Specificity of ABCA7-mediated lipid efflux and its effects on intracellular lipid metabolism in neural cells
ABCA7介导的脂质流出的特异性及其对神经细胞细胞内脂质代谢的影响
基本信息
- 批准号:10591201
- 负责人:
- 金额:$ 22.32万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-01-01 至 2024-12-31
- 项目状态:已结题
- 来源:
- 关键词:ATP-binding cassette transportAffectAfrican ancestryAgeAge YearsAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease pathologyAlzheimer&aposs disease patientAlzheimer&aposs disease riskAmyloid beta-ProteinAmyloid beta-Protein PrecursorAnimalsArchitectureAstrocytesBiochemicalBrainCell membraneCellsCessation of lifeCholesterolCholesterol HomeostasisChromosome 21DataDementiaDimensionsDiseaseDown SyndromeEarly Onset Familial Alzheimer&aposs DiseaseElectrospray IonizationEngineeringEtiologyEuropean ancestryExhibitsGenesGeneticGenetic Predisposition to DiseaseGenetic studyGlioblastomaHealthcare SystemsHigh Density LipoproteinsHippocampusHumanIndividualInduced pluripotent stem cell derived neuronsInvestigationKnowledgeLabelLate Onset Alzheimer DiseaseLecithinLinkLipidsLongevityMass Spectrum AnalysisMeasuresMediatingMediatorMetabolicMicrogliaNerve DegenerationNeuroblastomaNeuronsParietal LobePathogenesisPathologicPathologyPerformancePhospholipidsPhosphotransferasesPhysiologyPopulationProductivityProteinsPublishingRadioactiveResearch PersonnelRiskRoleShotgunsSpecificityTestingThin Layer ChromatographyTissuesTrisomyVariantcomparativeextracellulargene functiongenome wide association studyhigh density lipoprotein-1lipid metabolismlipidomicsloss of functionloss of function mutationmembermouse modelneuralneuron lossparticlepreferencetau Proteins
项目摘要
Project Summary/Abstract
Alzheimer's disease (AD) dementia has emerged as a major burden on the healthcare system and a major
barrier to human longevity, especially productive human longevity. Genetics of familial early-onset AD,
pathological changes in the brain of sporadic late-onset AD patients and pathological changes in the brain of
individuals with Down syndrome, who frequently have increased expression of amyloid precursor protein (APP)
owing to partial trisomy of chromosome 21, all point to APP and its cleavage product amyloid β (Aβ) peptide as
major causative factors in AD pathogenesis. However, other factors may also play a role. The genome-wide
association studies (GWAS) of the architecture of common genetic predisposition to AD, genetic investigations
of rare loss-function mutations and studies in mouse models of AD have implicated ATP-binding cassette
transport subfamily A member 7 (ABCA7) in AD pathogenesis. A closely related protein, ATP-binding cassette
transport subfamily A member 1 (ABCA1) has been implicated in AD in the GWAS and animal studies. In our
preliminary data, we show that individuals with low ABCA7 protein levels have a greater risk for developing AD
pathology. Both ABCA1 and ABCA7 mediate formation of high-density lipoprotein (HDL) particles from cell
lipids. In preliminary data, we show that ABCA7- and ABCA1-HDL significantly differ in the lipid composition.
Recently, we published the altered lipidostasis hypothesis that draws on the paradigms provided by ABCA1
and another ABC A transporter, ABCA4, and poses the existence of a neurodegenerative lipid that
continuously arises during normal physiology and promotes AD pathogenesis when it is not eliminated from
neural cells by ABCA7. ABCA1 and ABCA4 eliminate from specific cells deleterious lipids that these cells
accumulate during normal function. The purpose of the present exploratory project is to conduct comparative
ABCA7 vs ABCA1 studies in specificity of lipid efflux in neural cells and to test the prediction of the lipidostasis
hypothesis of AD that in the neural tissue ABCA7 mediates efflux of a specific lipid species (i.e., the
neurodegenerative lipid) that is not effluxed significantly by ABCA1. To test this prediction, we will use
metabolic radioactive labeling of lipids/high performance thin layer chromatography (HPTLC) and
multidimensional electrospray
ionization
`shotgun' mass spectrometry lipidomics to compare ABCA7- and
ABCA1-mediated lipid efflux/HDL and the effects that this efflux/HDL formation has on the lipid composition of
the plasma membrane and whole cell in microglia C20, astrocyte glioblastoma A172 and neuroblastoma SK-N-
SH cells inducibly expressing ABCA7 or ABCA1.
项目总结/文摘
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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Nicholas Lyssenko其他文献
Nicholas Lyssenko的其他文献
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{{ truncateString('Nicholas Lyssenko', 18)}}的其他基金
Toward precision medicine: modulation of ABCA7 associated risk of Alzheimer's disease by ancestry
迈向精准医疗:通过血统调节 ABCA7 相关阿尔茨海默病风险
- 批准号:
10323669 - 财政年份:2021
- 资助金额:
$ 22.32万 - 项目类别:
A mouse model and iPS cells to study hyperactive ABCA1 in the eye in age-related macular degeneration
小鼠模型和 iPS 细胞研究年龄相关性黄斑变性中过度活跃的 ABCA1
- 批准号:
10362536 - 财政年份:2021
- 资助金额:
$ 22.32万 - 项目类别:
ABCA1-mediated biogenesis of nascent HDL particles
ABCA1 介导的新生 HDL 颗粒的生物发生
- 批准号:
8061006 - 财政年份:2011
- 资助金额:
$ 22.32万 - 项目类别:
ABCA1-mediated biogenesis of nascent HDL particles
ABCA1 介导的新生 HDL 颗粒的生物发生
- 批准号:
8448765 - 财政年份:2011
- 资助金额:
$ 22.32万 - 项目类别:
ABCA1-mediated biogenesis of nascent HDL particles
ABCA1 介导的新生 HDL 颗粒的生物发生
- 批准号:
8262670 - 财政年份:2011
- 资助金额:
$ 22.32万 - 项目类别:
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