Development of Mass Spectrometry for Multidimensional Metabolome Analysis

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My DG research focuses on developing new analytical tools to overcome the current limitations of metabolome analysis, thereby opening new opportunities to use metabolomics for biological and medical applications. The ultimate goal of our research is to be able to analyze the whole metabolome (i.e., all the metabolites) at high temporal and spatial resolutions in biological systems (e.g., tissue, blood, and cells). One example of long-term visions is to produce a time-series of 3D-images of all metabolites from organs at different development stages, at the single cell resolution, to study spatial distributions and temporal changes of these metabolites and their functions. To reach the long-term goal, we need new ideas and tools. My lab is a leader in developing the high-performance chemical isotope labeling (CIL) liquid chromatography mass spectrometry (LC-MS) technology for very comprehensive analysis of the metabolome with high quantification accuracy and precision. We propose to advance this technology to a new level that will have breakthrough-impact on how metabolomics is used for biology studies and disease biomarker discovery. Our short-term research objectives and planned research activities include: Objective and Activity #1: Developing experimental metabolome databases (e-MDBs) for rapid metabolite identification and annotation. We will develop analytical methods to create the world's largest e-MDBs for different types of samples. An example is to create the Human e-MDB where all the metabolites from human sources including biofluids and cell lines will be detected and annotated. Objective and Activity #2: Developing a sensitive method for temporal metabolome analysis. We will develop nano-scale sample preparation methods, in combination with nanoflow LC-MS and e-MDB, to perform temporal metabolome analysis using trace amounts of samples. An example of the impact areas is for analyzing circulating tumor cells (CTCs) in blood of cancer patients for diagnosis and prognosis of cancers. Another example is to analyze 1 µL of finger blood that could be less-invasively taken over a period time for disease and health state monitoring. Objective and Activity #3: Developing a digital mass spectrometry (DMS) technique for spatial metabolome analysis. We will develop tissue cutting tools and fast LC-MS methods to analyze the metabolome of small cubic samples to produce 3D-images of thousands of detectable metabolites in tissues or organs. In summary, this DG research will allow us to create the world's largest e-MDBs for metabolomics of different types of samples, produce the world's most sensitive detection tool for metabolome analysis, and start the new research direction of DMS for 3D-imaging of thousands of metabolites with high spatial resolution. These activities will bring one major step closer to the realization of our ultimate goal. This research will also train HQP to become highly skilled and highly sought-after scientists.