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Atomic models of human tau filaments and development of tau ligands

人类 tau 丝的原子模型和 tau 配体的开发

基本信息

批准号：
10227086
负责人：
BERNARDINO Francesco GHETTI
金额：
$ 68.4万
依托单位：
INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10227086
关键词：
Address Affect Alzheimer&apos s Disease Alzheimer&apos s disease brain Alzheimer&apos s disease related dementia Amyloid Amyloid beta-Protein Argyrophilic Grain Disease Binding Binding Sites Biochemical Brain Code Collaborations Cryoelectron Microscopy Deposition Development Disease FTD with parkinsonism Family Filament Goals Human In Vitro Indiana Individual Inherited Laboratories Lead Ligands Manufactured football Maps Modeling Molecular Molecular Biology Morphology Mutation Nerve Degeneration Neurodegenerative Disorders Pathologic Pathology Patients Pick Disease of the Brain Positron-Emission Tomography Property Protein Isoforms Proteins Recording of previous events Role Structure Tauopathies Tracer Traumatic Brain Injury Universities Work base brain tissue chronic traumatic encephalopathy corticobasal degeneration early detection biomarkers human model in vivo in vivo imaging interest multidisciplinary novel paired helical filament response structural biology tau Proteins tau aggregation tau mutation

项目摘要

Recently, significant progress has been made in understanding tauopathies and how tau aggregates lead to neurodegeneration by the first description of the atomic structures of tau filaments from Alzheimer’s disease (AD) brain. The atomic models for the core of paired helical filaments (PHFs) and straight filaments (SFs) purified from the brain of an individual with AD were determined by cryo-electron microscopy (cryo-EM) through an ongoing collaborative effort between our laboratory at Indiana University and the MRC Laboratory of Molecular Biology. The studies proposed in this MPI application are a logical continuation of this groundbreaking work. These studies are in response to RFA-NS-18-015 “Structural Biology of Alzheimer's Disease Related Dementias (ADRDs) Proteinopathies” (U01). Our proposal has 3 specific aims. The first is to generate a cryo-EM map and determine the corresponding atomic models of tau filaments from the brain of individuals with sporadic and hereditary 3R and 4R tauopathies, in a collaborative effort between the Vidal and Ghetti laboratories at Indiana University and the Jiang laboratory at Purdue University. Importantly, our efforts will have the full support of our collaborators at MRC, Drs. Goedert and Scheres. Second, we will generate a cryo-EM map and determine the corresponding atomic models of tau filaments from the brain of individuals with a history of repetitive brain trauma. Lastly, in collaboration with Dr. Nilsson, a leader in the field of amyloid ligands, we will synthesize, identify and characterize 3R and 4R tau-specific ligands. These ligands will be validated using brain tissues of individuals with 3R and 4R tauopathies and working with the Jiang lab we will attempt to determine the corresponding binding site by cryo-EM.

最近，通过首次描述阿尔茨海默病 (AD) 大脑中 tau 蛋白丝的原子结构，在了解 tau 蛋白病以及 tau 蛋白聚集如何导致神经变性方面取得了重大进展。通过我们印第安纳大学实验室和 MRC 分子生物学实验室之间的持续合作，通过冷冻电子显微镜 (cryo-EM) 确定了从 AD 患者大脑中纯化的成对螺旋丝 (PHF) 和直丝 (SF) 核心的原子模型。本 MPI 申请中提出的研究是这项开创性工作的逻辑延续。这些研究是对 RFA-NS-18-015“阿尔茨海默病相关痴呆 (ADRD) 蛋白质病的结构生物学”(U01) 的回应。我们的提案有 3 个具体目标。第一个是在印第安纳大学 Vidal 和 Ghetti 实验室以及普渡大学 Jiang 实验室的合作下，生成冷冻电镜图并确定患有散发性和遗传性 3R 和 4R tau蛋白病的个体大脑中 tau 蛋白丝的相应原子模型。重要的是，我们的努力将得到 MRC 合作者 Drs. 的全力支持。戈德特和舍雷斯。其次，我们将生成冷冻电镜图，并确定有重复性脑外伤史的个体大脑中 tau 蛋白丝的相应原子模型。最后，我们将与淀粉样蛋白配体领域的领导者 Nilsson 博士合作，合成、鉴定和表征 3R 和 4R tau 特异性配体。这些配体将使用 3R 和 4R tau蛋白病个体的脑组织进行验证，并与 Jiang 实验室合作，尝试通过冷冻电镜确定相应的结合位点。