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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：
Jeff Kuret
金额：
$ 182.17万
依托单位：
OHIO STATE UNIVERSITY
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：
https://reporter.nih.gov/project-details/10522274
关键词：
Adopted Affinity Alzheimer&apos s Disease Alzheimer&apos s disease diagnosis Alzheimer&apos s disease pathology Alzheimer&apos s disease related dementia Anions Appearance Behavior Binding Biochemical Biological Biological Assay Biological Models Brain Brain imaging Cations Cells Characteristics Chemical Structure Chemicals Complex Conceptions Cryoelectron Microscopy Data Detection Development Differential Diagnosis Disease Engineering Environment Etiology Filament Funding Generations Genetic Polymorphism Goals Hardness Heterogeneity Individual Length Ligands Mediating Methods Microtubules Modeling Molecular Molecular Conformation Morphology Nature Nerve Degeneration Neurodegenerative Disorders Pathogenesis Pathologic Peer Review Pick Disease of the Brain Polymorph Population Process Protein Isoforms Protomer Role Route Severity of illness Shapes Staging Structure Structure-Activity Relationship Surface Tauopathies Testing Therapeutic Intervention computational chemistry covalent bond diagnostic strategy driving force imaging modality insight model design novel novel diagnostics prion-like scaffold small molecule targeted treatment tau Proteins tau aggregation tau phosphorylation transmission 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：
PLoS genetics
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：
Science advances
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：
The journal of physical chemistry letters
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：
Analytical biochemistry
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。