ELUCIDATING AN INHIBITORY ROLE OF MAP2 IN TAU FIBRILLIZATION
ELUCIDATING AN INHIBITORY ROLE OF MAP2 IN TAU FIBRILLIZATION
批准号:
9763419
负责人:
Martin Margittai
金额:
$18.46万
依托单位国家:
美国
项目类别:
财政年份:
2018
资助国家:
美国
项目状态:
已结题
起止时间:
2018-08-15 至 2021-04-30
关键词:
AffectAlzheimer&aposs DiseaseBindingBrainBrain DiseasesCellsDataDepositionDiseaseFoundationsFutureGoalsGrowthHumanIndividualInvestigationKnowledgeLaboratoriesLeadLengthLightMediatingMicrotubule-Associated Protein 2MicrotubulesMissionMolecularMolecular ConformationNeurodegenerative DisordersNeuronsOutcomePathologicPathologyPathway interactionsPharmaceutical PreparationsPhenotypePopulationPreventionPrevention strategyPreventivePrionsProteinsPublic HealthReportingResearchRoleSequence HomologyStructureTauopathiesTestingTherapeuticTherapeutic InterventionUnited StatesUnited States National Institutes of HealthVariantWorkbasebeta pleated sheetconformerinhibitor/antagonistinnovationinsightmonomernovel strategiesnovel therapeutic interventionpressurerecruittau Proteinstau aggregation
中文摘要
目前,还没有药物可以阻止阿尔茨海默病(AD)的发展。这就构成了
英文摘要
Currently, there are no drugs that halt the progression of Alzheimer's disease (AD). This constitutes an
important problem because >5 million people in the United Sates are affected. The deposition of Tau fibrils
throughout the brain is a pathological hallmark of the disease. Targeting the fibrils holds promise for
therapeutic intervention. MAP2 is a protein that is highly homologous to Tau and is found in close proximity to
Tau deposits. The objective of this proposal is to determine how MAP2 modulates Tau fibril formation. The
central hypothesis is that MAP2 caps Tau fibrils at the ends and thereby inhibits fibril growth. This hypothesis
has been formulated based on data produced in the applicant's laboratory that reveals specific interactions
between Tau fibrils and MAP2. The rationale is that once the modulatory roles of MAP2 are resolved, new
strategies can be developed that utilize MAP2 as a blocking agent of Tau fibril formation. Supported by strong
preliminary data the central hypothesis will be tested by pursuit of the following three specific aims. 1) Evaluate
the inhibitory effects of MAP2 on the elongation of AD-derived Tau fibrils. 2) Identify the molecular mechanism
of MAP2-mediated inhibition. 3) Determine how MAP2 modulates the propagation of distinct Tau fibril
conformers. The research is innovative because it establishes an endogeneous protein with high sequence
homology to Tau as a potent new inhibitor of Tau fibrillization. The proposed research is significant because it
is expected to lead to new strategies for the prevention and treatment of a wide range of Tau misfolding
diseases including AD. The research is exploratory and lays the foundation for future studies into the
phenotypic diversity of human Tauopathies and novel therapeutic approaches that utilize homology-based
inhibition of Tau fibrillization.
期刊论文(1)
专著(0)
科研奖励(0)
会议论文
DOI:
10.1016/j.jbc.2023.104891
发表时间:
2023-07
期刊:
JOURNAL OF BIOLOGICAL CHEMISTRY
影响因子:
4.8
作者:
[Holden, Michael R., Krzesinski, Brad J., Weismiller, Hilary A., Shady, Justin R., Margittai, Martin]
通讯作者:
Margittai, Martin
ESTABLISHING AN ASSAY FOR DETECTING SINGLE TAU FIBRILS
-
批准号:9251732
-
项目类别:
-
资助金额:$18.56万
-
财政年份:2016
-
负责人:Martin Margittai
-
依托单位:
ESTABLISHING AN ASSAY FOR DETECTING SINGLE TAU FIBRILS
-
批准号:9014868
-
项目类别:
-
资助金额:$21.52万
-
财政年份:2016
-
负责人:Martin Margittai
-
依托单位:
LINKING TAU FILAMENT STRUCTURE TO PHENOTYPIC DIVERSITY IN HUMAN TAUOPATHIES
-
批准号:8484466
-
项目类别:
-
资助金额:$29.29万
-
财政年份:2011
-
负责人:Martin Margittai
-
依托单位:
LINKING TAU FILAMENT STRUCTURE TO PHENOTYPIC DIVERSITY IN HUMAN TAUOPATHIES
-
批准号:8663324
-
项目类别:
-
资助金额:$30.09万
-
财政年份:2011
-
负责人:Martin Margittai
-
依托单位:
LINKING TAU FILAMENT STRUCTURE TO PHENOTYPIC DIVERSITY IN HUMAN TAUOPATHIES
-
批准号:8338799
-
项目类别:
-
资助金额:$30.3万
-
财政年份:2011
-
负责人:Martin Margittai
-
依托单位:
LINKING TAU FILAMENT STRUCTURE TO PHENOTYPIC DIVERSITY IN HUMAN TAUOPATHIES
-
批准号:8220645
-
项目类别:
-
资助金额:$30.36万
-
财政年份:2011
-
负责人:Martin Margittai
-
依托单位:
MODELING STRUCTURE AND STABILITY OF TAU PROTEIN AGGREGATES
-
批准号:8171901
-
项目类别:
-
资助金额:$0.11万
-
财政年份:2010
-
负责人:Martin Margittai
-
依托单位:
MODELING STRUCTURE AND STABILITY OF TAU PROTEIN AGGREGATES
-
批准号:7956362
-
项目类别:
-
资助金额:$0.08万
-
财政年份:2009
-
负责人:Martin Margittai
-
依托单位: