Mass spectrometry for small molecule profiling in the Scripps Florida DMPK core

Scripps Florida DMPK 核心中小分子分析的质谱分析

• 批准号: 8447955
• 负责人: Michael Darin Cameron
• 金额: $ 46.06万
• 依托单位: SCRIPPS FLORIDA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-25 至 2014-06-24
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8447955
• 关键词: Animals; Biochemical; Complex; Computer software; Data; Drug Kinetics; Equipment; Evaluation; Florida; Funding; Grant; In Vitro; Individual; Institution; Laboratories; Mass Spectrum Analysis; Metabolic; Metabolism; Performance; Pharmaceutical Preparations; Phase; Plasma; Postdoctoral Fellow; Process; Productivity; Property; Research; Research Personnel; Research Project Grants; Resolution; Sampling; Scanning; Specialist; Staging; System; Tissues; Training; Translational Research; United States National Institutes of Health; Vendor; Wages; Water; Writing; benefit sharing; drug discovery; drug metabolism; experience; instrument; mass spectrometer; new technology; research study; small molecule

DESCRIPTION (provided by applicant): This proposal seeks funding to purchase a ThermoFisher Q-Exactive rapid scanning high-resolution mass spectrometer with appropriate software that will become part of the drug metabolism and pharmacokinetic (DMPK) core dedicated to the study of small molecule disposition in vitro and in animals. This shared instrument will expand capabilities and support a range of research projects originating from sixteen NIH funded projects from seven institutions. The level of engagement for each of these projects with the DMPK core is high as demonstrated by the financial commitments in the respective grants to cover portions of technician salary and experimental expenses (13 of 16 investigators) or through chargebacks that are specifically written into grants (3 of 16). We present justification for the purchase of a Q-Exactive mass spectrometer system by demonstrating significant increases to the information content obtained from metabolism experiments performed using high resolution mass spectrometry. Incorporation of this new technology allows for the simultaneous acquisition of high-performance qualitative and quantitative data from complex samples. The current mass spectrometers in the Scripps DMPK core are triple-quadropole instruments ideally suited for determination of drug concentrations in plasma or other tissues, but lacking high resolution and mass accuracy which are essential for the characterization of unknown metabolites. Samples were prepared as Scripps Florida and sent to application specialists at three vendors for evaluation of the ThermoFisher Q-Exactive, the ABSciex 5600 tripleTOF, and the Waters Synapt G2 QTOF. The presented data demonstrates the benefits each major users will derive from the incorporation of high resolution mass spectrometry that are not currently possible with existing equipment. Data is also presented to rationalize the choice of the Q-Exactive over the other excellent systems. The majority of the grants that benefit from the shared instrument are probe optimization, translational science, and drug discovery grants. Significant increases in capacity to elucidate metabolic liabilities of individual compounds during the optimization phase will increase project productivity. Compound optimization is an iterative process and understanding the drug metabolism and pharmacokinetic properties of molecules at an early stage allows the whole molecule to be optimized instead of just the biochemical or cellular potency. This shared instrument will be installed in the Scripps Florida Mass Spectrometry Laboratory and will be maintained by a group of experienced mass spectroscopists, the PI and two senior research technicians. Several Post Doctoral fellows will be trained or continue their training on this instrument.

描述（由申请人提供）：本提案寻求资金购买配备适当软件的 ThermoFisher Q-Exactive 快速扫描高分辨率质谱仪，该质谱仪将成为致力于研究小分子分布的药物代谢和药代动力学 (DMPK) 核心的一部分体外和动物体内。该共享工具将扩展能力并支持来自 7 个机构的 16 个 NIH 资助项目的一系列研究项目。这些项目与 DMPK 核心的参与程度都很高，具体体现在各自拨款中的财务承诺，用于支付部分技术人员工资和实验费用（16 名研究人员中的 13 名）或通过专门写入拨款的退款（第 3 个（共 16 个）。我们通过证明使用高分辨率质谱进行的代谢实验获得的信息内容显着增加，证明了购买 Q-Exactive 质谱仪系统的理由。这项新技术的结合可以同时从复杂样品中采集高性能的定性和定量数据。目前 Scripps DMPK 核心中的质谱仪是三重四极杆仪器，非常适合测定血浆或其他组织中的药物浓度，但缺乏对于表征未知代谢物至关重要的高分辨率和质量准确度。样品在 Scripps Florida 制备，并发送给三个供应商的应用专家，以评估 ThermoFisher Q-Exactive、ABSciex 5600 TripleTOF 和 Waters Synapt G2 QTOF。所提供的数据表明，每个主要用户将从高分辨率质谱分析中获得的好处，而这是现有设备目前无法实现的。还提供了数据来合理选择 Q-Exactive 相对于其他优秀系统的选择。受益于共享仪器的大部分资助是探针优化、转化科学和药物发现资助。在优化阶段显着提高阐明单个化合物代谢负担的能力将提高项目生产力。化合物优化是一个迭代过程，在早期阶段了解分子的药物代谢和药代动力学特性可以优化整个分子，而不仅仅是生化或细胞效力。该共享仪器将安装在佛罗里达州斯克里普斯质谱实验室，并由一组经验丰富的质谱学家、PI 和两名高级研究技术人员进行维护。几名博士后研究员将接受有关该仪器的培训或继续培训。