microRNA (miRNA) signaling in Alzheimer's disease(AD)
microRNA (miRNA) signaling in Alzheimer's disease(AD)
批准号:
9176078
负责人:
WALTER J LUKIW
金额:
$36.5万
依托单位国家:
美国
项目类别:
财政年份:
2011
资助国家:
美国
项目状态:
已结题
起止时间:
2011-08-01 至 2021-04-30
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
中文摘要
阿尔茨海默病(AD)中的microRNA信号传导
英文摘要
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.
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Micro RNA-146a (miRNA-146a) signaling in Alzheimers disease (AD)
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批准号:8183976
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项目类别:
-
资助金额:$29.11万
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财政年份:2011
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负责人:WALTER J LUKIW
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依托单位:
Micro RNA-146a (miRNA-146a) signaling in Alzheimers disease (AD)
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批准号:8508780
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项目类别:
-
资助金额:$27.51万
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财政年份:2011
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负责人:WALTER J LUKIW
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依托单位:
Micro RNA-146a (miRNA-146a) signaling in Alzheimers disease (AD)
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批准号:8700279
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项目类别:
-
资助金额:$29.11万
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财政年份:2011
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负责人:WALTER J LUKIW
-
依托单位:
Micro RNA-146a (miRNA-146a) signaling in Alzheimers disease (AD)
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批准号:8307767
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项目类别:
-
资助金额:$29.11万
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财政年份:2011
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负责人:WALTER J LUKIW
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依托单位:
Micro RNA-146a (miRNA-146a) signaling in Alzheimers disease (AD)
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批准号:8897930
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项目类别:
-
资助金额:$28.24万
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财政年份:2011
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负责人:WALTER J LUKIW
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依托单位:
Gene Expression in Alzheimer's Disease
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批准号:7196144
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项目类别:
-
资助金额:$22.81万
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财政年份:2001
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负责人:WALTER J LUKIW
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依托单位:
Gene Expression in Alzheimer's Disease
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批准号:6721226
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项目类别:
-
资助金额:$23.77万
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财政年份:2001
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负责人:WALTER J LUKIW
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依托单位:
Gene Expression in Alzheimer's Disease
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批准号:6509745
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项目类别:
-
资助金额:$23.77万
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财政年份:2001
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负责人:WALTER J LUKIW
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依托单位:
Gene Expression in Alzheimer's Disease
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批准号:6855783
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项目类别:
-
资助金额:$23.77万
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财政年份:2001
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负责人:WALTER J LUKIW
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依托单位:
Gene Expression in Alzheimer's Disease
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批准号:6631474
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项目类别:
-
资助金额:$23.77万
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财政年份:2001
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负责人:WALTER J LUKIW
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依托单位:
Gene Expression in Alzheimer's Disease
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批准号:6333292
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项目类别:
-
资助金额:$23.77万
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财政年份:2001
-
负责人:WALTER J LUKIW
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依托单位:
Ocular HSV-Latency, Reactivation, and Recurrence
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批准号:8293325
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项目类别:
-
资助金额:$42.08万
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财政年份:1985
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负责人:WALTER J LUKIW
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依托单位:
海外基金