Stable Isotopes

Stable Isotopes-Resolved Metabolomics (SIRM)

The complexity of human metabolome, especially the redundant use of the same metabolites in many biochemical pathways, makes it impractical to obtain a mechanistic understanding of disease states and drug responses based on metabolite concentrations alone. For example, a metabolite such as glutamate can participate in >50 distinct pathways. As diseases and response to drugs can involve dysregulations in multiple specific pathways, it is imperative to utilize stable isotope tracers coupled with metabolomics (e.g. stable isotope-resolved metabolomics or SIRM) to robustly discern pathway participation and their dynamic changes. Once elucidated, key enzymes and/or regulator proteins in the pathways can be mapped onto transcriptomic or genomic data to deduce metabolic dysregulation at the gene level. Such metabolomic to transcriptomic or genomic linkages can facilitate and functionally annotate genome-wide association studies (GWAS). Moreover, the metabolome to transcriptome or genome association will help target specific protein(s) for queries into dysregulation at the protein expression and/or posttranslational levels.

As a resource core for the PMRN, we will apply SIRM to mechanistic model studies on cells derived from human patients and on mouse models in parallel to the proposed metabolite profiling of human subjects in the bridging projects. The model studies aim to define the metabolic and regulatory pathways associated with potential biomarkers uncovered from the patient studies.

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Here are some slides that exemplify the concept of Stable Isotopes Resolved Metabolomics and exemplify how the SIRM was used to investigate metabolic trafficking between neurons and Astrocytes.

Stable Isotopes Team

Teresa Fan  Andrew Lane  R.M. Higashi  Hunter Moseley  
Teresa FanAndrew LaneR.M. HigashiHunter Mosely



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