Chemical Control of Misfolded Protein Fate

7.项目摘要 与疾病进展同时发生的错误折叠蛋白质的积累是疾病进展的标志。 统称为蛋白质病的退行性疾病。其中包括痴呆症， 阿尔茨海默氏症、帕金森氏症和亨廷顿氏症等，以及全身性 淀粉样变性疾病。然而，如果以及如何聚集的物种有助于疾病的病因 进展仍然知之甚少。在过去的100年里， 在理解蛋白质病的病理特征和风险因素方面取得了进展， 疾病的分子机制仍然难以捉摸。在本申请中，我建议 开发新的化学工具，用于选择性地操纵细胞中的聚集体蛋白质稳态 并在体内使用靶向蛋白质降解方法。为了证明可行性， 方法以前被应用于研究错误折叠的tau，导致对tau的新见解， 额颞叶痴呆神经元细胞应激脆弱性的一种介质。有几种策略是 提出以提高这种方法在蛋白质病中的通量、范围和实用性， 以及未来的应用。 本研究的主要创新之处在于， 用于癌症治疗的靶向蛋白质降解（TPD）领域，其已经成为一个新的研究领域。 在过去的5年里，研究非常活跃和成功的领域，并将其应用于 神经退行性疾病的核心挑战，其中TPD尚未广泛应用。我 我相信这种方法有很大的潜力，在我们的两个方面都取得重大进展， 了解神经退行性疾病的分子机制， 寻找新的治疗策略来治疗它们。

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.