Chemical Control of Misfolded Protein Fate

错误折叠蛋白质命运的化学控制

• 批准号: 10473133
• 负责人: Fleur Marcia Ferguson
• 金额: $ 142.2万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-28 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10473133
• 关键词: Address; Alzheimer' s Disease; American; Amyloidosis; Area; Cells; Cellular Stress; Chemicals; Degenerative Disorder; Dementia; Development; Disease; Disease Progression; Etiology; Frontotemporal Dementia; Future; Goals; Huntington Disease; Mediator of activation protein; Molecular; Neurodegenerative Disorders; Neurons; Parkinson Disease; Pathologic; Pathology; Phenotype; Research; Risk Factors; Scientist; Technology; Therapeutic; cancer therapy; improved; in vivo; innovation; insight; misfolded protein; novel therapeutic intervention; protein degradation; proteostasis; small molecule; tau Proteins; tool

7. Project Summary The accumulation of misfolded proteins concurrent with disease progression is a hallmark of degenerative disorders known collectively as proteinopathies. These include dementias such as Alzheimer’s, Parkinson’s and Huntington’s Disease among many others, as well as systemic amyloidosis disorders. However, if and how aggregated species contribute to disease etiology and progression remains poorly understood. Over the past 100 years, there has been significant advancement in understanding the pathological signatures and risk factors of proteinopathies but the molecular mechanisms of disease have remained elusive. In this application, I propose the development of new chemical tools for selectively manipulating aggregate proteostasis in cells and in vivo using a targeted protein degradation approach. To demonstrate feasibility, this approach was previously applied to investigate misfolded tau, leading to new insights into tau as a mediator of cell stress vulnerability in frontotemporal dementia neurons. Several strategies are presented to improve the throughput, scope, and utility of this approach across proteinopathies, as well as future applications. The major innovation of the proposed research is to take technologies and concepts learned from the field of targeted protein degradation (TPD) for cancer therapy, which has been an exceptionally active and successful area of research over the past 5 years, and apply them to central challenges in neurodegenerative diseases, where TPD has yet to be applied broadly. I believe this approach has high potential to yield significant advancement in both our understanding of the molecular mechanisms underlying neurodegenerative diseases and in identifying new therapeutic strategies to treat them.

7.项目总结 在疾病进展的同时，错误折叠的蛋白质的积累是 退行性疾病统称为蛋白质病。这些包括痴呆症，如 阿尔茨海默氏症、帕金森氏症和亨廷顿氏病以及全身性 淀粉样变性疾病。然而，聚集的物种是否以及如何对疾病病因学做出贡献 而进展情况仍然知之甚少。在过去的100年里，发生了重大的 蛋白质病的病理特征和危险因素的研究进展 疾病的分子机制仍然难以捉摸。在此应用程序中，我建议使用 选择性操纵细胞内聚集态蛋白平衡的新化学工具的发展 并在体内使用有针对性的蛋白质降解方法。为了证明可行性，这一点 以前采用的方法是调查折叠错误的tau，导致对tau as的新见解 额颞叶痴呆神经元细胞应激易损性的介体。以下是几种策略 提出的目的是提高这种方法的吞吐量、范围和跨蛋白质病的实用性， 以及未来的应用。 拟议研究的主要创新之处是将借鉴的技术和概念 靶向蛋白质降解(TPD)用于癌症治疗的领域已经成为 过去5年中异常活跃和成功的研究领域，并将其应用于 神经退行性疾病的核心挑战，TPD尚未广泛应用。我 我相信这种方法有很大的潜力在我们的 了解神经退行性疾病的分子机制 确定新的治疗策略来治疗它们。