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: 10304089
• 负责人: DAVID A. AGARD
• 金额: $ 180.86万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 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/10304089
• 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; 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; structural genomics; tau Proteins; tau aggregation; tau mutation; therapy development; transcriptomics

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 病理性tau沉积发生在包括额颞部在内的一组神经退行性疾病中 伴有tau包裹体的叶状变性(FTLD-tau)。关于FTLD-tau的许多已知知识都是从 来自突变的tau模型或过度表达。然而，对tau新陈代谢的统一看法--从其 最初的生产，与分子伴侣的相互作用，翻译后修饰，目标是 据我们所知，溶酶体/自噬和由此产生的降解并没有产生很长时间- 这个拟议的无墙FTD中心(CWow)的任期目标是提高我们对 FTD-tau的病理生物学机制。它的总体目标是阐明基因， 调节tau新陈代谢并确定疾病影响的分子和途径- 相关的突变和变种。我们的中心假设是，正常的tau代谢需要 分子伴侣、辅助伴侣、PTM和降解的精确、协调作用 每一个都代表监管节点的机构。Tau和其他通路成员的基因突变 可扰乱tau代谢，导致tau蓄积、分泌和神经变性。《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Dr。 横山)和项目1：tau分子伴侣、靶向和蛋白分解(与Co-I Agard博士合作)。 大卫·阿加德博士将负责监督核心B：大分子和细胞结构核心。詹妮弗博士 横山将领导核心C：基因组学和转录学。最后，塞莱斯特·卡奇博士将领导该项目 2：牛磺酸半衰期和分泌物。我们将通过四个具体目标来实现这些目标。目标1： 将tau新陈代谢的正常过程理解为在调节过程中做出的一系列决定 节点。目标2：确定并测试MAPT和其他tau基因变异的功能相关性 代谢基因，在体外，细胞和iNeuron模型中，对每种tau代谢调节 节点。目标3：综合来自项目和核心的结果，以产生Tau新陈代谢和变体 数据库(TMVdb)，它将作为外地的参考点。目标4：综合以下方面的结果 项目和核心，以产生Tau多基因风险评分(TPR)，该评分将对儿童的遗传风险进行分层 紧张症。在成功完成这些目标后，拟议的电影发展署综合湾道将会提供 有关tau代谢的基本信息，定义了易患tau病的机械性节点 并产生了TMVdb和Tprs，这是肌病和神经退行性变领域的新资源 研究。它将产生关于tau动态平衡的至关重要的信息和一个基础 在此基础上建立和框定对tau病理生物学和毒性的后续调查。