Tau Metabolism in FTD: From Gene Mutations to Molecular Chaperones and Lysosomal Proteases

FTD 中的 Tau 代谢:从基因突变到分子伴侣和溶酶体蛋白酶

基本信息

  • 批准号:
    10304089
  • 负责人:
  • 金额:
    $ 180.86万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-09-27 至 2026-08-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY Pathological tau deposition occurs in a subset of neurodegenerative disorders including frontotemporal lobar degeneration with tau inclusions (FTLD-tau). Much of what is known about FTLD-tau is derived from mutant tau models or overexpression. However, a unified view of overall tau metabolism—from its initial production, interactions with molecular chaperones, post-translational modifications, targeting to lysosomes/autophagy, and resultant degradation, to our knowledge has not been generated The long- term goal of this proposed FTD Center without Walls (CWOW) is to improve our understanding of the pathobiological mechanisms underlying FTD-tau. Its overall objective is to elucidate the genes, molecules and pathways that regulate tau metabolism and to determine the impact of disease- associated mutations and variants. Our central hypothesis is that proper tau metabolism requires the precise, coordinated action of molecular chaperones, co-chaperones, PTMs and degradation machinery that each represent regulatory nodes. Genetic mutations in tau and other pathway members can disrupt tau metabolism, leading to tau accumulation, secretion and neurodegeneration. The Center will be led by Dr. Aimee Kao, who will also lead Core A: Administration and Data Core (with Co-lead Dr. Yokoyama) and Project 1: Tau Molecular Chaperones, targeting and proteolysis (with Co-I Dr. Agard). Dr. David Agard will oversee Core B: Macromolecular and Cellular Structure Core. Dr. Jennifer Yokoyama will lead Core C: Genomics and Transcriptomics. Finally, Dr. Celeste Karch will lead Project 2: Tau Half Life and Secretion. We will achieve these objectives through four Specific Aims. Aim 1: Understand the normal process of tau metabolism as a series of decisions that are made at regulatory nodes. Aim 2: Identify and test the functional relevance of genetic variants in MAPT and other tau metabolism genes, in in vitro, cell and iNeuron models, on each of the tau metabolism regulatory nodes. Aim 3: Integrate findings from Projects and Cores to produce a Tau Metabolism and Variant Database (TMVdb), that will serve as a reference point for the field. Aim 4: Integrate findings from Projects and Cores to produce a Tau Polygenic Risk Score (TPRS), which will stratify genetic risk for tauopathy. Upon successful completion of these Aims, the proposed FTD CWOW will have provided fundamental information about tau metabolism, defined mechanistic nodes predisposing to tauopathy and generated the TMVdb and TPRS, new resources for the fields of tauopathy and neurodegeneration research. It will generate critically important information about tau homeostasis and a foundational basis from which to build and frame subsequent investigations into tau pathobiology and toxicity.
项目总结

项目成果

期刊论文数量(0)
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会议论文数量(0)
专利数量(0)

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DAVID A. AGARD其他文献

DAVID A. AGARD的其他文献

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{{ truncateString('DAVID A. AGARD', 18)}}的其他基金

Chaperone protection in Lewy body and Alzheimer’s dementias: determining the structural, molecular and cellular mechanisms of a novel, non-canonical Hsp70 action blocking a-synuclein oligomerization
路易体和阿尔茨海默氏痴呆中的伴侣保护:确定阻断 α-突触核蛋白寡聚化的新型非典型 Hsp70 作用的结构、分子和细胞机制
  • 批准号:
    10649331
  • 财政年份:
    2023
  • 资助金额:
    $ 180.86万
  • 项目类别:
Structural biology core
结构生物学核心
  • 批准号:
    10512622
  • 财政年份:
    2022
  • 资助金额:
    $ 180.86万
  • 项目类别:
Core B: Macromolecular and Cellular Structure Core
核心B:高分子和细胞结构核心
  • 批准号:
    10304091
  • 财政年份:
    2021
  • 资助金额:
    $ 180.86万
  • 项目类别:
Core B: Macromolecular and Cellular Structure Core
核心B:高分子和细胞结构核心
  • 批准号:
    10493220
  • 财政年份:
    2021
  • 资助金额:
    $ 180.86万
  • 项目类别:
Tau Metabolism in FTD: From Gene Mutations to Molecular Chaperones and Lysosomal Proteases
FTD 中的 Tau 代谢:从基因突变到分子伴侣和溶酶体蛋白酶
  • 批准号:
    10493197
  • 财政年份:
    2021
  • 资助金额:
    $ 180.86万
  • 项目类别:
Structure and Mechanism: Hsp90 proteostasis, cilia biogenesis and the jumbo phage “nucleus”
结构和机制:Hsp90 蛋白质稳态、纤毛生物发生和巨型噬菌体 – 细胞核 –
  • 批准号:
    10407008
  • 财政年份:
    2016
  • 资助金额:
    $ 180.86万
  • 项目类别:
Structure and Mechanism: Hsp90 proteostasis, cilia biogenesis and the jumbo phage “nucleus”
结构和机制:Hsp90 蛋白质稳态、纤毛生物发生和巨型噬菌体 – 细胞核 –
  • 批准号:
    10164184
  • 财政年份:
    2016
  • 资助金额:
    $ 180.86万
  • 项目类别:
The Structure and Regulation of Microtubule Nucleation by y-tubulin
y-微管蛋白对微管成核的结构和调控
  • 批准号:
    8668220
  • 财政年份:
    2014
  • 资助金额:
    $ 180.86万
  • 项目类别:
Characterization of a bacteriophage tubulin involved in viral replication
参与病毒复制的噬菌体微管蛋白的表征
  • 批准号:
    8420103
  • 财政年份:
    2013
  • 资助金额:
    $ 180.86万
  • 项目类别:
Characterization of a bacteriophage tubulin involved in viral replication
参与病毒复制的噬菌体微管蛋白的表征
  • 批准号:
    9057082
  • 财政年份:
    2013
  • 资助金额:
    $ 180.86万
  • 项目类别:
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