MacMillan: Project 1; Technology Development and Research Project #1: Cytological Profiling (Linington)

麦克米伦：项目 1；

• 批准号: 9678971
• 负责人: Roger G Linington
• 金额: $ 23.21万
• 依托单位: UNIVERSITY OF CALIFORNIA SANTA CRUZ
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9678971
• 关键词: MacMillan; Project; Technology; Development; Research

Abstract: Determination of the precise mode of action (MOA) for bioactive metabolites remains one of the central challenges facing the botanical natural products community. Because of the technical challenges associated with this issue, and the complex nature of botanicals and natural products extracts, MOA determination is often not addressed until late in the discovery process, leading to a high rate of redundancy and attrition for drug discovery applications. This TRD project aims to invert the traditional natural product discovery process by developing a new platform for the prediction of compound identities and modes of action directly from primary screening of complex mixtures. This approach takes advantage of recently developed phenotypic image-based screening developed in our laboratories for assessing biological activities of natural product extracts, and combines this with high-resolution uPLC-MS analyses to connect chemical constituents with unique but not predefined biological phenotypes. By using the integration of these two information-rich orthogonal profiling methods we have been able to successfully demonstrate the de novo prediction of compound MOs, and validate these by downstream evaluation of pure compounds isolated using this methodology. This TRD project aims to 1) increase the resolution of the biological assay through the inclusion of additional cell lines, stain sets and reference compounds, 2) Develop a next-generation untargeted metabolomics platform specifically optimized for the analysis of natural product mixtures, and 3) Create new informatics tools to integrate and query these two information-rich profiling methods. At the conclusion of the project it is anticipated that we will have created a unique tool with broad utility within the botanical natural products field, which is accessible via a web interface and is configured for facile inclusion of samples and extracts from all interested researchers both nationally and internationally.

摘要：生物活性代谢物的精确作用模式（MOA）的测定仍然是确定生物活性代谢物的精确作用模式（MOA）的方法之一。 植物天然产品界面临的主要挑战。由于技术挑战 与这个问题相关，以及植物和天然产物提取物的复杂性，MOA 通常直到发现过程的后期才确定，从而导致高冗余率 和药物发现应用的损耗。这个TRD项目旨在颠覆传统的天然产品 通过开发预测化合物特性和作用模式的新平台来实现发现过程 直接来自复杂混合物的初步筛选。该方法利用了最近开发的 我们的实验室开发了基于表型图像的筛选，用于评估天然物质的生物活性 产品提取物，并将其与高分辨率 uPLC-MS 分析相结合，以连接化学成分 具有独特但未预先定义的生物表型。通过整合这两个丰富的信息 正交分析方法我们已经能够成功地证明从头预测 化合物 MO，并通过使用该方法分离的纯化合物的下游评估来验证这些 方法论。该 TRD 项目旨在 1) 通过纳入提高生物测定的分辨率 额外的细胞系、染色组和参考化合物，2) 开发下一代非靶向 专为天然产物混合物分析而优化的代谢组学平台，以及 3) 创建新的 信息学工具可以集成和查询这两种信息丰富的分析方法。会议结束时 预计我们将创建一个在植物自然领域具有广泛用途的独特工具 产品字段，可通过 Web 界面访问，并配置为轻松包含样品和 摘自国内外所有感兴趣的研究人员。