Molecular Chaperones and Small Molecules

描述（由申请人提供）：分子伴侣，如Hsp70和Hsp90，可能有助于预防神经退行性疾病，如阿尔茨海默氏症和亨廷顿氏病，这是由异常蛋白质错误折叠引起的。然而，缺乏小分子伴侣限制了我们在这些疾病模型中探测其功能的能力。Gestwicki实验室的长期目标是发现伴侣的抑制剂和激动剂，为这一领域的探索开辟新的机会。这项特别提议的目的是鉴定和表征Hsp70的激动剂，并利用这些来研究这种伴侣在亨廷顿病的聚谷氨酰胺扩增（polyQ）模型中的作用。我们的中心假设是直接刺激Hsp70可以缓解polyQ错误折叠。在初步研究中，我们已经发现了促进Hsp70功能并保护酵母和哺乳动物疾病细胞模型的小分子。此外，我们已经使用这些化学探针来暗示Hsp70是聚集的关键介质。在这一强有力的初步证据的指导下，我们提出了三个具体目标：(1)确定修饰Hsp70的伴侣活性的其他小分子；(2)探索这些化合物与Hsp70之间的相互作用；(3)使用这些化学工具研究Hsp70如何保护polyQ自组装。这种方法是创新的，因为其他策略依赖于启动全局细胞应激反应来调节Hsp70功能。相比之下，我们的方法直接针对伴侣蛋白而不干扰其他细胞过程。这很重要，因为我们的化学探针可能使我们第一次确定Hsp70作为神经退行性疾病的药物靶点，并更多地了解它在疾病中的作用。公共卫生相关性：神经退行性疾病是人口老龄化面临的最大威胁之一，药物干预的前景不确定。我们已经开发了一种新的方法来发现这一领域的直接靶向分子伴侣。

DESCRIPTION (provided by applicant): Molecular chaperones, such as Hsp70 and Hsp90, may help protect against neurodegenerative disorders, such as Alzheimer's and Huntington's diseases, which are caused by aberrant protein misfolding. However, a dearth of small molecule partners for the chaperones have limited our ability to probe their function in models of these diseases. The long-term goal of the Gestwicki laboratory is to uncover inhibitors and agonists of the chaperones to open new opportunities for exploration in this area. The objective of this particular proposal is to identify and characterize agonists of Hsp70 and use these to study the role of this chaperone in polyglutamine expansion (polyQ) models of Huntington's disease. Our central hypothesis is that direct stimulation of Hsp70 will provide relief from polyQ misfolding. In preliminary studies, we have uncovered small molecules that promote Hsp70's function and protect yeast and mammalian cell models of disease. Moreover, we have used these chemical probes to implicate Hsp70 as a crucial mediator of aggregation. Guided by this strong preliminary evidence, we propose three specific aims: (1) Identify additional small molecules that modify Hsp70's chaperone activity (2) Explore the interaction between these compounds and Hsp70 (3) Use these chemical tools to investigate how Hsp70 protects against polyQ self-assembly. This approach is innovative because other strategies have relied on initiation of the global cellular stress responses to modulate Hsp70 function. In contrast, our approach directly targets the chaperone without perturbing other cellular processes. This is significant because our chemical probes might allow us to, for the first time, identify Hsp70 as a drug target for neurodegenerative disorders and learn more about its role in disease. PUBLIC HEALTH RELEVANCE: Neurodegenerative disease is one of the greatest threats facing an aging population and the outlook for pharmaceutical intervention is uncertain. We have developed a new approach to discovery in this area by directly targeting molecular chaperones.