GE AKTAEXPLORER CHROMOTOGRAPHY SYSTEM

描述(申请人提供)：在全球范围内，抗菌剂的抗药性正在上升，迫切需要新的抗菌剂来对抗严重的人类病原体，如疟疾和耐药细菌。药物开发的转化努力依赖于高通量筛选小分子化合物文库，以识别抑制微生物细胞功能或毒素作用的新分子。这些通过筛选确定的“热门”化合物，是可能成为新的抗菌化合物开发的支柱的先导化合物。这种筛选工作的一个关键组成部分是对大量要筛选的微生物酶靶标进行纯化。我们的实验室已经成功地对两个这样的目标进行了筛选，并正在开发对其他几个微生物目标的分析。为此目的，请求支持GE AktaExplorer液相色谱系统。该系统具有多个自动化功能(如pH和柱检测)，专为快速开发和优化生物分子纯化而设计。其他组件包括组分收集(基于内置的UV、pH、时间或电导率监测)、自动采样和可为多个用户提供极大灵活性的简单操作软件。收购这一系统将极大地帮助目前受限于现有层析设备的高通量筛选工作。美国国立卫生研究院资助的研究项目包括：(1)治疗疟疾和其他人类寄生虫病的药物开发(贝弗利、奥多姆、西布利和托利亚)；(2)细菌抗毒素药物开发(Haslam)；(3)抗病毒药物开发(法语)；以及受体配体相互作用(Bu、Schwartz)。该项目汇集了几个由NIH资助的研究人员，他们对高端蛋白质纯化系统有类似的需求。所有研究人员都在儿科和分子微生物学系，包括这两个系的各自主席。所有实验室都在麦克唐纳儿科研究大楼内，AKTA系统将在那里安装。作为首席研究员，奥多姆博士将主要负责监督这些设备。已经召集了一个由主要用户组成的咨询委员会，以监督该仪器的使用和维护。在住房和维护Akta系统方面有强有力的机构和部门承诺。为此，儿科已承诺为维护和服务合同提供资金，确保AKTA系统至少在未来10至15年内处于巅峰状态，继续支持华盛顿大学NIH资助的研究。 与公共健康相关：一个由来自华盛顿大学医学院儿科和分子微生物学系的七名NIH支持的研究人员组成的合作小组申请资助购买Atka Explorer 100空气液体色谱系统。每个研究人员都需要高度纯化的蛋白质来回答关于人类疾病的基本问题，或者对具有潜力的小分子抑制剂进行高通量筛选(HTS)，这些小分子抑制剂具有对抗寄生虫、病毒和毒素介导的疾病的新疗法。因此，Akta探索者将直接促进每个研究人员进行的研究，并直接为人类健康做出贡献。

DESCRIPTION (provided by applicant): Globally, resistance to antimicrobial agents is on the rise, and new antimicrobial agents are urgently needed to counter severe human pathogens such as malaria and resistant bacteria. Translational efforts towards drug development depend on high-throughput screening of small molecule compound libraries, in order to identify new molecules that inhibit microbial cellular function or toxin action. These "hits," identified by screening, are lead compounds that may be the backbone of new antimicrobial compound development. A key component of such screening efforts is purification of large amounts of the microbial enzymatic target that is to be screened. Our laboratories have already successfully implemented screens against two such targets and are developing assays for several additional microbial targets. To this end, support is requested for a GE AktaExplorer liquid chromatography system. With multiple automated features (such as pH and column scouting), this system is designed for rapid development and optimization of biomolecular purification. Additional components include fraction collection (on the basis of built-in UV, pH, time, or conductivity monitoring), autosampling, and straightforward operational software that would provide significant flexibility for multiple users. Acquisition of this system would significantly aid high- throughput screening efforts that are currently limited by current chromatographic equipment. NIH funded research projects to be supported by this shared instrument include the following: (1) drug development for malaria and other human parasitic diseases (Beverley, Odom, Sibley, and Tolia); (2) bacterial anti-toxin drug development (Haslam); (3) anti-viral drug development (French); and receptor ligand interactions (Bu, Schwartz). The project brings together several NIH-funded investigators with similar needs for a high-end protein purification system. All of the investigators are in the Departments of Pediatrics and Molecular Microbiology, including respective Chairs of both Departments. All laboratories are within the McDonnell Pediatric Research Building, where the AKTA system will be housed. As principal investigator, Dr. Odom will be principally responsible for overseeing the equipment. An Advisory Committee comprised of major users has been convened to oversee usage and maintenance of the apparatus. There is strong institutional and departmental commitment to housing and maintaining the AKTA system. To that end, the Department of Pediatrics has committed to providing funds for maintenance and service contracts, ensuring the Akta system will function in peak form for at least the next 10 to 15 years in ongoing support of NIH-funded research at Washington University. PUBLIC HEALTH RELEVANCE: A collaborative group of seven NIH-supported investigators from the Departments of Pediatrics and Molecular Microbiology at Washington University School of Medicine request funding for the purchase of an ATKA Explorer 100 Air liquid chromatography system. Each of the investigators requires highly purified proteins to answer basic questions about human disease or to perform high-throughput screening (HTS) of small molecule inhibitors that hold potential as novel therapies against parasitic, viral, and toxin-mediated diseases. As such, the AKTA Explorer will directly facilitate the research undertaken by each investigator and contribute directly to human health.