MRI: Development of a next-generation MALDI ion mobility mass spectrometry platform for molecular imaging and training

该提案旨在开发一种“先进的分子显微镜”，用于可视化化学复杂和多样化的基质，包括生物组织和材料（例如，聚合物药物递送系统）。该仪器将为生物分子的可视化提供革命性的能力，极大地扩展了我们对细胞系统的理解。拟议的仪器结合了国家的最先进的激光光学和质谱分析到一个单一的分子成像平台。该仪器将能够同时对数千个生物分子进行超高空间分辨率成像。将与国际公认的科学家合作开发和评估该仪器，这些科学家的项目是根据他们对拟议技术的迫切需要而专门选定的。每个项目提出的挑战将推动进一步的技术发展。这些项目涵盖众多应用领域，包括工程药物递送系统、天然产物发现和鉴定、生命科学基础研究以及植物代谢和生物燃料。这种下一代分子成像平台将成为未来的基础仪器。待开发的仪器是最先进的超高空间分辨率基质辅助激光解吸/电离（MALDI）捕获离子迁移谱（TIMS）正交四极飞行时间（TOF）分子成像平台。MALDI成像质谱将质谱的灵敏度和分子特异性与经典显微镜的空间保真度相结合。成像MS是无标记的，非靶向的（同时检测数千种化学上不同的分子种类），灵敏的（毫微微摩尔检测限）和特异性的（区分差异为0.001 Da的分子）。商业成像质谱平台是对用于其他目的的仪器的改编，因此仅提供有限的成像能力，缺乏解决复杂化学系统所面临的深入挑战的性能。提出的新型MALDI timsTOF分子成像系统将提供前所未有的超高空间分辨率成像能力组合，（1微米激光束直径），高性能质量分析（精度：2 ppm，分辨率：50，000），高分辨率离子迁移率分离（分辨能力：150-200），以及来自单个像素的高度多路复用碎片化（200 MS/MS事件/s）。该仪器将成为范德比尔特大学质谱研究中心的基石分子成像平台。该操作工具将解决范德比尔特大学以及区域，国家和国际科学界的关键研究需求。该奖项反映了NSF的法定使命，并已被认为是值得通过使用基金会的智力价值和更广泛的影响审查标准进行评估的支持。

This proposal is to develop an "advanced molecular microscope" for visualizing chemically complex and diverse substrates, including biological tissues and materials (e.g., polymeric drug delivery systems). This instrument will provide revolutionary capabilities for the visualization of biological molecules, dramatically expanding our understanding of cellular systems. The proposed instrument combines state-of-the-art laser optics and mass spectrometric analysis into a single molecular imaging platform. This instrument will enable ultra-high spatial resolution imaging of thousands of biomolecules virtually at the same time. Development and assessment of the instrument will be done in collaboration with internationally recognized scientists whose projects were specifically chosen based on their critical need for the proposed technologies. The challenges raised by each project will drive further technology development. These projects span numerous application areas, including engineered drug delivery systems, natural product discovery and identification, fundamental research in life science, and plant metabolism and biofuels. This next-generation molecular imaging platform will be the foundational instrument of tomorrow. The instrument to be developed is a state-of-the-art ultra-high spatial resolution matrix assisted laser desorption/ionization (MALDI) trapped ion mobility spectrometry (TIMS) orthogonal quadrupole time-of-flight (TOF) molecular imaging platform. MALDI imaging mass spectrometry combines the sensitivity and molecular specificity of mass spectrometry with the spatial fidelity of classical microscopy. Imaging MS is label-free, untargeted (concurrently detects thousands of chemically diverse molecular species), sensitive (femtomole limits-of-detection), and specific (discriminates molecules that differ by 0.001 Da). Commercial imaging mass spectrometry platforms are adaptations of instruments built for other purposes and thus offer only limited imaging capabilities, lacking the performance to solve in-depth challenges that complex chemical systems present. The proposed novel MALDI timsTOF molecular imaging system will provide an unprecedented combination of ultra-high spatial resolution imaging capability (1 micrometer laser beam diameter), high-performance mass analysis (accuracy: 2 ppm, resolving power: 50,000), high resolving power ion-mobility separations (resolving power: 150-200), and highly multiplexed fragmentation from a single pixel (200 MS/MS events/s). This instrument will be the cornerstone molecular imaging platform of the Vanderbilt University Mass Spectrometry Research Center. The operational instrument will address the critical research needs of Vanderbilt University as well as the regional, national and international scientific communities.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.