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 陶氏病是一组临床上显着的神经退行性疾病，其特征是以积累为特征 原纤维聚集体由大脑内的tau蛋白组成。阿尔茨海默氏病是最普遍的tauopathy 因为它占全球痴呆症的大多数情况。痴呆症的患病率预计 在接下来的几十年中，至少是两倍，迫切需要发现有关的新颖基本信息 这些疾病根源的异常Tau聚集。最近允许的冷冻电子显微镜的出现 为了对tauopathies的前所未有的结构见解，揭示了广泛的结构多态性 在这些tauopathies根源的细丝中。这一发现具有许多重要的含义。首先，直接 表明不同的病理细胞状况塑造了疾病中的tau聚集体。其次，都不同 迄今为止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 对于聚集至关重要，意味着在聚合过程中的某种程度的共性可能是 通过治疗剥削。第三，每种疾病中独特的结构的存在直接表明 开发特定于结构的化学探针的可能性。我的初步数据证明了 在阐明所有这三个领域的关键见解中的结构生物学，以及在此提出的项目 奖学金申请旨在扩大这些结果，以提供对tau聚合的基本见解， 多态性和配体结合。 AIM 1将表征多个病理细胞的结构影响 条件模仿tau丝的结构。这种结构分析特别旨在发现新颖 有关tauopathies根源的潜在病因的信息。 AIM 2将得出有关如何的详细机制 两个体外诱导剂启动并塑造聚集过程。这种方法将发现新颖的洞察力 如何触发tau聚集并确定破坏聚集的潜在治疗靶标。目标3 将表征配体在Tau细丝上与特定位点结合的驱动力。这样的基本 机械信息将揭示高亲和力配体设计的细节，并有助于目标开发 疾病特异性成像剂。总体而言，该提议具有创新性，因为它将对 使用结构驱动的方法的auopathies的多个关键方面。这项研究很重要，因为 特别发现有关异常tau聚集和多态性的病因和发病机理的信息， 因此为急需的治疗干预提供了新的途径。此外，这项研究很重要 因为本文得出的机械信息将有助于未来的疾病特异性效果的发展 发射断层扫描示踪剂，进而有助于进行许多临床研究并跟踪疾病进展。