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，通过首先描述阿尔茨海默氏病（AD）大脑的tau丝原子结构的首次描述，在理解tauopathies以及如何导致神经变性方面取得了重大进展。通过Cryo-Electron显微镜（Cryo-EM）确定了配对螺旋丝（PHF）和直丝（PHF）和直丝（SFS）核心的原子模型，这是通过我们在印第安纳大学的实验室与MRC MRC Laborator之间的持续合作努力来确定的。在此MPI应用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“阿尔茨海默氏病相关痴呆症（ADRDS）蛋白质病的结构生物学”（U01）。我们的建议具有3个具体目标。首先是生成一个冷冻EM图，并确定来自散发性和遗传性3R和4R陶氏病个体的tau细丝的相应原子模型，这是在印第安纳大学和吉安大学实验室与普杜格大学的Jiang Laborator的Vidal和Ghetti Laboratore之间的合作努力。重要的是，我们的努力将得到MRC Drs的合作者的全部支持。 Goedert和Scheres。其次，我们将生成一个冷冻EM图，并确定来自具有重复性脑创伤病史的个体大脑的Tau细丝的相应原子模型。最后，与淀粉样配体领域的领导者尼尔森博士合作，我们将合成，识别和表征3R和4R tau特定的配体。这些配体将使用3R和4R aopathies的个体的脑组织进行验证，并与Jiang Lab合作，我们将尝试通过Cryo-EM确定相应的结合位点。