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: 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
• 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' 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

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.

项目摘要 Tau病是一组临床上显著的神经退行性疾病，其特征在于Tau蛋白的积累。 脑内由tau蛋白组成的纤维状聚集体。阿尔茨海默病是最普遍的tau蛋白病 因为它占了全球痴呆症的大多数病例。随着痴呆症的患病率预计在 在未来的几十年里，至少翻一番，迫切需要发现新的基本信息 异常的tau蛋白聚集是这些疾病的根源。低温电子显微镜的出现 对tau蛋白病的结构洞察达到了前所未有的水平，揭示了广泛的结构多态性 在这些Tau病变的根源的细丝之间。这一发现有许多重要的意义。首先，它直接 表明不同的病理细胞条件塑造疾病中的tau聚集体。第二，所有不同的 迄今发现的多晶型物保留了先前显示的两个关键六肽成核基序中的至少一个 对聚合至关重要，这意味着聚合过程中存在某种程度的共性， 治疗上的剥削第三，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。我的初步数据显示了 结构生物学在阐明所有这三个领域的关键见解，并在此提出的项目 奖学金申请旨在扩展这些结果，以提供对tau聚集的基本见解， 多态性和配体结合。目的1将表征多种病理性细胞的结构影响， 条件模拟tau细丝的结构。这种结构分析的目的是揭示小说 关于tau蛋白病的潜在病因学的信息。Aim 2将推导出详细的机制， 两种体外诱导剂引发并形成聚集过程。这种方法将揭示新的见解， 如何触发tau聚集并鉴定用于破坏聚集的潜在治疗靶标。目标3 将表征配体与tau细丝上的特定位点结合背后的驱动力。等基本 机制信息将揭示高亲和力配体设计的细节，并有助于靶向开发 疾病特异性成像剂的研究。总的来说，这项建议是创新的，因为它将提供新的见解， 利用结构驱动的方法研究tau蛋白病的多个关键方面。这项研究意义重大，因为它将 特别是揭示异常tau聚集和多态性的病因学和发病机制的信息， 从而为急需的治疗干预提供了新的途径。此外，这项研究具有重要意义。 因为在此得到的机理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，反过来又有助于许多临床研究和跟踪疾病进展。