRNA-7, miRNA-9, miRNA 34a and miRNA-146a and their targeted
disruption of UBE2A (ubiquitin conjugase protein) and TREM2 (triggering receptor expressed in
microglial cells) signaling in AD brain, and in in vitro and in vivo AD models. We will also
analyze the applicability of selective NF-kB inhibitors and anti-miRNA (AM) strategies in
restoring homeostasis in this system. Our long term goal is the therapeutic manipulation of
these miRNA-regulated epigenetic pathways to provide an efficacious treatment for the clinical
management of AD at an early stage.
阿尔茨海默病(AD)中的microRNA(miRNA)信号传导
通过广泛的基于miRNA和DNA的表达阵列、LED Northern、ELISA,
基于Western,免疫学和生物信息学的分析,我们发现了一个高度
NF-κ B敏感性、上调的促炎microRNAs(miRNAs)的相互作用网络
以及它们下调的信使RNA(mRNA)靶点和这些mRNA的蛋白质
散发性阿尔茨海默病(AD)大脑中的编码。这些致病基因的上调
miRNAs及其下调的mRNA靶点在应激的人类中得到了进一步的分析。
原代培养物中的脑细胞和5xFAD淀粉样蛋白过表达转基因小鼠系中的脑细胞。
通过miRNA和mRNA丰度分析,miRNA-mRNA互补作图,
结合能量(EA)指数,ELISA和Western分析,我们可以解释大部分的
观察AD过程的神经病理学特征,通过分析
选择性miRNA-mRNA信号传导。我们的假设是存在一个至少6人的小家庭,
AD大脑中负责靶向和下调
一组负责淀粉样蛋白生成的致病信使RNA(mRNA)靶标,tau
病理学和神经炎症伴随突触发生缺陷,先天性,
免疫、吞噬作用和Aβ42肽清除的进行性损害。
我们之前的5年NIA R 01的更新将调查此
一组6种促炎性、致病性miRNA在散发性AD脑中上调,在应激性AD脑中上调,
在5xFAD小鼠脑中的原代培养物中的人脑细胞。6个上调的亲-
待详细研究的炎性微RNA是miRNA-7、miRNA-9、miRNA-34 a、miRNA-125 b,
miRNA-146 a和miRNA-155。压力源将是那些在老化的AD大脑中发现的压力源
- 这些包括活性氧(ROS)、促炎细胞因子IL-1β和TNFα
和Aβ42肽。具体目标1将分析这些因素在中度至中度
晚期散发性AD和唐氏综合征(DS)大脑;具体目标2将分析
这些因子在应激人脑细胞中的作用,即在神经元-神经胶质原代细胞中的作用,
具体目标3将分析这些因素在5xFAD淀粉样蛋白中的作用,
表达转基因小鼠品系。我们将特别强调对最高层的研究-
调节的miRNA:miRNA-7、miRNA-9、miRNA 34 a和miRNA-146 a及其靶向的
UBE 2A(泛素缀合酶蛋白)和TREM 2(在细胞中表达的触发受体)的破坏
在AD脑中以及在体外和体内AD模型中的微胶质细胞)信号传导。我们还将
分析选择性NF-κ B抑制剂和抗miRNA(AM)策略在
恢复这个系统的平衡我们的长期目标是治疗操纵
这些miRNA调节的表观遗传途径为临床提供了有效的治疗。
在早期阶段管理AD。
项目成果
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{{ truncateString('WALTER J LUKIW', 18)}}的其他基金
Micro RNA-146a (miRNA-146a) signaling in Alzheimers disease (AD)
阿尔茨海默病 (AD) 中的微小 RNA-146a (miRNA-146a) 信号传导
- 批准号:
8183976 - 财政年份:2011
- 资助金额:
$ 36.5万 - 项目类别:
Micro RNA-146a (miRNA-146a) signaling in Alzheimers disease (AD)
阿尔茨海默病 (AD) 中的微小 RNA-146a (miRNA-146a) 信号传导
- 批准号:
8508780 - 财政年份:2011
- 资助金额:
$ 36.5万 - 项目类别:
Micro RNA-146a (miRNA-146a) signaling in Alzheimers disease (AD)
阿尔茨海默病 (AD) 中的微小 RNA-146a (miRNA-146a) 信号传导
- 批准号:
8700279 - 财政年份:2011
- 资助金额:
$ 36.5万 - 项目类别:
Micro RNA-146a (miRNA-146a) signaling in Alzheimers disease (AD)
阿尔茨海默病 (AD) 中的微小 RNA-146a (miRNA-146a) 信号传导
- 批准号:
8307767 - 财政年份:2011
- 资助金额:
$ 36.5万 - 项目类别:
Micro RNA-146a (miRNA-146a) signaling in Alzheimers disease (AD)
阿尔茨海默病 (AD) 中的微小 RNA-146a (miRNA-146a) 信号传导
- 批准号:
8897930 - 财政年份:2011
- 资助金额:
$ 36.5万 - 项目类别:
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