NCRR: UCSC Integrated Small Molecule Screening Facility

描述(由申请人提供)：生物活性小分子的发现已成为学术研究的一个主要主题，也是NIH路线图倡议的核心。使用简单的设备和独特的天然和合成化合物集合，我们在加州大学圣迭戈分校建立了一个充满活力的小分子筛选计划，并取得了丰硕的成果。然而，我们目前的筛选吞吐量太慢了，跟不上我们不断扩大的化合物收集的步伐。随着最近新的高通量纯化技术的实施，Crews实验室的天然产品收藏大幅增加，收购商业和私人化合物图书馆将使我们的内部收藏总量在今年年底达到50,000多件。我们目前的筛选实验室由手动化合物转移装置和低通量液体处理设备组成，能够一次在一个平板上进行操作。这项提议是要求高通量筛查(HTS)设备，以便在加州大学圣迭戈分校建立最先进的筛查设施。基于建议的筛选，这一设施将导致鉴定下列生物学过程的新型小分子探针：细胞周期检查点、细胞生长、RNA剪接、转录延伸、染色质重塑、炎症(由脂氧合酶活性引起)、肌动蛋白动力学、细菌生物膜形成、疟疾感染和细胞质分裂。因此，在加州大学圣迭戈分校建立一个现代化的HTS设施将有助于发现与各种疾病状态相关的潜在治疗线索和药物靶点。相关性：高通量筛选预计将对公共部门的小分子探针发现产生重大影响，就像它在加快工业中的药物先导发现方面发挥的作用一样。为了实现这一目标，必须向研究人员提供集成的HTS设备，以验证和实施高通量格式的屏幕。

DESCRIPTION (provided by applicant): The discovery of bioactive small molecules has emerged as a major theme in academic research and is central to the NIH Roadmap initiative. Using modest equipment and a unique collection of natural and synthetic compounds, we have established a vibrant small molecule screening program at UCSC that has yielded fruitful results. Our current screening throughput, however, is far too slow to keep pace with our expanding compound collection. The Crews lab's natural product collection has grown substantially with the recent implementation of new high-throughput purification techniques, and the acquisition of commercial and private compound libraries will bring our total in-house collection to more than 50,000 by the end of this year. Our current screening lab consists of a manual compound transfer device and low throughput liquid handling equipment capable of performing operations on one plate at a time. This proposal is to request high-throughput screening (HTS) equipment for the establishment of a state-of-the-art screening facility at UCSC. Based on the screens proposed, this facility will lead to the identification of novel small molecule probes of the following biological processes: cell cycle checkpoints, cell growth, RNA splicing, transcription elongation, chromatin remodeling, inflammation (due to lipoxygenase activity), actin dynamics, bacterial biofilm formation, malaria infection, and cytokinesis. The creation of a modern HTS facility at UCSC will thus facilitate the discovery of potential therapeutic leads and drug targets related to a variety of disease states. Relevance: High throughput screening is expected to have a major impact in small molecule probe discovery in the public sector just as it has played a role in speeding up drug lead discovery in industry. In order to bring this goal to fruition, integrated HTS equipment must be available to researchers for the validation and implementation of screens in high throughput format.