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
- 来源:
- 关键词:AdoptedAffinityAlzheimer&aposs DiseaseAmyloid beta-ProteinBindingBiologicalBiological ModelsBrainBrain imagingCell NucleusCentrifugationClinical TrialsComplexConflict (Psychology)DataDementiaDepressed moodDescriptorDevelopmentDiagnosisDiagnosticDimerizationDiseaseDisease VectorsEquilibriumEventFilamentFosteringGenerationsGoalsHumanImageKineticsLeadLengthLesionLigand BindingLigandsLiteratureMapsMass Spectrum AnalysisMediator of activation proteinMethodsMicrotubulesModelingMolecularMolecular ConformationMolecular ProbesMorphologyNatureNerve DegenerationNervous system structureNeurofibrillary TanglesNeuronsPathogenesisPathologyPathway interactionsPatientsPeptidesPharmacologyPopulationPositron-Emission TomographyProcessResearchRoleSiteSourceStagingStructureStudy SectionSurfaceSurrogate MarkersTauopathiesTestingTherapeutic AgentsThermodynamicsToxic effectTransgenic OrganismsWorkaggregation pathwaybeta pleated sheetbiophysical techniqueschemical synthesischeminformaticsdensitydimerdisease diagnosisdrug discoveryextracellularinhibitor/antagonistinsightmathematical modelmolecular dynamicsmonomernovelnovel diagnosticsnovel therapeuticsoverexpressionpolymerizationprion-likeradiotracersingle moleculesmall moleculetau Proteinstau aggregationtomography
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
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:
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:
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