From Physiological Liquids to Pathological Gels: Regulation of Protein Phase Separation in Neurodegenerative Disease
From Physiological Liquids to Pathological Gels: Regulation of Protein Phase Separation in Neurodegenerative Disease
批准号:
9089249
负责人:
Shana Elbaum
金额:
$9.11万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-04-01 至 2018-03-31
关键词:
AgeAgingBiogenesisBiological ModelsCaenorhabditis elegansCellsComplexCytoplasmic GranulesDependenceDiseaseEngineeringEnvironmentEvolutionGelGenerationsGoalsHealthLinkLiquid substanceMaintenanceMapsMentorsMethodologyMolecularMorphologyNerve DegenerationNeurodegenerative DisordersPathologyPathway interactionsPhasePhase TransitionPhysicsPhysiologicalPropertyProtein ConformationProteinsQuality ControlRNARNA-Binding Protein FUSRegulationRoleStressSymptomsTechniquesTestingTherapeuticTherapeutic InterventionToxic effectWorkamyloid formationin vivoinnovationinsightlensliquid dynamicsmaterials sciencemolecular targeted therapiesnovelnovel therapeuticspreventprotein TDP-43protein aggregateprotein aggregationpublic health relevancesingle molecule
中文摘要
英文摘要
DESCRIPTION (provided by applicant): Pathological protein aggregation is ubiquitously associated with neurodegenerative disease, but the underlying mechanisms are largely unclear. Recent groundbreaking work suggests a role for intracellular liquid phase transitions in governing the assembly and organization of functional protein assemblies or granules with liquid-like properties. This proposal seeks to test the hypothesis that misregulation of intracellular liquid phase separation leads to detrimental protein aggregation. In the mentored phase, Aim 1 seeks to define the physicochemical parameters and phase landscape of stress granule proteins implicated in disease. This aim will be achieved through applying principles of engineering and soft matter physics along with unique rheological methodologies previously developed by Dr. Elbaum. Aim 2 seeks to determine the relationship between liquid phases, aggregation and toxicity in vivo as a function of aging and stress. Using the C. elegans model system, this aim will establish whether liquid protein phases prevent or promote amyloid formation, and garner insight into whether aging and/or stress contribute to regulation of protein assembly. In the independent phase, Aim 3 seeks to identify molecular pathways regulating protein assembly and further resolve the molecular mechanisms underlying regulation. This aim will be achieved through a unique multi-scale approach combining single molecule techniques, material science methodologies, and organismal level interrogation. Together, this innovative strategy will offer novel insight into the biogenesis of pathological protein aggregation, and define new pathways and distinct molecular targets for therapeutic interventions aimed at preventing or reducing the health burdens of neurodegenerative disease.
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会议论文
Architecture, dynamics and cell-specific behavior of tau condensates
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批准号:10662730
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项目类别:
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资助金额:$39.19万
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财政年份:2023
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负责人:Shana Elbaum
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依托单位:
海外基金