Molecular Chaperones and Small Molecules

分子伴侣和小分子

• 批准号: 7460981
• 负责人: Jason E Gestwicki
• 金额: $ 28.76万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-02-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7460981
• 关键词: ATP phosphohydrolase; Aging; Agonist; Alzheimer' s Disease; Animal Model; Area; Bacteria; Binding; Binding Sites; Biological Assay; Biological Factors; Biology; Cell Cycle; Cell Death; Cell model; Cell physiology; Cells; Cellular Stress Response; Chemical Stimulation; Chemicals; Class; Collaborations; Collection; Computing Methodologies; Disease; Disease model; Drug Delivery Systems; Emotional; Family; Fluorescence Polarization; Geldanamycin; Generations; Genetic; Goals; Heat-Shock Proteins 70; Human; Huntington Disease; In Vitro; Intervention; Knowledge; Laboratories; Lead; Learning; Libraries; Ligands; Localized; Luciferases; Mammalian Cell; Mediating; Mediator of activation protein; Methodology; Modeling; Molecular Chaperones; Mutagenesis; Neurodegenerative Disorders; Nuclear Magnetic Resonance; Nucleotides; Oryctolagus cuniculus; Outcome; Patients; Pharmacologic Substance; Positioning Attribute; Protein Binding; Proteins; Public Health; Reagent; Role; Series; Site; Staging; Structure; Surface Plasmon Resonance; System; Time; Transgenic Organisms; Work; Yeasts; aging population; base; cancer cell; cellular targeting; design; high throughput screening; inhibitor/antagonist; innovation; microwave electromagnetic radiation; monorden; mutant; novel strategies; polyglutamine; polypeptide; professor; protein misfolding; research study; response; scaffold; self assembly; small molecule; small molecule libraries; tool

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.

描述（由申请人提供）：分子伴侣，如Hsp70和Hsp90，可以帮助预防神经退行性疾病，如阿尔茨海默病和亨廷顿病，这些疾病由异常蛋白质错误折叠引起。然而，由于缺乏小分子伴侣， 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分子伴侣的抑制剂和激动剂，为这一领域的探索开辟新的机会。这个特别的建议的目的是确定和表征热休克蛋白70的激动剂，并使用这些来研究该分子伴侣在亨廷顿病的多聚谷氨酰胺扩增（polyQ）模型中的作用。我们的中心假设是，Hsp70的直接刺激将提供polyQ错误折叠的救济。在初步研究中，我们发现了促进Hsp70功能并保护酵母和哺乳动物细胞疾病模型的小分子。此外，我们已经使用这些化学探针牵连热休克蛋白70作为一个重要的调解人的聚集。在这一强有力的初步证据的指导下，我们提出了三个具体的目标：（1）确定额外的小分子修饰Hsp70的伴侣活性（2）探索这些化合物和Hsp70之间的相互作用（3）使用这些化学工具来研究Hsp70如何防止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，我们的方法直接靶向分子伴侣，而不干扰其他细胞过程。这是重要的，因为我们的化学探针可能使我们能够首次将Hsp70确定为神经退行性疾病的药物靶点，并更多地了解其在疾病中的作用。 公共卫生关系：神经退行性疾病是老龄化人口面临的最大威胁之一，药物干预的前景尚不确定。我们已经开发了一种新的方法来发现在这一领域的直接针对分子伴侣。