The role of sulfatide in myelin stability
The role of sulfatide in myelin stability
批准号:
10373193
负责人:
Jeffrey L. Dupree
金额:
$19.41万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
已结题
起止时间:
2021-09-30 至 2023-08-31
关键词:
AdultAgeAlzheimer&aposs DiseaseAttentionAutoimmune DiseasesAxonBiochemicalBiologicalBrainCell Differentiation processCell ProliferationCell-Cell AdhesionComplementComplexConfocal MicroscopyConsequentialismDemyelinationsDeteriorationDevelopmentDiseaseDisease ProgressionElectron MicroscopyElectronsElectrophysiology (science)EventFractionationGeneticGlycosphingolipidsGolgi ApparatusHealthImmunofluorescence ImmunologicImmunologicsImpairmentLateralLifeLinkLipidsMembraneMethodsMotorMultiple SclerosisMusMyelinMyelin ProteinsMyelin SheathNeurodegenerative DisordersNeuronsOligodendrogliaOnset of illnessPathologicPathologyPathway interactionsPlayProteinsRegulationReportingRoleSNAP receptorSensorySiteSpinal CordStructureSulfoglycosphingolipidsTechniquesTertiary Protein StructureTestingVesicleWorkaxonal degenerationbasecell typecognitive disabilitydesignhuman diseaseinsightintercellular communicationmyelin degenerationneuron lossnovelpre-clinicalprotein transportrecruittraffickingvesicle transport
中文摘要
总结
英文摘要
Summary
Multiple sclerosis (MS) is an autoimmune disease characterized by CNS demyelination.
Estimates suggest that MS effects >700,000 US citizens. Although there are ~20 approved
therapies, treatments have limited efficacies and there is no cure. The cause of MS is unknown
but involves an interaction of environmental, immunologic and genetic factors. Although no
genetic link has been established, studies consistently report a significant reduction of the
myelin lipid sulfatide prior to demyelination. Specific and early reduction of sulfatide is consistent
with the depletion of this lipid playing a causative role in disease onset and progression.
Although the function of sulfatide has not been fully elucidated, it has been implicated in a
variety of biological roles including protein trafficking, cell-cell adhesion, membrane
organization, and cell differentiation and proliferation. Interestingly, depletion of sulfatide has
also been identified as an early and consistent event in neurodegenerative diseases including
Alzheimer’s disease and multiple sclerosis. Strong evidence suggests that in AD reduced levels
of sulfatide impairs intercellular communication between oligodendrocytes and neurons resulting
in compromised neuronal health. Its role in multiple sclerosis has received far less attention but
may facilitate myelin instability and subsequent axonal degeneration.
Based on work from my lab using a mouse incapable of synthesizing sulfatide, it appears that
depletion of this lipid results in pathologies consistent with myelin deficits observed in MS.
However, our previous work was based on a mouse that lacked sulfatide at all stages of life
including early development. Therefore, these myelin abnormalities may be consequential of
abnormal development rendering the applicability of the findings based on the sulfatide deficient
mice somewhat in question with regard to adult onset disease. To overcome this limitation, we
have generated a new mouse that allows us to deplete sulfatide with cell type- and age- specific
regulation. Using this mouse, we will investigate the structural and functional consequences of
adult onset sulfatide loss and relate these pathologies with known pathologies of MS.
Additionally, we propose that sulfatide plays a role in intracellular trafficking and in MS, and our
novel mouse, myelin protein trafficking to the mature myelin sheath is compromised leading to
the loss in myelin integrity. Completion of the studies outlined in this proposal will not only
provide quantitation of progressive myelin and axon degeneration consequential of sulfatide
depletion but will investigate a sulfatide specific mechanism, that may be compromised in MS,
that regulates myelin stability and function.
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The role of sulfatide in myelin stability
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The Potential of Didox as an Oral Therapy for Multiple Sclerosis
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Generation of a floxed CST mouse
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Generation of a floxed CST mouse
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