BSL3 Drug Screening Core

摘要（核心1） 高通量筛选（HTS）已经成为工业和医学领域现代药物发现的基石。 学术界，允许开展大规模的筛查活动， 可以测试化合物以寻找针对给定疾病的新药。但绝 现有的高温超导设施和专用设备大多设置在生物安全等级较低的实验室中 (BSL)条件这使得不可能对高致病性微生物实施该方法， 如球孢子菌属，由于这些病原体工作需要在高级别内进行， 生物防护设施因此，该药物筛选核心的总体目标是建立独特的 在BSL-3条件下的能力，这将允许实施快速，高效和经济的 HTS技术用于大规模筛选化学文库以鉴定新型抗球虫药物 剂.更具体地说，我们建议：i）开发低密度和高密度微量滴定板为基础的模型， 球孢子菌属在我们的BSL-3设施内进行HTS敏感性测试，以及ii）充分开发 基于成像流式细胞术（IFC）的新型真菌细胞学分析（FCP）系统，并使其适用于药物 筛选和确定新药的作用方式。在CCRC内部，该核心将支持 项目1中的筛选和真菌细胞学分析活动，为顶级真菌的向下选择提供服务， 项目2中体内评价的候选人，并支持项目3中检查免疫学的活动 抗真菌药物和候选疫苗的有效性。此外，一旦完全建立， 该核心的能力将提供给整个球孢子菌科学界以及其他人 在医学真菌学领域，以及潜在的其他研究人员与BSL-3生物。

Summary (Core 1) High-throughput screening (HTS) has become the cornerstone of modern drug discovery both in Industry and Academia, allowing for the implementation of large-scale screening campaigns where thousands of compounds can be tested in search for novel drugs against a given disease. However, the overwhelming majority of existing HTS facilities and specialized equipment are set up in laboratories under low biosafety level (BSL) conditions. This makes it impossible to implement this approach for highly pathogenic microorganisms, such as Coccidioides spp., since work with these pathogens needs to be conducted inside high level biocontainment facilities. Thus, the overarching goal of this Drug Screening Core is to establish unique capabilities within BSL-3 conditions, which will allow for the implementation of fast, efficient and economical HTS techniques for large-scale screening of chemical libraries for the identification of novel anti-coccidioidal agents. More specifically, we propose to: i) develop low- and high-density microtiter plate-based models for Coccidioides spp. susceptibility testing amenable to HTS inside our BSL-3 facility, and ii) to fully develop a novel fungal cytological profiling (FCP) system based on imaging flow cytometry (IFC), and adapt it for drug screening and to determine the mode of action of novel drugs. Within the CCRC, this Core will support the screening and fungal cytological profiling activities in Project 1, provide services for down-selection of top candidates for in vivo evaluation in Project 2, and support Project 3 activities examining immunotherapeutic efficacy of antifungal drugs and vaccine candidates. Furthermore, once fully established, the technical capabilities of this Core will be provided to the Coccidioides scientific community at large, as well as to others in the field of Medical Mycology, and potentially other investigators working with BSL-3 organisms.