Metabolomics technology development - Announcements: fellowships, grants, & awards

Environmental Health Perspectives, Nov 15, 2003

The Institutes and Centers of the National Institutes of Health (NIH) invite applications for development and application of new technologies in metabolomics to enable research aimed at elucidating biological pathways and networks. The purpose of this initiative is to encourage the development of highly innovative and sensitive tools for identifying and quantifying cellular metabolites and their fluxes at high anatomical, spatial, and temporal resolution. The general aim of metabolomics is to identify, measure and interpret the complex time-related concentration, activity and flux of endogenous metabolites in cells, tissues, and other biosamples such as blood, urine, and saliva. For the purposes of this solicitation, metabolites include small molecules that are the products and intermediates of metabolism, but also carbohydrates, peptides, and lipids. The need for innovative technologies for measuring and quantifying metabolites involved in cellular pathways and networks was articulated in the 2003 NIH Roadmapping Initiative. It is expected that the technologies developed under this initiative will play a major role in transferring capabilities to laboratories and research institutes that are investigating the underlying pathways involved in cellular homeostasis, perturbation, development, and aging. Many ongoing research programs focus on development of new genomics and proteomics tools and utilization of those approaches for studying cellular function. In contrast, relatively few research programs focus on metabolomics technology development and application. This initiative is to encourage the development of highly innovative and sensitive tools for identifying and quantifying cellular metabolites and their fluxes at high anatomical resolution--extending to subcellular--and at a temporal resolution that would be appropriate to understanding cellular processes at biologically relevant timescales. The scope of projects that would be appropriate ranges from techniques for improving and refining the process of sample separation and processing; to new methods, reagents or instrumentation for identifying and measuring metabolites and their fluxes; to the development and utilization of data reduction, management, and analysis tools needed to establish proof of principle for the technology. New technologies that, if successful, have the potential to be scalable, either as high-throughput applications or as advances that would be used in a large number of laboratories, are especially encouraged. While it is also important to develop data storage, data mining, and pathway modeling capabilities for metabolomics, these issues are explicitly not included in this particular solicitation.

Metabolomics presents unique challenges for sample collection and extraction and for determining analyte identity, concentration, structure, activity and flux in cells. The cellular metabolome is complex, involving several compound classes of small molecules (peptides, lipids, amino acids, carbohydrates) that vary in subunit concentration, size, structure, polarity, and functional groups. Technologies currently in use for metabolomic analysis include NMR, chromatography and mass spectrometry, each of which has significant limitations in quantification, scope, and/or throughput. No one technology can effectively measure, identify and quantify, with sufficient sensitivity and precision, the diverse range of metabolites and their dynamic fluctuations in cells. An integrated set of technologies is needed to address the entire spectrum of challenges for metabolomics. Ideally, new technologies should yield quantitative, comprehensive data and be applicable to achieving anatomical resolution at the cellular and sub-cellular level.

This initiative seeks to encourage technology developments to address three interrelated components of metabolomics: (1) sample collection, extraction, recovery and validation for specific classes of metabolites; (2) analyte detection, identification, quantification, and structure elucidation; and (3) and data management, reduction and analysis. Specific areas of research emphasis include approaches to address the large dynamic range of metabolite concentration in biological samples, the complexity of metabolite mixtures, the inherent noise of the metabolite profile, the vast number of unidentified compounds present within single samples, and the rapidly changing temporal and spatial variability (flux) of the cell's metabolite complement. It is imperative that new technology incorporate approaches for data management, reduction and analysis to support the technology development. This initiative encourages applications that seek to improve existing technologies, including scaling up to high throughput application, as well as those that seek to develop new approaches that have the potential for measuring entire cellular metabolomes or subsets (e.g., amino acid derivatives, peptide derivatives) whose analysis provides enabling technologies, including appropriate tools for data reduction and analysis.