Structure and Genesis of tau Aggregates
tau 聚集体的结构和成因
基本信息
- 批准号:10522274
- 负责人:
- 金额:$ 182.17万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-06-01 至 2025-08-31
- 项目状态:未结题
- 来源:
- 关键词:AdoptedAffinityAlzheimer&aposs DiseaseAlzheimer&aposs disease diagnosisAlzheimer&aposs disease pathologyAlzheimer&aposs disease related dementiaAnionsAppearanceBehaviorBindingBiochemicalBiologicalBiological AssayBiological ModelsBrainBrain imagingCationsCellsCharacteristicsChemical StructureChemicalsComplexConceptionsCryoelectron MicroscopyDataDetectionDevelopmentDifferential DiagnosisDiseaseEngineeringEnvironmentEtiologyFilamentFundingGenerationsGenetic PolymorphismGoalsHardnessHeterogeneityIndividualLengthLigandsMediatingMethodsMicrotubulesModelingMolecularMolecular ConformationMorphologyNatureNerve DegenerationNeurodegenerative DisordersPathogenesisPathologicPeer ReviewPick Disease of the BrainPolymorphPopulationProcessProtein IsoformsProtomerRoleRouteSeverity of illnessShapesStagingStructureStructure-Activity RelationshipSurfaceTauopathiesTestingTherapeutic Interventioncomputational chemistrycovalent bonddiagnostic strategydriving forceimaging modalityinsightmodel designnovelnovel diagnosticsprion-likescaffoldsmall moleculetargeted treatmenttau Proteinstau aggregationtau phosphorylationtransmission process
项目摘要
PROJECT SUMMARY
Tau aggregation is a shared pathology of Alzheimer's disease and related dementias known as tauopathies.
Despite commonalities in aggregation mechanism, each disorder develops unique filamentous morphologies
that reflect differential vulnerability of their constituent cell populations. In addition to providing clues about the
cellular conditions associated with tauopathic neurodegeneration, the appearance of unique polymorphs in each
tauopathy implicates prion-like mechanisms of templating and spread that may influence the course and severity
of disease. As a result, aggregate polymorphism is a potential target for therapeutic intervention as well as for
differential diagnosis of tauopathies through development of whole-brain imaging methods. This proposal seeks
to advance these goals by clarifying mechanisms underlying aggregate nucleation, propagation and interaction
with small-molecule probes using biochemical and structural biological approaches. Specifically it aims to (1)
determine the effects of aggregation inducers including tau phosphorylation on polymorph formation, (2) clarify
mechanisms through which nucleation sequence motifs common to all tau isoforms trigger aggregation, (3)
rigorously test whether tau polymorphism can propagate through prion-like seeding mechanisms, and (4) identify
molecular interactions that mediate the binding affinity and selectivity of tau-aggregate directed ligands.
Accomplishing these goals will clarify the molecular basis of tauopathy pathogenesis and catalyze efforts toward
creating novel diagnostic strategies tailored toward individual tau aggregate polymorphs.
项目摘要
Tau聚集是阿尔茨海默病和相关痴呆症的共同病理学,称为Tau病。
尽管聚集机制有共性,但每种疾病都发展出独特的丝状形态
这反映了其组成细胞群的不同脆弱性。除了提供线索,
与tau蛋白病性神经变性相关的细胞状况,在每个细胞中出现独特的多晶型物,
tau蛋白病涉及朊病毒样的模板和传播机制,可能影响病程和严重程度
疾病。因此,聚集体多态性是治疗性干预的潜在靶标,也是治疗性干预的潜在靶标。
通过开发全脑成像方法鉴别诊断tau蛋白病。该提案寻求
通过澄清聚集体成核、传播和相互作用的基本机制来推进这些目标
使用生物化学和结构生物学方法的小分子探针。具体而言,它旨在(1)
确定包括tau磷酸化在内的聚集诱导剂对多晶型物形成的影响,(2)阐明
所有tau同种型共有的成核序列基序触发聚集的机制,(3)
严格测试tau多态性是否可以通过朊病毒样播种机制传播,以及(4)鉴定
介导tau聚集体定向配体的结合亲和力和选择性的分子相互作用。
实现这些目标将阐明tau蛋白病发病机制的分子基础,并促进
创造了针对个体tau聚集体多晶型物定制的新诊断策略。
项目成果
期刊论文数量(7)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Identification of gene networks mediating regional resistance to tauopathy in late-onset Alzheimer's disease.
鉴定基因网络,介导了晚期阿尔茨海默氏病中对tauopathy的区域抗性。
- DOI:10.1371/journal.pgen.1010681
- 发表时间:2023-03
- 期刊:
- 影响因子:4.5
- 作者:
- 通讯作者:
Computational integration of nanoscale physical biomarkers and cognitive assessments for Alzheimer's disease diagnosis and prognosis.
- DOI:10.1126/sciadv.1700669
- 发表时间:2017-07
- 期刊:
- 影响因子:13.6
- 作者:Yue T;Jia X;Petrosino J;Sun L;Fan Z;Fine J;Davis R;Galster S;Kuret J;Scharre DW;Zhang M
- 通讯作者:Zhang M
A New Approach for Estimating the Free Energy Differences among Multiple Thermodynamic States in Statistical Simulations.
估计统计模拟中多个热力学状态之间的自由能差异的新方法。
- DOI:10.1021/acs.jpclett.3c00620
- 发表时间:2023
- 期刊:
- 影响因子:0
- 作者:Yang,Jaehoon;Singer,SherwinJ
- 通讯作者:Singer,SherwinJ
A liquid chromatography tandem mass spectroscopy approach for quantification of protein methylation stoichiometry.
用于定量蛋白质甲基化化学计量的液相色谱串联质谱方法。
- DOI:10.1016/j.ab.2018.01.018
- 发表时间:2018
- 期刊:
- 影响因子:2.9
- 作者:Cooper,GraceL;Huseby,CarolJ;Chandler,ClaireN;Cocuron,Jean-Christophe;Alonso,AnaP;Kuret,Jeff
- 通讯作者:Kuret,Jeff
A theoretical study of polymorphism in VQIVYK fibrils.
VQIVYK原纤维多态性的理论研究。
- DOI:10.1016/j.bpj.2021.01.032
- 发表时间:2021
- 期刊:
- 影响因子:3.4
- 作者:Yang,Jaehoon;Agnihotri,MithilaV;Huseby,CarolJ;Kuret,Jeff;Singer,SherwinJ
- 通讯作者:Singer,SherwinJ
{{
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 }}
Jeff Kuret其他文献
Jeff Kuret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('Jeff Kuret', 18)}}的其他基金
Imaging agents for synucleinopathy drug discovery
用于突触核蛋白病药物发现的显像剂
- 批准号:
9182629 - 财政年份:2016
- 资助金额:
$ 182.17万 - 项目类别:
Imaging agents for synucleinopathy drug discovery
用于突触核蛋白病药物发现的显像剂
- 批准号:
9318582 - 财政年份:2016
- 资助金额:
$ 182.17万 - 项目类别:
STRUCTURE, FUNCTION, AND REGULATION OF CASEIN KINASE-1
酪蛋白激酶-1 的结构、功能和调控
- 批准号:
6386731 - 财政年份:1997
- 资助金额:
$ 182.17万 - 项目类别:
STRUCTURE, FUNCTION, AND REGULATION OF CASEIN KINASE-1
酪蛋白激酶-1 的结构、功能和调控
- 批准号:
6031731 - 财政年份:1997
- 资助金额:
$ 182.17万 - 项目类别:
相似海外基金
Construction of affinity sensors using high-speed oscillation of nanomaterials
利用纳米材料高速振荡构建亲和传感器
- 批准号:
23H01982 - 财政年份:2023
- 资助金额:
$ 182.17万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Affinity evaluation for development of polymer nanocomposites with high thermal conductivity and interfacial molecular design
高导热率聚合物纳米复合材料开发和界面分子设计的亲和力评估
- 批准号:
23KJ0116 - 财政年份:2023
- 资助金额:
$ 182.17万 - 项目类别:
Grant-in-Aid for JSPS Fellows
Platform for the High Throughput Generation and Validation of Affinity Reagents
用于高通量生成和亲和试剂验证的平台
- 批准号:
10598276 - 财政年份:2023
- 资助金额:
$ 182.17万 - 项目类别:
Development of High-Affinity and Selective Ligands as a Pharmacological Tool for the Dopamine D4 Receptor (D4R) Subtype Variants
开发高亲和力和选择性配体作为多巴胺 D4 受体 (D4R) 亚型变体的药理学工具
- 批准号:
10682794 - 财政年份:2023
- 资助金额:
$ 182.17万 - 项目类别:
Collaborative Research: DESIGN: Co-creation of affinity groups to facilitate diverse & inclusive ornithological societies
合作研究:设计:共同创建亲和团体以促进多元化
- 批准号:
2233343 - 财政年份:2023
- 资助金额:
$ 182.17万 - 项目类别:
Standard Grant
Collaborative Research: DESIGN: Co-creation of affinity groups to facilitate diverse & inclusive ornithological societies
合作研究:设计:共同创建亲和团体以促进多元化
- 批准号:
2233342 - 财政年份:2023
- 资助金额:
$ 182.17万 - 项目类别:
Standard Grant
Molecular mechanisms underlying high-affinity and isotype switched antibody responses
高亲和力和同种型转换抗体反应的分子机制
- 批准号:
479363 - 财政年份:2023
- 资助金额:
$ 182.17万 - 项目类别:
Operating Grants
Deconstructed T cell antigen recognition: Separation of affinity from bond lifetime
解构 T 细胞抗原识别:亲和力与键寿命的分离
- 批准号:
10681989 - 财政年份:2023
- 资助金额:
$ 182.17万 - 项目类别:
CAREER: Engineered Affinity-Based Biomaterials for Harnessing the Stem Cell Secretome
职业:基于亲和力的工程生物材料用于利用干细胞分泌组
- 批准号:
2237240 - 财政年份:2023
- 资助金额:
$ 182.17万 - 项目类别:
Continuing Grant
ADVANCE Partnership: Leveraging Intersectionality and Engineering Affinity groups in Industrial Engineering and Operations Research (LINEAGE)
ADVANCE 合作伙伴关系:利用工业工程和运筹学 (LINEAGE) 领域的交叉性和工程亲和力团体
- 批准号:
2305592 - 财政年份:2023
- 资助金额:
$ 182.17万 - 项目类别:
Continuing Grant