Uncovering Protein Interactions and Membrane Phase Preferences that alter the Plasma Membrane trafficking of Peripheral Myelin Protein 22
Uncovering Protein Interactions and Membrane Phase Preferences that alter the Plasma Membrane trafficking of Peripheral Myelin Protein 22
批准号:
10011580
负责人:
Justin Tyler Marinko
金额:
$1.59万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2019
资助国家:
美国
项目状态:
已结题
起止时间:
2019-07-01 至 2020-12-12
关键词:
ActinsAddressAdhesionsAffectAlzheimer&aposs DiseaseBindingBiologicalBiological AssayCell membraneCell physiologyCell surfaceCellsCharcot-Marie-Tooth DiseaseCholesterolCollaborationsConfocal MicroscopyCrowdingCytoskeletonDNA Sequence AlterationDataDiseaseEndoplasmic ReticulumEnvironmentFlow CytometryGene DeletionGene DosageGene DuplicationGenesGoalsHela CellsHereditary neuropathy with liability to pressure palsies HydrophobicityImpairmentIndividualIntegral Membrane ProteinLeadLinkMass Spectrum AnalysisMediatingMembraneMembrane ProteinsMicroscopyMissense MutationMolecularMolecular ConformationMonitorMusMutateMutationMutation AnalysisMyelinNeurodegenerative DisordersNeuropathyPMP22 geneParkinson DiseasePatientsPeripheral Nervous SystemPeripheral Nervous System DiseasesPhasePlayPost-Translational Protein ProcessingProcessProtein GlycosylationProteinsProteomicsQuality ControlRattusResearchResearch PersonnelRoleSchwann CellsScientistSmall Interfering RNASyndromeSystemTestingTherapeuticTransfectionVesicleWorkbasecareerhuman diseaseknock-downmembermigrationmutantnovelnovel therapeuticsoverexpressionpalmitoylationpreferenceprotein expressionprotein foldingscreeningsmall moleculesmall molecule librariessymptom managementtrafficking
中文摘要
项目总结:作为一名独立研究人员,我职业生涯的一个主要目标是了解如何整合
英文摘要
PROJECT SUMMARY: A major goal of my career as an independent researcher is to understand how integral
membrane proteins fold in the crowded environment of the endoplasmic reticulum (ER). Disruptions in the fidelity of this
process lead to a number of human diseases including Alzheimer’s, Parkinson’s and Charcot-Marie-Tooth Disease
(CMTD). By better understanding this process, I hope to eventually identify novel therapeutic strategies for treating
patients afflicted with these diseases. CMTD is the most common neuropathy of the peripheral nervous system (PNS) and
afflicts 1 in 2,500 individuals. Over 80% of patients afflicted with this disease have a mutation in the protein encoding
PMP22 gene. PMP22 is a tetraspan integral membrane protein that is highly expressed at the plasma membrane (PM) of
myelinating Schwann cells of the PNS. Improper gene dosage of PMP22 in CMTD patients results in either too much or
too little PMP22 at the PM of Schwann cells. The altered amount of PMP22 at the PM is believed to cause the myelin
abnormalities observed in these patients. There are currently no treatments for CMTD. PMP22 folds in the ER under the
surveillance of the ER quality control (QC) system. This system both helps PMP22 to fold as well as mediates the
ultimate decision whether to traffic PMP22 forward towards the PM or to retain the protein in the ER and ultimately target
it for degradation. The goals of this proposal are to understand the factors that mediate this decision process. Previous
results show that wild type (WT) PMP22 and PMP22 disease mutants have different protein interactions in the ER QC
system leading to varying PM expression. Preliminary data shows that selective modulation of protein expression in ER
can alter the cell surface trafficking of PMP22 and its disease mutants. Additionally, PMP22 associates with cholesterol
rich membrane domains at the PM. It has been shown for another membrane protein of the PNS, P0, that association with
cholesterol in the ER is necessary for cell surface trafficking. Schwann cells derived from PMP22 -/- mice show
decreased migration and adhesion capabilities and lower PM cholesterol content compared to WT Schwann cells. This
indicates that PMP22 association with cholesterol rich domains is important for Schwann cell function. It is my
hypothesis that PMP22 cell surface trafficking can be modulated by both changing its protein interaction network in the
ER and through altering its ability to associate with cholesterol rich membrane domains. To address this hypothesis, I
will: (1) uncover mutation specific changes to the PMP22 interactome in the ER that modulate its cell surface trafficking
and (2) examine the factors that cause PMP22 to associate with cholesterol rich membrane domains and assess the effects
of cholesterol association on PMP22 trafficking. The results from this proposal will uncover novel protein interactions and
factors that affect PMP22 trafficking and cholesterol association. This information will open novel avenues for scientists
attempting to develop therapeutics for patients who suffer from CMTD.
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会议论文
Uncovering the Role of UFM1 in the Release of Arrested Peptides from Stalled Ribosomes at the Endoplasmic Reticulum (ER) Membrane
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批准号:10462233
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项目类别:
-
资助金额:$0.0万
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财政年份:2022
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负责人:Justin Tyler Marinko
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依托单位:
海外基金