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：
10493197
负责人：
DAVID A. AGARD
金额：
$ 180.34万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
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

来源：
https://reporter.nih.gov/project-details/10493197
关键词：
Age Autophagocytosis Cells Cellular Structures DNA Sequence Alteration Data Databases Deposition Disease Foundations Frontotemporal Dementia Frontotemporal Lobar Degenerations Gene Mutation Genes Genetic Risk Genomics Goals Half-Life Homeostasis In Vitro Investigation Knowledge Lead Leadership Life Light Lysosomes Metabolism Mission Modeling Molecular Chaperones Molecular Structure Mutation Nerve Degeneration Neurodegenerative Disorders Online Systems Pathologic Pathway interactions Peptide Hydrolases Population Post-Translational Protein Processing Process Production Proteolysis Public Health Research Resources Risk Series Structure Tauopathies Testing Toxic effect United States National Institutes of Health Update Variant Work base burden of illness design genetic variant improved member multicatalytic endopeptidase complex mutant overexpression polygenic risk score protein structure public health relevance risk variant tau Proteins tau aggregation tau mutation therapy development transcriptomics

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.

项目摘要病理tau沉积发生在神经退行性疾病的子集中，包括额颞 Lobar变性与Tau夹杂物（FTLD-TAU）。关于ftld-tau已知的大部分内容是得出的来自突变的tau模型或过表达。但是，统一的TAU代谢的统一观点初始产生，与分子伴侣的相互作用，翻译后修饰，针对据我们所知，溶酶体/自噬和导致的降解尚未产生长期该提议的FTD中心没有墙壁（CWOW）的术语目标是提高我们对 FTD-TAU的病理生物学机制。它的总体目标是阐明基因，调节tau代谢并确定疾病的影响的分子和途径相关的突变和变体。我们的中心假设是，适当的tau代谢需要分子伴侣，联合伴侣，PTM和降解的精确，协调的作用每个代表调节节点的机械。 TAU和其他途径成员的基因突变可以破坏tau代谢，从而导致tau积累，分泌和神经退行性。中心将由Aimee Kao博士领导，他还将领导核心A：管理和数据核心（与共同领导Dr. Yokoyama）和项目1：Tau分子伴侣，靶向和蛋白水解（与Agard博士一起）。 David Agard博士将监督B：大分子和细胞结构核心。詹妮弗博士横山将领导C核C：基因组学和转录组学。最后，Celeste Karch博士将领导项目 2：tau半生和分泌。我们将通过四个特定目标实现这些目标。目标1：了解TAU代谢的正常过程是在调节中做出的一系列决策节点。目标2：识别并测试MAPT和其他TAU中遗传变异的功能相关性代谢基因，体外，细胞和无神经元模型，在每种tau代谢调节上节点。目标3：整合项目和核心的发现以产生TAU代谢和变体数据库（TMVDB），将作为该字段的参考点。目标4：整合发现的结果产生TAU多基因风险评分（TPRS）的项目和核心，这将使遗传风险分层 tauopathy。成功完成这些目标后，拟议的FTD CWOW将提供有关TAU代谢，定义的机械节点的基本信息易于tauopathy 并生成了TMVDB和TPRS，Tauopathy和NeuroDegeneration领域的新资源研究。它将产生有关TAU稳态和基础的至关重要的信息构建和构建对TAU病理生物学和毒性的基础。