Characterizing and Targeting Filament Polymorphism in Tauopathies

Tau蛋白病中丝状多态性的表征和靶向

• 批准号: 10707033
• 负责人: Dmitry Malyshka
• 金额: $ 4.28万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 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/10707033
• 关键词: Affinity; Alzheimer' 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; Micelles; Microtubules; Modeling; Molecular Conformation; Mutation; Neurodegenerative Disorders; Pathogenesis; Pathologic; 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; beta pleated sheet; clinically significant; design; driving force; hyperphosphorylated tau; imaging agent; in vivo; inhibitor therapy; innovation; insight; member; molecular dynamics; novel; permissiveness; radioligand; small molecule; structural biology; tau Proteins; tau aggregation; tau interaction; therapeutic target

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.

项目总结 肌萎缩侧索硬化症是一组临床上显著的神经退行性疾病，其特征是积聚的 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直肠肌萎缩症 因为它占了世界上大多数痴呆症病例。预计痴呆症的患病率将达到 在接下来的几十年里至少翻一番，迫切需要发现关于 这些疾病的根源是tau的异常聚集。最近出现的低温电子显微镜允许 对tauopathy的结构洞察达到前所未有的水平，揭示了广泛的结构多态 在这些变态的根部的细丝中。这一发现具有许多重要的影响。首先，它直接 这表明，在疾病中，不同的病理细胞条件塑造了tau聚集体。第二，都是不同的 到目前为止发现的多态至少保留了前面所示的两个关键六肽成核基序中的一个 对聚合至关重要，这意味着聚合过程中可能存在某种程度的共性 在治疗上被剥削。第三，每种疾病的独特结构的存在直接表明 开发特定结构的化学探针的可能性。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，以及在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， 多态和配基结合。目标1将描述多种病理细胞的结构影响 条件模拟了tau细丝的结构。这一结构分析专门旨在揭示小说 有关肌萎缩侧索硬化症的潜在病因学的信息。目标2将得出详细的机制，说明如何 两个体外诱导剂启动并塑造了聚集过程。这种方法将揭示出对 Tau聚集是如何被触发的，并确定破坏聚集的潜在治疗靶点。目标3 将表征与tau细丝上特定位置结合的配体背后的驱动力。这样的基本原理 机械信息将揭示高亲和力配体设计的细节，并帮助定向开发 疾病特异性显像剂。总体而言，这项提议是创新的，因为它将为 利用结构驱动型方法进行治疗的多个关键方面。这项研究具有重要意义，它将 具体揭示tau异常聚集和多态的病因和发病机制， 从而为急需的治疗干预提供了新的途径。此外，这项研究还具有重要意义。 因为这里得到的机理信息将有助于未来疾病特异性正电子的发展 发射断层扫描示踪器，反过来帮助许多临床研究和跟踪疾病进展。