Characterizing and Targeting Filament Polymorphism in Tauopathies

Tau蛋白病中丝状多态性的表征和靶向

基本信息

批准号：
10538019
负责人：
Dmitry Malyshka
金额：
$ 4.12万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10538019
关键词：
Affinity Alzheimer&apos s Disease Amino Acid Sequence Area Automobile Driving Binding Binding Sites Biochemical Biological Biological Assay Brain Cations Characteristics Chemicals Clinical Research Complex Cryoelectron Microscopy Data Dementia Development Diagnosis Disease Disease Progression Electrostatics Elements Etiology Fellowship Filament Fluorescence Future Genetic Polymorphism Heterogeneity Human In Vitro Individual Kinetics Length Libraries Ligand Binding Ligands Mediating Mediator of activation protein Micelles Microtubules Modeling Molecular Conformation Mutation Neurodegenerative Disorders Pathogenesis Pathologic Plant Roots Polymorph Positron-Emission Tomography Prevalence Process Property Protein Isoforms Reaction Recombinants Research Role Sedimentation process Shapes Site Site-Directed Mutagenesis Structure Sulfate Surface Tauopathies Therapeutic Therapeutic Intervention Tracer Visualization Work base beta pleated sheet clinically significant density design driving force imaging agent in vivo inhibitor therapy innovation insight member molecular dynamics novel radioligand small molecule structural biology tau Proteins tau aggregation tau interaction therapeutic target

项目摘要

PROJECT SUMMARY Tauopathies are a set of clinically-significant neurodegenerative disorders characterized by accumulation of fibrillar aggregates composed of tau protein within the brain. Alzheimer's disease is the most prevalent tauopathy as it accounts for the majority cases of dementia worldwide. With the prevalence of dementia expected to at least double in the next few decades, there is a desperate need to discover novel fundamental information about the aberrant tau aggregation at the root of these diseases. The recent advent of cryoelectron microscopy allowed for an unprecedented level of structural insight into the tauopathies, revealing extensive structural polymorphism among the filaments at the root of these tauopathies. This discovery has many vital implications. First, it directly suggests that distinct pathologic cellular conditions shape the tau aggregates in disease. Second, all distinct polymorphs discovered thus far retain at least one of the two key hexapeptide nucleation motifs previously shown to be vital for aggregation, implying some degree of commonality in the aggregation process that could be exploited therapeutically. Third, the presence of unique structures in each disease directly suggests the possibility of developing structure-specific chemical probes. My preliminary data demonstrates the power of structural biology in elucidating key insights into all three of these areas, and the project proposed in this fellowship application aims to expand on these results to deliver fundamental insights into tau aggregation, polymorphism, and ligand binding. Aim 1 will characterize the structural impact of multiple pathological cellular condition mimics on the structure of tau filaments. This structural analysis specifically aims to uncover novel information about the potential etiology at the root of tauopathies. Aim 2 will derive detailed mechanisms for how two in vitro inducers initiate and shape the aggregation process. This approach will uncover novel insight into how tau aggregation is triggered and identify potential therapeutic targets for disruption of aggregation. Aim 3 will characterize the driving forces behind ligand binding to specific sites on tau filaments. Such fundamental mechanistic information will unveil specifics for high-affinity ligand design and aid in the targeted development of disease-specific imaging agents. Overall, this proposal is innovative because it will deliver novel insight into multiple key aspects of tauopathies utilizing a structure-driven approach. This research is significant as it will specifically uncover information on the etiology and pathogenesis of aberrant tau aggregation and polymorphism, thus providing novel avenues for much-needed therapeutic intervention. Additionally, this research is significant because the mechanistic information derived herein will aid in the future development of disease-specific positron emission tomography tracers, in turn assisting with many clinical studies and in tracking of disease progression.

项目概要 Tau蛋白病是一组具有临床意义的神经退行性疾病，其特征是大脑内由 tau 蛋白组成的纤维状聚集体。阿尔茨海默病是最常见的 tau 蛋白病因为它占全世界痴呆症病例的大多数。随着痴呆症的患病率预计将达到在未来几十年内至少翻一番，迫切需要发现有关的新颖的基本信息这些疾病的根源是异常的 tau 蛋白聚集。最近冷冻电子显微镜的出现使得对tau蛋白病的结构洞察达到前所未有的水平，揭示广泛的结构多态性在这些tau蛋白病根源的细丝中。这一发现具有许多重要意义。首先，直接表明不同的病理细胞条件塑造了疾病中的 tau 蛋白聚集体。二、各有特色迄今为止发现的多晶型物至少保留了先前显示的两个关键六肽成核基序中的至少一个对于聚合至关重要，这意味着聚合过程中存在某种程度的共性进行治疗性利用。第三，每种疾病中独特结构的存在直接表明开发结构特异性化学探针的可能性。我的初步数据证明了结构生物学阐明了对所有这三个领域的关键见解，以及本报告中提出的项目奖学金申请旨在扩展这些结果，以提供对 tau 聚合的基本见解，多态性和配体结合。目标 1 将描述多种病理细胞的结构影响条件模仿 tau 丝的结构。这种结构分析的具体目的是发现新颖的有关 tau 蛋白病根源的潜在病因的信息。目标 2 将得出详细的机制两种体外诱导剂启动并塑造聚集过程。这种方法将揭示新的见解如何触发 tau 蛋白聚集并确定破坏聚集的潜在治疗靶点。目标 3 将表征配体与 tau 丝上特定位点结合背后的驱动力。如此基本的机械信息将揭示高亲和力配体设计的细节并有助于靶向开发疾病特异性显像剂。总的来说，这个提议是创新的，因为它将提供新的见解利用结构驱动方法进行 tau蛋白病的多个关键方面。这项研究意义重大，因为它将特别揭示有关异常 tau 聚集和多态性的病因和发病机制的信息，从而为急需的治疗干预提供新途径。此外，这项研究意义重大因为这里得出的机制信息将有助于疾病特异性正电子的未来发展发射断层扫描示踪剂，进而协助许多临床研究和跟踪疾病进展。