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

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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.