Peroxisomal fatty acid metabolism in genetic and age-related disorders
遗传和年龄相关疾病中的过氧化物酶体脂肪酸代谢
基本信息
- 批准号:10559614
- 负责人:
- 金额:$ 12.5万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-02-01 至 2024-01-31
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalATP HydrolysisATP phosphohydrolaseATP-Binding Cassette TransportersAcyl Coenzyme AAdrenoleukodystrophyAffectAffinityAgingAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAntibodiesAreaAxonBile Acids and SaltsBindingBiochemical ReactionBiogenesisBiological AssayBiologyBiophysicsBiotinylationBrainCatalytic DomainCell LineCell membraneCell physiologyCellsCentral Nervous SystemCentral Nervous System DiseasesCoenzyme AComplexConfocal MicroscopyCoupledCouplingCryo-electron tomographyCryoelectron MicroscopyCytoplasmCytoplasmic ReceptorsCytosolDefectDemyelinationsDiabetes MellitusDiseaseEnzymesEquilibriumEthersEukaryotic CellEventFatty AcidsFosteringFunctional disorderGene DeletionGenerationsGeneticGoalsHeartHereditary DiseaseHomeostasisHumanIonsLengthLibrariesLipidsLiverMass Spectrum AnalysisMeasuresMediatingMedium chain fatty acidMembraneMembrane ProteinsMentorsMetabolic DiseasesMetabolic PathwayMetabolismMitochondriaMolecularMolecular ChaperonesMolecular ConformationMolecular StructureMorphologyMutationMyelin SheathNADHNeurodegenerative DisordersNeurogliaNeuronsNucleotidesOrganOrganellesOrthologous GeneOxidative StressPancreasPathogenesisPhasePlantsPlayProcessProteinsProtocols documentationReactionReactive Oxygen SpeciesReportingResearchResearch PersonnelResolutionRoleScanning Electron MicroscopyScientistSideSiteSpecificityStreptavidinStructureSulfhydryl CompoundsTestingTrainingVisualizationZellweger Syndromeage relatedage related neurodegenerationanalogbranched chain fatty acidcell agecryogenicselectron tomographyexperiencefatty acid metabolismfatty acid transportgene repressionknock-downlenslipid metabolismloss of functionmembermutantoxidationperoxisomeperoxisome lumenperoxisome membranepreservationprotein structureresponsetoolverdin photosensitizer
项目摘要
Project Summary/Abstract
Peroxisomes are ubiquitous eukaryotic organelles that form a focal point for multiple metabolic pathways. Lipid
metabolism, and in particular, fatty acid transport related to it, depend heavily on peroxisomal membrane
proteins that have specifically evolved for such purposes. The ATP-dependent cassette (ABC) transporters of
‘D’ subfamily’ reside in the peroxisomal membrane and are responsible for fatty acid import into the
peroxisomes, defects in which process are related to various metabolic disorders. Mutations in ABCD1 cause
X-linked adrenoleukodystrophy (X-ALD) which manifests as mild to severe central nervous system (CNS)
demyelination. Dysfunction of ABCD3 and/or peroxisome biogenesis factors (PEXs) may cause Zellweger
syndrome (ZS), a heterogeneous group of peroxisome assembly disorders. In addition to inherited diseases,
reduced peroxisomal function is associated with aging and pathogenesis of age-related acquired diseases like
diabetes, neurodegenerative disorders. Key gaps in understanding the function of ABCDs in metabolism and
disease are due to lack of structural details, particularly of their conformational plasticity during substrate
transport, and how this is compromised during aging and disease. My goal is to understand the involvement
of peroxisomal fatty acid metabolism in aging and age-related neurodegenerative diseases, specifically
Alzheimer’s disease and ultimately to lead a research group as an independent researcher in this area.
I propose to elucidate the structural basis for function of ABCDs at atomic level using CryoEM in the absence
and presence of substrate, and ATP (Aim 1a and 1b, mentored), coupling between ATPase and thioesterase
activity, and fatty acid binding and transport (Aim 2a and 2b, mentored). I will determine atomic structures of
ABCDs in complex with PEXs (Pex3 and Pex19) using CryoEM (Aim 3a, mentored) and assess alterations in
peroxisomal morphology using Cryo-Electron Tomography; function and membrane composition of ABCD(1-3)
knockdown cell lines, aged cells and Alzheimer’s disease (AD) model cell lines (Aim 3b, 3c, 3d mentored/
independent phase). These aims foster my long-term aim of studying peroxisome function and its relation to
cellular physiology and disease, while obtaining training and experience in forefront tools of structural
biophysics. For executing these aims, I have support of a very strong team of mentors, consultants and
advisors. My mentor Prof. Robert Stroud is a pioneer in membrane protein structure and mechanism, my co-
mentor Prof. Peter Walter is a pioneer in the unfolded protein response (UPR) and specializes in cell and
organelle biology. My co-mentor Dr. Adam Frost is at the forefront of CryoEM/CryoET. Consultant Prof. Eric
Verdin is a leading scientist in aging. Consultant Prof. Martin Kampmann is discovering new molecular players
in AD. Scientific advisors Prof. Yifan Cheng pioneered CryoEM and Prof. Charles Craik has developed
antibody and Fab libraries as tools. Together, this proposal will utilize their expertise in the respective fields,
while leveraging my passion to study organellar biology through a structural lens.
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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Meghna Gupta其他文献
Meghna Gupta的其他文献
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{{ truncateString('Meghna Gupta', 18)}}的其他基金
Peroxisomal fatty acid metabolism in genetic and age-related disorders
遗传和年龄相关疾病中的过氧化物酶体脂肪酸代谢
- 批准号:
10371815 - 财政年份:2022
- 资助金额:
$ 12.5万 - 项目类别:
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