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/文摘

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)

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Jeff Kuret其他文献

Jeff Kuret的其他文献

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{{ 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:

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