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Tools for Systems Biology applications – UMC Groningen

Contact Details

UMC Groningen

Antonius Deusinglaan 1, 9713 AV Groningen

Prof. Dr. B.M. Bakker Dr. J.C. Wolters

0031 (0)50 361 1542 0031 (0)50 363 6276

Hotel Description

The goal of the department is to use Systems Biology approaches to unravel the mechanisms underlying inborn and acquired metabolic diseases. We aim to understand how different proteins and metabolites in a complex metabolic network modulate disease outcome. This helps us to understand which people are at risk and develop personalized therapies. Our approach is based on interplay between experimental work and computational modeling.

Our department has established computational models on a range of pathways mostly related to central energy metabolism. Furthermore, we have an established workflow for quantitative, targeted proteomics applications. Assays including standards are available for pathways in energy metabolism (glycolysis, mitochondrial fatty-acid oxidation, TCA cycle and respiration). Within the various projects the models and targeted proteomics assays are being extended and these applications provide potential valuable tools for other research questions related to the same biological processes. Finally, we work on targeted metabolomics approaches, including workflows for analysis of stable isotopes.

 

Systems biology
Public
  • Biomedical & health
  • Targeted proteomics
  • Computational modelling

Expertise and Track Record

Prof Dr.  Bakker is coordinator of Marie Skłodowska Curie International Training Network ‘PoLiMeR’ (Polymers in the Liver: Metabolism and Regulation); www.polimer-itn.eu.

She applies the Systems Biology approaches for the computational modelling of metabolic networks based on ordinary differential equations and enzyme kinetics. The analytical platforms to support the modeling include targeted metabolomics and stable isotope fluxomics for specific metabolites.

Dr. Wolters has established the targeted proteomics workflow within the department for various applications. The method development of the mitochondrial targets has been published as methodology paper (Wolters, 2016) and the applications for the modeling are amongst others, published in relation to the MCAD deficiency mouse models (van Eunen, 2016) and a study dedicated to mouse aging mechanisms (Stolle, 2018). The developed methods have already been applied by external collaborators as well (Janssens 2017; van Erp, 2018).

Alternative applications for the targeted proteomics ranged from targeting proteins related to the bile acid metabolism (Hoogerland, 2019), quantification of patient specific (heterozygote) mutations in patients (Oldoni, 2018) to quantification of protein complexes in combination with silencing of specific components in these complexes (Fedeseioenko, 2018). Additionally, all assays are developed in such way that they are applicable both for human and mouse targets, making them widely applicable for animal models, cell lines and patient materials alike.

  • den Besten G, Havinga R, Bleeker A, Rao S, Gerding A, van Eunen K, Groen AK, Reijngoud DJ, Bakker BM (2014) The short-chain fatty acid uptake fluxes by mice on a guar gum supplemented diet associate with amelioration of major biomarkers of the metabolic syndrome. PLoS One. 9(9):e107392.
  • Fedoseienko A, Wijers M, Wolters JC, Dekker D, Smit M, Huijkman N, Kloosterhuis N, Klug H, Schepers A, Willems van Dijk K, Levels JHM, Billadeau DD, Hofker MH, van Deursen J, Westerterp M, Burstein E, Kuivenhoven JA, van de Sluis B. (2018) The COMMD Family Regulates Plasma LDL Levels and Attenuates Atherosclerosis Through Stabilizing the CCC Complex in Endosomal LDLR Trafficking. Circ Res. 122(12):1648-1660.
  • Haanstra JR, Gerding A, Dolga AM, Sorgdrager FJH, Buist-Homan M, du Toit F, Faber KN, Holzhütter HG, Szöör B, Matthews KR, Snoep JL, Westerhoff HV, Bakker BM (2017) Targeting pathogen metabolism without collateral damage to the host. Sci Rep. 2017 Jan 13;7:40406.
  • Hoogerland JA, Lei Y, Wolters JC, de Boer JF, Bos T, Bleeker A, Mulder NL, van Dijk TH, Kuivenhoven JA, Rajas F, Mithieux G, Haeusler RA, Verkade HJ, Bloks VW, Kuipers F, Oosterveer MH (2019) Glucose-6-Phosphate Regulates Hepatic Bile Acid Synthesis in Mice. Hepatology. doi: 10.1002/hep.30778. [Epub ahead of print].
  • Janssens S, Ciapaite J, Wolters JC, van Riel NA, Nicolay K, Prompers JJ. (2017) An In Vivo Magnetic Resonance Spectroscopy Study of the Effects of Caloric and Non-Caloric Sweeteners on Liver Lipid Metabolism in Rats. 10;9(5). pii: E476.
  • Oldoni F, van Capelleveen JC, Dalila N, Wolters JC, Heeren J, Sinke RJ, Hui DY, Dallinga-Thie GM, Frikke-Schmidt R, Hovingh KG, van de Sluis B, Tybjærg-Hansen A, Kuivenhoven JA. (2018) Naturally Occurring Variants in LRP1 (Low-Density Lipoprotein Receptor-Related Protein 1) Affect HDL (High-Density Lipoprotein) Metabolism Through ABCA1 (ATP-Binding Cassette A1) and SR-B1 (Scavenger Receptor Class B Type 1) in Humans. Arterioscler Thromb Vasc Biol. 38(7):1440-1453.
  • van Erp AC, Rebolledo RA, Hoeksma D, Jespersen NR, Ottens PJ, Nørregaard R, Pedersen M, Laustsen C, Burgerhof JGM, Wolters JC, Ciapaite J, Bøtker HE, Leuvenink HGD, Jespersen B. (2018) Organ-specific responses during brain death: increased aerobic metabolism in the liver and anaerobic metabolism with decreased perfusion in the kidneys. Sci Rep. 8(1):4405.
  • van Eunen K, Volker-Touw CM, Gerding A, Bleeker A, Wolters JC, van Rijt WJ, Martines AM, Niezen-Koning KE, Heiner RM, Permentier H, Groen AK, Reijngoud DJ, Derks TG, Bakker BM. (2016) Living on the edge: substrate competition explains loss of robustness in mitochondrial fatty-acid oxidation disorders. BMC Biol. 14(1):107.
  • van Eunen K, Simons SM, Gerding A, Bleeker A, den Besten G, Touw CM, Houten SM, Groen BK, Krab K, Reijngoud DJ, Bakker BM (2013)Biochemical competition makes fatty-acid β-oxidation vulnerable to substrate overload. PLoS Comput Biol. 2013;9(8):e1003186.
  • Stolle S, Ciapaite J, Reijne AC, Talarovicova A, Wolters JC, Aguirre-Gamboa R, van der Vlies P, de Lange K, Neerincx PB, van der Vries G, Deelen P, Swertz MA, Li Y, Bischoff R, Permentier HP, Horvatovitch PL, Groen AK, van Dijk G, Reijngoud DJ, Bakker BM. (2018) Running-wheel activity delays mitochondrial respiratory flux decline in aging mouse muscle via a post-transcriptional mechanism. Aging Cell. 17 (1).
  • Wegrzyn AB, Stolle S, Rienksma RA, Martins Dos Santos VAP, Bakker BM, Suarez-Diez M (2019) Cofactors revisited – Predicting the impact of flavoprotein-related diseases on a genome scale. Biochim Biophys Acta Mol Basis Dis. 1865(2):360-370.
  • Wolters JC, Ciapaite J, van Eunen K, Niezen-Koning KE, Matton A, Porte RJ, Horvatovich P, Bakker BM, Bischoff R, Permentier HP. (2016) Translational Targeted Proteomics Profiling of Mitochondrial Energy Metabolic Pathways in Mouse and Human Samples. J Proteome Res. 15(9):3204-13.

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