Tau structure and dynamics in Alzheimer's disease
阿尔茨海默病中的 Tau 结构和动力学
基本信息
- 批准号:10659553
- 负责人:
- 金额:$ 51.02万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-08-15 至 2028-04-30
- 项目状态:未结题
- 来源:
- 关键词:AccelerationAdoptedAffectAlzheimer&aposs DiseaseAlzheimer&aposs disease modelAlzheimer&aposs disease pathologyAmyloidAxonBindingBiochemicalBiological AssayBiomedical ResearchBrainC-terminalChargeChemicalsComplexCryoelectron MicroscopyDataDemocracyDiagnosisDiseaseDissociationDrug DesignElectron MicroscopyEpitopesFilamentFutureHeparinHumanIn VitroJointsLabelLengthLightMAPT geneMeasuresMediatingMembraneMembrane LipidsMethodsMicrotubulesModernizationModificationMolecularMolecular ConformationMolecular StructureMusMutationN-terminalNMR SpectroscopyNeurodegenerative DisordersNeurofibrillary TanglesNeuronsPathologicPathologyPhosphorylationPhosphorylation SitePost-Translational Protein ProcessingProcessProline-Rich DomainPropertyProteinsRecombinantsResearchShapesSiteSocietiesStagingStructureSurfaceSynaptic MembranesTauopathiesTertiary Protein StructureTestingTherapeutic InterventionToxic effectWild Type MouseWorkcofactordrug discoveryexperimental studyin vitro Modelmicroscopic imagingmimeticsmolecular dynamicsmonomermutantneuropathologyneurotoxicitynovelpaired helical filamentphospho-L-arginineprion-likereconstructionsolid statesolid state nuclear magnetic resonancetau Proteinstau aggregationtau interactiontau-1unilamellar vesicle
项目摘要
Project Summary - Despite decades of research into Alzheimer's disease (AD), disease-modifying
treatments for AD remain elusive. This is significantly due to challenges in understanding the molecular and
structural basis of AD. One of the two hallmarks of AD is the neurofibrillary tangles formed by the
intrinsically disordered microtubule (MT)-associated protein tau. Spreading of tau filaments in the brain is
the basis of neuropathological staging of AD. AD tau is hyperphosphorylated, truncated, and decorated with
other posttranslational modifications (PTMs). However, how these PTMs cause tau to dissociate from MTs
and misfold into -sheet amyloids, and how tau crosses the lipid membrane to spread its pathology, is not
known. AD paired helical filament (PHF) tau fibrils have a C-shaped -sheet core that encompasses part of
the MT-binding repeats. But the majority of the protein, which contains most of the disease-relevant PTMs,
is too disordered to be seen in cryo-electron microscopy data. Here we propose to employ solid-state NMR
(ssNMR) spectroscopy, electron microscopy, mouse neuron toxicity assays, and other biochemical
approaches to understand the molecular structures and dynamics of AD tau filaments, membrane-bound
tau, and MT-bound tau. We hypothesize that specific charge-charge interactions underlie the varying
conformations, dynamics and properties of tau when self-aggregated and when bound to its cellular
partners. In the last four years, we demonstrated the feasibility of applying ssNMR to study the structures
and dynamics of full-length tau fibrils formed in vitro and seeded by AD PHF tau. We will now apply this
expertise to answer three questions. In Aim 1, we will investigate how phosphorylation and truncation cause
AD PHF tau by determining the structures of phosphorylated tau (p-tau) fibrilized without anionic cofactors;
searching for minimum constructs that replicate the AD PHF tau structure and properties; and
characterizing the dynamic structures of the semi-mobile proline-rich region of tau. In Aim 2, we will
investigate tau interactions with lipid membranes by measuring the conformation, dynamics and membrane
insertion of monomeric tau bound to small and large unilamellar vesicles. We will determine the structures
of membrane-induced tau aggregates, and probe how phosphorylation and truncation affect the structure
and dynamics of membrane-bound tau. These experiments should shine light on how lipid membranes
nucleate tau aggregates and how aggregated tau crosses the membrane. In Aim 3, we will investigate the
structures of MT-bound tau as a function of phosphorylation, and probe how arginine-phosphate
interactions in the R' domain affect tau binding to MTs. A joint study of the fibrillar, membrane-bound and
MT-bound tau is crucial for understanding how tau converts from its intrinsically disordered structure to an
aggregated structure that propagates in a prion-like manner. This understanding should inform the future
design of drugs that interfere with this process.
项目总结-尽管对阿尔茨海默病(AD)进行了数十年的研究,但疾病改善
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Mei Hong其他文献
Mei Hong的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Mei Hong', 18)}}的其他基金
Molecular structures of tau aggregates studied by solid-state NMR
通过固态核磁共振研究 tau 聚集体的分子结构
- 批准号:
10230898 - 财政年份:2018
- 资助金额:
$ 51.02万 - 项目类别:
Solid-state NMR of the influenza M2 protein in lipid bilayers
脂质双层中流感 M2 蛋白的固态 NMR
- 批准号:
8508272 - 财政年份:2009
- 资助金额:
$ 51.02万 - 项目类别:
Solid-state NMR of the influenza M2 protein in lipid bilayers
脂质双层中流感 M2 蛋白的固态 NMR
- 批准号:
9231933 - 财政年份:2009
- 资助金额:
$ 51.02万 - 项目类别:
Structures and Dynamics of Proton and Cation-Dependent Channels and Transporters
质子和阳离子依赖性通道和转运蛋白的结构和动力学
- 批准号:
10659039 - 财政年份:2009
- 资助金额:
$ 51.02万 - 项目类别:
Solid-state NMR of influenza M2 protein in lipid bilayers
脂质双层中流感 M2 蛋白的固态 NMR
- 批准号:
7939909 - 财政年份:2009
- 资助金额:
$ 51.02万 - 项目类别:
Structures and Dynamics of Proton and Cation-Dependent Channels and Transporters
质子和阳离子依赖性通道和转运蛋白的结构和动力学
- 批准号:
10296879 - 财政年份:2009
- 资助金额:
$ 51.02万 - 项目类别:
Quadruple-resonance HFXY 1.3 mm CP-MAS probe for a solid-state NMR wide-bore magnet
用于固态 NMR 大口径磁体的四共振 HFXY 1.3 mm CP-MAS 探头
- 批准号:
10798817 - 财政年份:2009
- 资助金额:
$ 51.02万 - 项目类别:
Solid-state NMR of the influenza M2 protein in lipid bilayers
脂质双层中流感 M2 蛋白的固态 NMR
- 批准号:
9306548 - 财政年份:2009
- 资助金额:
$ 51.02万 - 项目类别:
Solid-state NMR of the influenza M2 protein in lipid bilayers
脂质双层中流感 M2 蛋白的固态 NMR
- 批准号:
8894893 - 财政年份:2009
- 资助金额:
$ 51.02万 - 项目类别:
相似海外基金
How novices write code: discovering best practices and how they can be adopted
新手如何编写代码:发现最佳实践以及如何采用它们
- 批准号:
2315783 - 财政年份:2023
- 资助金额:
$ 51.02万 - 项目类别:
Standard Grant
One or Several Mothers: The Adopted Child as Critical and Clinical Subject
一位或多位母亲:收养的孩子作为关键和临床对象
- 批准号:
2719534 - 财政年份:2022
- 资助金额:
$ 51.02万 - 项目类别:
Studentship
A comparative study of disabled children and their adopted maternal figures in French and English Romantic Literature
英法浪漫主义文学中残疾儿童及其收养母亲形象的比较研究
- 批准号:
2633211 - 财政年份:2020
- 资助金额:
$ 51.02万 - 项目类别:
Studentship
A material investigation of the ceramic shards excavated from the Omuro Ninsei kiln site: Production techniques adopted by Nonomura Ninsei.
对大室仁清窑遗址出土的陶瓷碎片进行材质调查:野野村仁清采用的生产技术。
- 批准号:
20K01113 - 财政年份:2020
- 资助金额:
$ 51.02万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
A comparative study of disabled children and their adopted maternal figures in French and English Romantic Literature
英法浪漫主义文学中残疾儿童及其收养母亲形象的比较研究
- 批准号:
2436895 - 财政年份:2020
- 资助金额:
$ 51.02万 - 项目类别:
Studentship
A comparative study of disabled children and their adopted maternal figures in French and English Romantic Literature
英法浪漫主义文学中残疾儿童及其收养母亲形象的比较研究
- 批准号:
2633207 - 财政年份:2020
- 资助金额:
$ 51.02万 - 项目类别:
Studentship
The limits of development: State structural policy, comparing systems adopted in two European mountain regions (1945-1989)
发展的限制:国家结构政策,比较欧洲两个山区采用的制度(1945-1989)
- 批准号:
426559561 - 财政年份:2019
- 资助金额:
$ 51.02万 - 项目类别:
Research Grants
Securing a Sense of Safety for Adopted Children in Middle Childhood
确保被收养儿童的中期安全感
- 批准号:
2236701 - 财政年份:2019
- 资助金额:
$ 51.02万 - 项目类别:
Studentship
A Study on Mutual Funds Adopted for Individual Defined Contribution Pension Plans
个人设定缴存养老金计划采用共同基金的研究
- 批准号:
19K01745 - 财政年份:2019
- 资助金额:
$ 51.02万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Structural and functional analyses of a bacterial protein translocation domain that has adopted diverse pathogenic effector functions within host cells
对宿主细胞内采用多种致病效应功能的细菌蛋白易位结构域进行结构和功能分析
- 批准号:
415543446 - 财政年份:2019
- 资助金额:
$ 51.02万 - 项目类别:
Research Fellowships