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.

项目概要 tau 蛋白病疗法发展的瓶颈是缺乏经过验证的 tau 蛋白病模型、小鼠、细胞或体外模型。 这反映在当前的现实中，即通过冷冻电镜从死后解析tau蛋白病特异性原纤维结构 患者脑组织从未在患者体外复制，即不在小鼠、细胞或体外复制。 衍生的 tau 蛋白病原纤维提供了关键的目标，但它们本身并不是可行的治疗靶点。 例如，开发正电子发射断层扫描 (PET) 配体来诊断和追踪阿尔茨海默病 (AD) 或皮质基底节变性 (CBD) 疾病进展依赖于筛选与 CBD 或 AD 表型原纤维——尚无人知道如何构建的结构 还有很多因素需要考虑。 用于复制 tau 聚集的病理途径，但复制疾病表型 tau 原纤维是最小的 和必要的要求，以及迄今为止尚未达到的治疗开发工具的主要知识差距。 该提案旨在关闭体外复制 tau 蛋白病特异性原纤维的机制和工具（目标 1）， 以及启动细胞中 tau 蛋白错误折叠形成疾病表型形状的关键细胞和分子因素 如果我们能够成功复制任何一种 tau 蛋白病表型 tau 折叠，甚至促进聚集（目标 2）。 折叠 tau 结构的一部分，例如具有播种能力的 CBD 或 AD 的迷你发夹折叠，它将具有 对正在进行的治疗开发产生直接影响，例如对 tau 蛋白病特异性 PET 配体的开发， 该团队将采用一套创新的结构生物学工具，包括抗体和小分子药物。 脉冲双电子共振 (DEER)、TEM 和冷冻电镜，以及重点关注的计算工具 捕获 tau 蛋白整体的完整折叠和聚集途径，从其本质无序到 该团队将同时使用创新的细胞生物学工具和部分折叠和完全融合的原纤维状态。 专用 tau 受体和转运蛋白的知识的有力前提是，可以通过以下方式增强 tau 播种： 内体逃逸以及 tau 局部环境疏水性增强是一个有效因素的知识 启动错误折叠、聚集和繁殖，同时发现有能力的种子和的定义属性。 使用本提案中开发的种子实现形状繁殖将是一个突破，独立于此 如果成功的话，我们将开发实验和计算工具来评估种子形状是否 传播已经发生，或者形状是否全部、部分或没有传播 拥有评估传播的工具。 形状传播机制将改变游戏规则 解决上述问题缺乏进展。 知识差距并不是由于世界顶尖实验室缺乏投资，而是由于自身的缺陷 Han 和 Kosik 以及 Shea 将依靠各自的融合。 领域并投入一致努力，使用创新工具来解决 tau 蛋白病研究中长期存在的问题。