Developing a screening platform to identify inhibitors of pathological self-assembly of Tau

开发筛选平台来鉴定 Tau 病理性自组装抑制剂

• 批准号: 10323679
• 负责人: Priya R. Banerjee
• 金额: $ 15.77万
• 依托单位: STATE UNIVERSITY OF NEW YORK AT BUFFALO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-15 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10323679
• 关键词: Affect; Age of Onset; Alzheimer' s Disease; Alzheimer' s disease care; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease therapeutic; Biochemical; Biological Assay; Biology; Brightfield Microscopy; Cell Culture Techniques; Cellular biology; Clinical; Clinical Trials; Data; Degenerative Disorder; Disease; Disease Progression; Economic Burden; Elderly; Ensure; Functional disorder; Goals; Image; In Vitro; Individual; Intervention; Label; Libraries; Link; Liquid substance; Logistics; MAPT gene; Mediating; Medical; Methods; Microtubule Bundle; Microtubule Polymerization; Microtubules; Modeling; Neurodegenerative Disorders; Onset of illness; Partner in relationship; Pathologic; Pathology; Pharmaceutical Preparations; Pharmacology; Phase; Physical condensation; Physiological; Physiology; Play; Process; Proteins; Reporting; Role; Site; Solid; System; Therapeutic; Therapeutic Intervention; Time; Toxic effect; Tubulin; Use Effectiveness; Validation; base; bench to bedside; drug candidate; fluorophore; in vivo; inhibitor; laser tweezer; link protein; monomer; novel; optogenetics; prevent; protein aggregation; recruit; screening; screening program; selective prevention; self assembly; side effect; small molecule; tau Proteins; tau aggregation; therapeutically effective; tool

Alzheimer’s disease (AD) is an irreversible and progressive neurodegenerative disorder that currently affects an estimated 5.7 million individuals in the USA. This age onset disorder affects elderly individuals disproportionately. It is estimated that by 2050, the number of AD patients in the US will increase to ~14 million. In the absence of effective therapeutic interventions that can prevent or reverse AD pathologies, the disease is likely to impose a significant economic burden, estimated to be $234 billion (in addition to the $259 billion spent in the medical care of AD patients). Therefore, there is a dire need to identify pharmacologic agents that can prevent/reverse/slow-down AD progression. Recent advances in our understandings of Tau biology suggest that liquid-liquid phase separation (LLPS) plays crucial roles in both Tau physiology and pathology. For example, LLPS of Tau aids microtubule assembly and/or stabilizes pre-formed microtubule bundles (physiologic role of Tau LLPS). On the other hand, Tau condensates can initiate pathologic protein aggregation (role of LLPS in Tau pathology). Based on these observations and our preliminary data, here, we propose to develop and implement a screening pipeline that selectively targets pathologic liquid-to-solid transformation of Tau. For our screening program, we will employ state-of-the-art optical tweezer-based condensate fusion assay that provides a label- free method for characterizing condensate material state(s). In Aim 1, we will identify pharmacologic compounds that prevent Tau condensate-derived protein aggregation without altering (or minimally perturbing) Tau’s physiologic condensation. In Aim 2, we will validate these compounds’ effectiveness using biochemical and cell biology methods. We posit that our proposed approach will be broadly applicable to many other physiologic protein condensates whose aggregations are linked to degenerative disorders.

阿尔茨海默氏病（AD）是一种不可逆的进行性神经退行性疾病，目前影响 据估计，美国有 570 万人患有这种年龄发病性疾病。 据估计，到 2050 年，美国 AD 患者人数将增加到约 1400 万。 在缺乏可以预防或逆转 AD 病理的有效治疗干预措施的情况下，该疾病 可能会造成重大经济负担，估计为 2,340 亿美元（此外还花费了 2,590 亿美元） 因此，迫切需要确定可以治疗 AD 患者的药物。 预防/逆转/减缓 AD 进展。 我们对 Tau 生物学理解的最新进展表明，液-液相分离 (LLPS) 在 Tau 生理学和病理学中都起着至关重要的作用，例如，Tau 的 LLPS 有助于微管组装。 和/或稳定预先形成的微管束（Tau LLPS 的生理作用）。 冷凝物可以引发病理性蛋白质聚集（LLPS 在 Tau 病理学中的作用）。 根据这些观察和我们的初步数据，我们建议制定并实施一项 选择性靶向 Tau 病理性液固转化的筛选管道 用于我们的筛选。 计划中，我们将采用最先进的基于光镊的冷凝融合测定，提供标签- 表征凝聚态材料状态的自由方法 在目标 1 中，我们将鉴定药理化合物。 防止 Tau 凝聚物衍生的蛋白质聚集，而不改变（或最小程度地干扰）Tau 在目标 2 中，我们将使用生化和细胞验证这些化合物的有效性。 我们认为我们提出的方法将广泛适用于许多其他生理学方法。 蛋白质凝聚物，其聚集与退行性疾病有关。