Phase separation of nuclear tau and its role in gene regulation
Phase separation of nuclear tau and its role in gene regulation
批准号:
10710398
负责人:
Galia Debelouchina
金额:
$18.48万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
已结题
起止时间:
2022-09-30 至 2024-08-31
关键词:
AffectAffinityAlzheimer&aposs DiseaseAlzheimer&aposs disease brainAlzheimer&aposs disease patientAmyloidAmyloid FibrilsArchitectureBehaviorBindingBiological AssayBiophysicsCell CommunicationCell NucleusCell physiologyCellsChromatinChromatin Remodeling FactorChromosomal StabilityCoupledCrowdingCytoplasmDNADNA BindingDNA DamageDNA SequenceDevelopmentDiseaseEnvironmentExperimental DesignsFluorescence MicroscopyFluorescence Recovery After PhotobleachingGelGene ExpressionGene Expression RegulationGene SilencingHeterochromatinHistonesImageIn VitroKnock-outLiquid substanceLiteratureMagicMethylationMicrotubule-Associated ProteinsMicrotubulesMolecularMonitorMutationNMR SpectroscopyNeurofibrillary TanglesNeuronsNormal CellNuclearNuclear ProteinsNucleic AcidsPhasePhosphorylationPlayPost-Translational Protein ProcessingProcessProteinsPublished CommentRegulationRelaxationResearchRibosomal DNARoleSatellite DNAStressTestingUntranslated RNAUp-Regulationbiophysical propertiesdiagnostic strategyepigenetic markerexperimental studygene repressionin vivolive cell imagingmimeticsnovel diagnosticsnovel therapeuticsreconstitutionsolid state nuclear magnetic resonancetau Proteinstau aggregationtau expressiontau functiontau interactiontau-1transcriptome sequencing
中文摘要
项目总结
Tau是一种微管相关蛋白,存在于阿尔茨海默病患者脑内的神经原纤维缠结中
病人。Tau在体外和体内都能形成淀粉样纤维,并能在体内发生液-液相分离。
拥挤剂和核酸的存在。虽然tau的大部分研究都集中在它的微管上
相关功能和异常聚集在阿尔茨海默病的背景下,tau也在
原子核。越来越多的证据表明,核tau可能在DNA保护、染色体中发挥作用。
稳定性和异染色质的形成,尽管这些功能背后的分子机制
这在很大程度上仍然是个谜。
Tau在异染色质中的存在特别耐人寻味,因为它定位于一个
预测它会与其他已知蛋白质相分离的环境。因此,在
这个探索性的提议,
我们的目标是验证tau可能在异染色质调节中起作用的假设。
通过相分离机制。我们还假设异常的磷酸化和疾病-
相关突变可能会扰乱这一过程,并可能导致细胞调节基因的能力受损
表情。我们建议通过体外生物物理和结构分析来检验这些假说,
通过基于细胞的实验来更好地了解潜在的功能和生物物理
原子核tau的性质。我们的目标是为研究其背后的分子机制提供一个新的观点。
阿尔茨海默病不同于淀粉样蛋白假说,并希望告知新的发展
治疗和诊断方法。
英文摘要
Project summary
Tau is a microtubule-associated protein found in neurofibrillary tangles in the brains of Alzheimer’s disease
patients. Tau can form amyloid fibrils both in vitro and in vivo and can undergo liquid-liquid phase separation in
the presence of crowding agents and nucleic acids. While much of tau research has focused on its microtubule
associated functions and aberrant aggregation in the context of Alzheimer’s disease, tau is also found in the
nucleus. Mounting evidence has suggested that nuclear tau might play a role in DNA protection, chromosome
stability, and heterochromatin formation although the molecular mechanisms behind these functions have
largely remained enigmatic.
Tau’s presence in heterochromatin is especially intriguing, since it localizes to an
environment where it would be predicted to phase separate, with other proteins known to do so. Therefore, in
this exploratory proposal,
we aim to test a hypothesis that tau might play a role in heterochromatin regulation
through a phase separation mechanism. We also hypothesize that aberrant phosphorylation and disease-
relevant mutations may disrupt this process and may lead to compromised cellular ability to regulate gene
expression. We propose to test these hypotheses through in vitro biophysical and structural assays, coupled
with cell-based experiments designed to gain better understanding of the potential functions and biophysical
properties of nuclear tau. We aim to provide a new viewpoint regarding the molecular mechanisms behind
Alzheimer’s disease that is distinct from the amyloid hypothesis and hope to inform the development of new
therapeutic and diagnostic approaches.
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Phase separation of nuclear tau and its role in gene regulation
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批准号:10524696
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项目类别:
-
资助金额:$22.49万
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财政年份:2022
-
负责人:Galia Debelouchina
-
依托单位:
Structural biology of chromatin in vitro and in cells
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批准号:10190974
-
项目类别:
-
资助金额:$37.04万
-
财政年份:2020
-
负责人:Galia Debelouchina
-
依托单位:
Structural biology of chromatin in vitro and in cells
-
批准号:10028896
-
项目类别:
-
资助金额:$36.94万
-
财政年份:2020
-
负责人:Galia Debelouchina
-
依托单位:
Structural biology of chromatin in vitro and in cells
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批准号:10797358
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项目类别:
-
资助金额:$2.64万
-
财政年份:2020
-
负责人:Galia Debelouchina
-
依托单位:
Structural transformations of dementia-related proteins: droplets, gels and amyloids
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批准号:10055682
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项目类别:
-
资助金额:$41.34万
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财政年份:2020
-
负责人:Galia Debelouchina
-
依托单位:
Structural biology of chromatin in vitro and in cells
-
批准号:10657350
-
项目类别:
-
资助金额:$37.04万
-
财政年份:2020
-
负责人:Galia Debelouchina
-
依托单位:
Structural biology of chromatin in vitro and in cells
-
批准号:10439927
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项目类别:
-
资助金额:$37.04万
-
财政年份:2020
-
负责人:Galia Debelouchina
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依托单位:
海外基金