Drivers of Pathological Tau Aggregation

病理性 Tau 聚集的驱动因素

• 批准号: 10446174
• 负责人: Songi Han
• 金额: $ 71.18万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA BARBARA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-15 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10446174
• 关键词: Address; Alzheimer' s Disease; Alzheimer' s disease pathology; Antibodies; Binding; Biological; Brain; Bypass; Cell Line; Cells; Cellular biology; Chemistry; Competence; Cromolyn Sodium; Cytoplasm; Detection; Development; Diagnosis; Diagnostic; Disease; Disease Progression; Electrons; Environment; Event; Feedback; Fostering; Foundations; Generations; Goals; Hand; Heparin; Human; Hydrophobic Surfaces; Hydrophobicity; In Vitro; Inclusion Bodies; Induced pluripotent stem cell derived neurons; Investments; Knowledge; Laboratories; Learning; Ligands; Light; Lipids; Liquid substance; Location; Mediating; Modeling; Molecular; Morphology; Mus; Mutation; Neurofibrillary Tangles; Organoids; Pathologic; Pathology; Pathway interactions; Patients; Persons; Pharmaceutical Preparations; Phase; Phenotype; Physiologic pulse; Play; Population; Positron-Emission Tomography; Progressive Supranuclear Palsy; Property; Proxy; Research; Seeds; Shapes; Structure; System; Tauopathies; Testing; Therapeutic; Tissues; Transmission Electron Microscopy; Travel; Work; aggregation pathway; base; brain tissue; clinical phenotype; cofactor; computerized tools; corticobasal degeneration; cryogenics; diagnostic value; disease phenotype; experimental study; innovation; notch protein; protein folding; receptor; screening; self assembly; small molecule; structural biology; success; tau Proteins; tau aggregation; therapeutic target; therapy development; tool; uptake

PROJECT SUMMARY The bottleneck for tauopathy therapy development is the lack of validated tauopathy models, mouse, cell or in vitro. This is reflected in the current reality that tauopathy-specific fibril structures solved by cryo-EM from post mortem patient brain tissue have never been replicated outside a patient, i.e. not in a mouse, cell or in vitro. While the patient- derived tauopathy fibrils offer critical goal posts, they are not in and of themselves viable therapeutic targets. For example, the development of Positron Emission Tomography (PET) ligands to diagnose and track Alzheimer’s disease (AD) or corticobasal degeneration (CBD) disease progression relies on screening small molecule binding to CBD- or AD-phenotypic fibrils—the very construct that nobody knows how to build yet. There are many more factors to consider for replicating the pathological pathway of tau aggregation, but replicating disease phenotypic tau fibrils is a minimal and necessary requirement, and so far an unattained tool for therapy development. The major knowledge gap that this proposal aims to close is the mechanism and tools to replicate tauopathy specific fibrils in vitro (Aim 1), and the key cellular and molecular factors that initiate misfolding of tau in cell to disease phenotypic shapes and facilitate aggregation (Aim 2). If we can successfully replicate any one tauopathy-phenotypic tau fold, or even a part of a folded tau structure, such as a mini-hairpin fold of CBD or AD with seeding competency, it will have an immediate impact on ongoing therapy developments, such as on the development of tauopathy-specific PET ligands, antibodies and small molecule drugs. This team will employ an innovative set of structural biology tools encompassing pulsed double electron-electron resonance (DEER), TEM and cryo-EM, as well as computational tools to focus on capturing the full folding and aggregation pathway of the tau protein ensemble from its intrinsically disordered to partially folded and fully converged fibril states. This team will concurrently use innovative cell biological tools with a strong premise of the knowledge of a dedicated tau receptor and transporter that can enhance tau seeding by endosomal escape and the knowledge that enhanced hydrophobicity of the local environment of tau is a potent factor to initiate misfolding, aggregation and propagation. While discovering the defining property of a competent seed and achieving shape propagation with seeds developed in this proposal will be a breakthrough, independent of this success, we will have developed experimental and computational tools to evaluate whether seeded shape propagation has occurred, or whether all, part, or none of the shape propagates. To have the tools to evaluate the mechanism of shape propagation will be a game changer. The lack of progress in closing the above-described knowledge gap is not due to a lack of investment by top notch laboratories around the world, but due to shortcomings of existing concepts and tools. Han and Kosik, together with Shea, will rely on the convergence of their respective fields and investing concerted effort using innovative tools to address long-standing questions in tauopathy research.

项目摘要 陶氏病治疗发展的瓶颈是缺乏经过验证的陶氏病模型，小鼠，细胞或体外。 这反映在当前的现实中，即验收验收的cryo-em在验尸后求解的特异性原纤维结构 患者脑组织从未在患者外面复制，即不在小鼠，细胞或体外。而患者 - 衍生的tauopathy纤维提供了关键的目标柱，它们本身并没有可行的治疗靶标。为了 例如，正电子发射断层扫描（PET）配体的发展以诊断和跟踪阿尔茨海默氏病 （AD）或皮质型变性（CBD）疾病进展依赖于筛选小分子与CBD或CBD的结合 广告型原纤维 - 既不知道如何构建的结构。还有更多因素要考虑 复制tau聚集的病理途径，但是复制疾病表型tau纤维是最小的 和必要的需求，到目前为止，是治疗开发的无关工具。主要知识差距 该建议旨在关闭该提案是在体外复制tauopathy特定原纤维的机制和工具（AIM 1）， 以及启动tau在细胞中折叠对疾病表型形状的关键细胞和分子因子 并促进聚集（目标2）。如果我们可以成功复制任何一个tauopathy-phenotypic tau折叠，甚至 折叠tau结构的一部分，例如CBD的迷你发行折叠或具有播种能力的AD，它将具有一个 对正在进行的疗法发展的直接影响，例如针对特异性宠物配体的发展， 抗体和小分子药物。该团队将采用一套创新的结构生物学工具 脉冲双电子共振（DEER），TEM和CRYO-EM，以及专注于的计算工具 捕获Tau蛋白质合奏的完整折叠和聚集途径，从本质上无序到 部分折叠并完全融合的原纤维状态。该团队将同时使用创新的细胞生物学工具 专用的tau接收器和运输蛋白的知识有很强的前提，可以通过 内体逃生以及提高tau当地环境的疏水性的知识是一个有效的因素 引发错误折叠，聚集和传播。在发现有能力的种子的定义特性和 在本提案中开发的种子实现形状传播将是一个突破，与此无关 成功，我们将开发实验和计算工具来评估是否种子形状 传播发生了，或者是全部，部分或任何形状都传播的。拥有评估工具 形状传播的机制将改变游戏规则。关闭上述方面缺乏进展 知识差距不是由于世界各地的顶级实验室缺乏投资，而是由于缺点 现有的概念和工具。汉和科西克与乳木果一起将依靠他们各自的融合 使用创新工具来解决Tauopathy研究中的长期问题，领域和投资共同努力。