Identification of compounds that reverse cellular toxicity of A beta peptide in a

鉴定逆转 A β 肽细胞毒性的化合物

• 批准号: 8233393
• 负责人: Susan L. Lindquist
• 金额: $ 4.88万
• 依托单位: WHITEHEAD INSTITUTE FOR BIOMEDICAL RES
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8233393
• 关键词: Alzheimer' s Disease; Animal Model; Biological Assay; Brain; Cell model; Cells; Chemicals; Data; Defect; Development; Disease; Drug Kinetics; Etiology; Eukaryotic Cell; Future; Galactose; Genetic; Genetic Screening; Growth; Homeostasis; Hour; Human; Laboratories; Libraries; Link; Mammalian Cell; Mitochondria; Modeling; Monitor; Nerve Degeneration; Neurodegenerative Disorders; Neurofibrillary Tangles; Neurons; Optics; Parkinson Disease; Pathology; Patients; Peptides; Poison; Presenile Alzheimer Dementia; Protein-Folding Disease; Proteins; Raffinose; Relative (related person); Rotenone; Saccharomyces cerevisiae; Sorting - Cell Movement; Toxic effect; Transgenic Mice; Yeast Model System; Yeasts; age related; cellular pathology; density; efficacy testing; gene discovery; link protein; mouse model; neurotoxicity; pre-clinical; promoter; public health relevance; synuclein; tool; trafficking

DESCRIPTION (provided by applicant): Our laboratory has used yeast to model the cellular defects caused by the human proteins implicated in neurodegenerative diseases. We propose a high- throughput chemical screen using a yeast strain expressing human A2, a protein linked to Alzheimer's disease. Data from a pilot screen demonstrate that our yeast A2 assay is robust and reproducible. The proposed screen will enable us to probe a larger library at multiple concentrations and cover a broader chemical space. Hit compounds from this screen will be counter-screened against yeast models of other neurodegenerative diseases to determine selectivity, and will be further screened for toxicity in mammalian cells and efficacy in mammalian neurons. The ideal chemical candidates would have activity in both our primary yeast and secondary neuronal toxicity assays and would have a pharmacokinetic profile suitable for studies in transgenic mouse models of AD. These chemical probes will provide a complementary approach to deciphering the tangled mechanisms of toxicity and protection that we have begun to uncover through our genetic screens. PUBLIC HEALTH RELEVANCE: A2 peptide accumulates in the brains of patients with Alzheimer disease and may cause neurodegeneration, but its mechanism of action is not known. We propose to identify compounds that can alleviate the cellular toxicity of A2 and validate these in neuronal models. These probes will be valuable tools for dissecting A2 pathology and could potentially become the focus for future pre- clinical development.

描述（由申请人提供）：我们的实验室使用酵母来模拟与神经退行性疾病有关的人类蛋白质引起的细胞缺陷。我们提出使用表达人 A2（一种与阿尔茨海默病相关的蛋白质）的酵母菌株进行高通量化学筛选。中试筛选数据表明，我们的酵母 A2 检测方法稳健且可重复。所提出的屏幕将使我们能够在多个浓度下探测更大的库并覆盖更广泛的化学空间。此次筛选的命中化合物将针对其他神经退行性疾病的酵母模型进行反筛选，以确定选择性，并将进一步筛选其在哺乳动物细胞中的毒性和在哺乳动物神经元中的功效。理想的候选化学物质应在我们的初级酵母和次级神经元毒性测定中均具有活性，并且具有适合 AD 转基因小鼠模型研究的药代动力学特征。这些化学探针将提供一种补充方法来破译我们已经开始通过基因筛选发现的复杂的毒性和保护机制。 公共健康相关性：A2 肽在阿尔茨海默病患者的大脑中积聚，可能导致神经退行性变，但其作用机制尚不清楚。我们建议鉴定可以减轻 A2 细胞毒性的化合物，并在神经元模型中验证这些化合物。这些探针将成为解剖 A2 病理学的宝贵工具，并有可能成为未来临床前开发的焦点。