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Grants and Contracts Details
Description
Recent advances in metabolomics technologies, especially those that combine the complementarity of mass
spectrometry (MS) and nuclear magnetic resonance spectroscopy (NMR) enables rapid analysis of thousands
of peaks representing hundreds of metabolites. Yet, key barriers remain for large-scale metabolomics
applications, most notably: even higher throughput with robust metabolite assignment and quantification;
identification of unknown metabolites; analysis of low abundance/labile metabolites; and reconstruction of
metabolic networks and regulation. Here, we propose an integrated approach that uses chemoselective (CS)
tagging of key metabolite functional groups to boost the speed and accuracy of metabolite identification and
enhance detection. Such tagged metabolites are inherently amenable for multiplexed analysis and reliable
relative quantification via stable isotope encoding. This approach will accelerate analytical throughput while
widening the classes of analytes, including metabolically enriched isotopologues, far beyond current limits. We
will achieve our goals via the following specific aims: SA1. To develop CS probes for tagging metabolites by
targeting functional groups: Hydrophobic quaternary ammonium (QA)-based CS probes will be developed for
tagging carbonyl, amino, thiol, & diol functional groups (FG) in metabolites, optimized for direct infusion FTICR-
MS detection & assignment; SA2. To develop a set of isotope-encoded CS probes for metabolite
identification and multiplexed quantification by FT-ICR-MS and NMR: Developing 13C-encoded QA-CS probes
will facilitate integrated structural analysis of metabolites by 13C edited 2D NMR and FT-ICR-MS, & multiplexed
analysis by FT-ICR-MS; SA3. To develop web-based software for large-scale CS-adducted metabolite
assignment & pathway reconstruction: Algorithm for robust automated MS assignment of metabolite & labeled
isotopologues will be developed based on isotopologue cliques, FG profile, & molecular formula (MF). NMRderived
substructure & MF will be combined with MS data for semi-automated assignment of metabolite
isotopomers & unknowns. Atom-resolved human metabolic database will be refined and tools developed for
pathway reconstruction based on labeled metabolite profiles; SA4. To demonstrate the integrated CS profiling
and biochemo-informatic approach in three basic and translational projects: Metabolic reprogramming driven
by oncogenic gene defects or enzyme deletion in human lung and kidney cancers will be mapped using Stable
Isotope-Resolved Metabolomics (SIRM) enhanced by newly developed CS tagging chemistry and automated
assignment tools. Our long-term goal is to decipher human disease metabolic networks for drug discovery &
early diagnosis.
Status | Finished |
---|---|
Effective start/end date | 4/26/14 → 8/31/19 |
Funding
- National Institute of Environmental Health Sciences: $3,224,449.00
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Projects
- 1 Finished
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Supplement: Integrated Chemoselective and Informatic Platform for Large-Scale Metabolomics
Fan, W.-M. (PI), Higashi, R. (CoI) & Lane, A. (CoI)
National Institute of Environmental Health Sciences
4/26/14 → 8/31/19
Project: Research project