Mass spectrometer for high-resolution metabolite analysis

• Subject Area: Medicine
• Term: Funded in 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 521566180

Metabolites are key regulators of systems homeostasis. Changes in concentrations and fluxes of specific groups of metabolites may reflect various disease states. In CKD, metabolic imbalances play a pivotal role in the disease genesis and progression and on CVD progression. The applicants recently identified pathological metabolite-associated post-translational modifications in the disease progression of CKD and CVD. Using synthetic chemical compounds mimicking reactive metabolites, the applicants were able to recreate the pathological PTMs in vitro. However, due to technical analytic limitations, the applications were not able to analyse the corresponding metabolites in vivo from clinical samples. Metabolites can also directly mediate hepatic and intestinal diseases onset and progression. The gut and liver act as one functional entity in health and disease, functionally interconnected by the exchange of endocrine mediators, cytokines, immune cells and metabolites. Metabolites originate from the gut microbiota or are degraded products of proteins within the gastrointestinal tract and can induce or aggravate liver disease by exposing the organ to pro-inflammatory and pro-fibrotic processes. Thus, the identification of these CKD-associated and gut-derived metabolites and potential culprits in kidney, heart, liver and gut pathogenesis are of critical importance. Mass spectrometry is the state-of-the-art method to analyse entire metabolomes to both identify and quantify novel metabolites in the context of diseases like CKD and CKD-associated CVD as well as in the interaction of the gut and the liver. However, without prior knowledge of the chemical composition of novel metabolites, their identification requires superior mass resolution below 800 Dalton for the analyses of their elemental composition, requiring a minimum mass resolution of 50,000. Due to insufficient mass resolution, the identification of metabolites from clinical samples is not feasible with the currently available mass-spectrometers of the applicants. Amongst various research groups are the University hospital RWTH Aachen, the main focus of two currently funded Sonderforscherungsbereiche SFB/TRR219 and CRC1382 are focused on the clinical impact of metabolites and post-translational modifications in the onset and progression of CKD and CVD and gut and liver diseases, respectively. Although further research is needed in this area, metabolome and PTM mass-spectrometry is likely to be translatable into clinical applications and is expected to become a standard tool in clinical practice and provide information complementary to that obtained using existing diagnostic methods. Given that mass spectrometry is able to extract metabolome spectral signatures from pathological plasma samples, this technique provides a novel platform to study the effect of metabolome changes in CKD and CKD-associated CVD and metabolome-associated gut-liver diseases.

• DFG Programme: Major Research Instrumentation
• Major Instrumentation: Massenspektrometer für hochauflösende Metabolitenanalyse
• Instrumentation Group: 1700 Massenspektrometer
• Applicant Institution: Rheinisch-Westfälische Technische Hochschule Aachen
• Leader: Professor Dr. Joachim Jankowski