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）是一种不可逆且进行性的神经退行性疾病，目前会影响 美国估计有570万个人。这种年龄发作障碍会影响老年人 不成比例。据估计，到2050年，美国的AD患者人数将增加到约1400万。 如果没有有效的治疗干预措施可以预防或逆转AD病理，则该疾病是 可能会施加巨大的经济伯恩，估计为2340亿美元（除了2590亿美元 在AD患者的医疗保健中）。因此，迫切需要确定可以 预防/反向/减速广告进展。 我们对tau生物学的理解的最新进展表明，液 - 液相分离（LLP） 在tau生理和病理学中扮演至关重要的角色。例如，tau艾滋病微管组件的LLP 和/或稳定预成型的微管束（Tau LLP的生理作用）。另一方面，tau 冷凝物可以启动病理蛋白聚集（LLP在TAU病理学中的作用）。 根据这些观察结果和我们的初步数据，我们建议开发和实施 筛选管道有选择地靶向tau的病理液体向固定转化。为了我们的筛选 程序，我们将采用最先进的光学镊子冷凝水融合测定法，该测定法提供标签 - 表征凝结物材料状态的免费方法。在AIM 1中，我们将确定药物学化合物 这可以防止Tau凝结的蛋白质聚集，而不会改变（或微弱）tau的蛋白质 生理冷凝。在AIM 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。我们肯定我们提出的方法将广泛适用于许多其他生理学 蛋白质凝结的聚集与退化性疾病有关。