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.

阿尔茨海默病是一种不可逆转的进行性神经退行性疾病，目前影响 据估计，美国有570万人。这种老年性起病影响老年人。 不成比例。据估计，到2050年，美国AD患者的数量将增加到约1400万人。 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，这种疾病是 可能会造成巨大的经济负担，估计为2340亿美元(不包括花费的2590亿美元 在AD患者的医疗护理中)。因此，迫切需要确定能够 防止/逆转/减缓AD进展。 我们对牛磺酸生物学认识的最新进展表明，液-液相分离(LLP) 在牛磺酸的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)。另一方面，Tau 凝集物可启动病理性蛋白质聚集(LLP在Tau病理中的作用)。 基于这些观察和我们的初步数据，在这里，我们建议开发和实施一种 筛选选择性靶向Tau病理性液-固转化的管道。为了我们的放映 计划，我们将使用最先进的基于光钳的冷凝液融合分析，提供一种标记- 表征凝析油物质状态的自由方法(S)。在目标1中，我们将鉴定药理化合物 在不改变(或最小程度干扰)Tau的情况下防止Tau冷凝物衍生的蛋白质聚集 生理性冷凝。在目标2中，我们将使用生化和细胞来验证这些化合物的有效性 生物学方法。我们假设我们提出的方法将广泛适用于许多其他生理学。 蛋白质凝聚体，其聚集与退行性疾病有关。