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

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
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
已结题
起止时间:
2021-01-15 至 2024-12-31

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中文摘要
翻译
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。这种年龄发作的疾病影响老年人 不成比例。据估计,到2050年,美国的AD患者数量将增加至约1400万。 在缺乏可以预防或逆转AD病理的有效治疗干预的情况下, 可能造成重大的经济负担,估计为2340亿美元(除了2590亿美元的支出外 在AD患者的医疗护理中)。因此,迫切需要鉴定能够 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的生理学和病理学中起着关键作用。例如,Tau的LLPS有助于微管组装 和/或稳定预形成的微管束(Tau LLPS的生理作用)。另一方面,Tau 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,我们建议制定和实施一个 筛选管道,其选择性地靶向Tau的病理性液体至固体转化。为了我们的放映 计划,我们将采用最先进的光学镊子为基础的冷凝物融合分析,提供一个标签- 用于表征冷凝物状态的自由方法。在目标1中,我们将鉴定药理化合物 其防止Tau缩合物衍生的蛋白质聚集而不改变(或最低限度地干扰)Tau’s 生理浓缩在目标2中,我们将使用生物化学和细胞生物学方法验证这些化合物的有效性。 生物学方法我们认为,我们提出的方法将广泛适用于许多其他生理 其聚集与变性疾病有关的蛋白质浓缩物。
英文摘要
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.
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