Structure and Genesis of tau Aggregates

tau 聚集体的结构和成因

基本信息

  • 批准号:
    9311789
  • 负责人:
  • 金额:
    $ 236.34万
  • 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 2022-08-31
  • 项目状态:
    已结题

项目摘要

Project Summary/Abstract The study of tau misfunction in tauopathic neurodegenerative disorders such as Alzheimer's disease is at a crossroads. Recent discoveries point to tau aggregation as being essential for prion-like spread of misfolding from neuron to neuron, implying a key role for aggregation in neurodegeneration, yet are contradicted by evidence from transgenic tau overexpression models that aggregation lies downstream of toxicity and may actually be neuroprotective. Indeed, it is well established that tau is hyperphosphorylated in disease, and that this event alone can lead to loss of microtubule function irrespective of aggregation, yet a clinical trial involving a potent inhibitor of tau hyperphosphorylation failed to modify the course of a human tauopathy. Classic studies showed that filamentous aggregates dominate the population of tau that accumulates in authentic neurofibrillary lesions, but other evidence implicates soluble oligomers potentially unrelated to cross-β-sheet structure as mediators of tau misfunction. With respect to aggregation kinetics, recent work has identified a role for secondary processes such as breakage and secondary nucleation that produce abundant small species, yet authentic lesions are dominated by aggregates that adopt filamentous morphology and achieve substantial lengths. Small-molecules that bind to tau aggregates or modulate their formation have been disclosed in the literature, but the mechanisms through which they act are ambiguous or involve substantial off-target liability. As a result of these conflicting ideas, the full potential of tau lesion pharmacology remains ambiguous. This project seeks to harmonize the many disparate observations made on tau aggregation and pharmacology using a biophysical approach. First, it will characterize and quantify tau aggregation kinetics while including a novel secondary pathway involving aggregate annealing. The analysis will be extended to the level of energetics, and to the relationship between aggregate structure and biological toxicity. Second, it will identify descriptors of ligand binding to tau aggregates, providing insight into the molecular features that influence binding affinity and therefore utility for premortem diagnosis. Finally, it will characterize the mechanism of action of non-covalent tau aggregation inhibitors associated with clearance of tau aggregates, including the nature of their binding targets, and the structure of their protective complexes. Successfully completed, the project will impact the field by clarifying targets for tauopathy drug discovery and by deducing molecular concepts important for optimizing premortem diagnostic agents.
项目总结/摘要 在tau蛋白病性神经退行性疾病如阿尔茨海默病中tau蛋白功能障碍的研究正处于一个新的阶段。 十字路口最近的发现指出,tau蛋白聚集是朊病毒样错误折叠传播的关键 从神经元到神经元,这意味着聚集在神经变性中的关键作用,但与 来自转基因tau蛋白过表达模型的证据表明,聚集位于毒性的下游, 实际上是神经保护的。事实上,已经确定tau蛋白在疾病中过度磷酸化, 这一事件本身可导致微管功能丧失,而与聚集无关,但一项涉及 tau蛋白过度磷酸化的有效抑制剂不能改变人tau蛋白病的进程。经典 研究表明,丝状聚集体占主导地位的tau群体, 但其他证据表明可溶性寡聚体可能与交叉β折叠无关 结构作为tau功能失调的介质。关于聚集动力学,最近的工作已经确定了一个作用, 对于产生大量小物质的二次过程如断裂和二次成核, 然而,真实的病变主要是聚集体,其采用丝状形态并实现实质性的 长度与tau聚集体结合或调节其形成的小分子已在《分子生物学》中公开 这些法律文献中有一些是明确的,但它们的作用机制不明确,或涉及大量的脱靶赔偿责任。 由于这些相互冲突的想法,tau病变药理学的全部潜力仍然模糊不清。 该项目旨在协调对tau聚集的许多不同观察, 药理学使用生物物理方法。首先,它将表征和量化tau聚集动力学 同时包括涉及聚集体退火的新的次级途径。分析将扩展到 能量学水平,以及聚集体结构与生物毒性之间的关系。二是会 识别配体与tau聚集体结合的描述符,提供对分子特征的深入了解, 从而影响结合亲和力并因此影响其用于死前诊断的效用。最后,它将描述 与tau聚集体清除相关的非共价tau聚集抑制剂的作用机制, 包括其结合靶的性质和其保护性复合物的结构。成功 完成后,该项目将通过澄清tau蛋白病药物发现的目标和推导出 分子概念的重要优化死前诊断剂。

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 }}

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

Structure and Genesis of tau Aggregates
tau 聚集体的结构和成因
  • 批准号:
    10522274
  • 财政年份:
    2017
  • 资助金额:
    $ 236.34万
  • 项目类别:
Structure and Genesis of tau Aggregates
tau 聚集体的结构和成因
  • 批准号:
    10158623
  • 财政年份:
    2017
  • 资助金额:
    $ 236.34万
  • 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:
    9182629
  • 财政年份:
    2016
  • 资助金额:
    $ 236.34万
  • 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:
    $ 236.34万
  • 项目类别:
The tau code of Alzheimer's disease
阿尔茨海默病的 tau 密码
  • 批准号:
    8484896
  • 财政年份:
    2012
  • 资助金额:
    $ 236.34万
  • 项目类别:
The tau code of Alzheimer's disease
阿尔茨海默病的 tau 密码
  • 批准号:
    8399904
  • 财政年份:
    2012
  • 资助金额:
    $ 236.34万
  • 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:
    $ 236.34万
  • 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:
    $ 236.34万
  • 项目类别:
STRUCTURE AND GENESIS OF TAU FILAMENTS
TAU 丝的结构和起源
  • 批准号:
    2683182
  • 财政年份:
    1997
  • 资助金额:
    $ 236.34万
  • 项目类别:
STRUCTURE AND GENESIS OF TAU FILAMENTS
TAU 丝的结构和起源
  • 批准号:
    2002359
  • 财政年份:
    1997
  • 资助金额:
    $ 236.34万
  • 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:
    $ 236.34万
  • 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:
    $ 236.34万
  • 项目类别:
    Grant-in-Aid for JSPS Fellows
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:
    $ 236.34万
  • 项目类别:
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:
    $ 236.34万
  • 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:
    $ 236.34万
  • 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:
    $ 236.34万
  • 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:
    $ 236.34万
  • 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:
    $ 236.34万
  • 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:
    $ 236.34万
  • 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:
    $ 236.34万
  • 项目类别:
    Continuing Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了