WormJam: A consensus<i>C. elegans</i>Metabolic Reconstruction and Metabolomics Community and Workshop Series

Hastings, Janna; Mains, Abraham; Artal‐Sanz, Marta; Bergmann, Sven; Braeckman, Bart P.; Bundy, Jake G.; Cabreiro, Filipe; Dobson, Paul D.; Ebert, Paul R.; Hattwell, Jake P. N.; Hefzi, Hooman; Houtkooper, Riekelt H.; Jelier, Rob; Joshi, Chintan; Kothamachu, Varun B.; Lewis, Nathan E.; Lourenço, Artur B.; Nie, Yu; Norvaišas, Povilas; Pearce, Juliette; Riccio, Cristian; Rodríguez, Nicolás; Santermans, Toon; Scarcia, Pasquale; Schirra, Horst Joachim; Sheng, Ming; Smith, Reuben L.; Suriyalaksh, Manusnan; Towbin, Benjamin D.; Tuli, Mary Ann; Weeghel, Michel van; Weinkove, David; Zecic, Alexandra; Zimmermann, Johannes; Novère, Nicolas Le; Kaleta, Christoph; Witting, Michael; Casanueva, Olivia

doi:10.1080/21624054.2017.1373939

Cited by 14 publications

(9 citation statements)

References 14 publications

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“…GSMMs are mathematical representations of all known metabolic reactions in an organism. Three such models have been recently published for C. elegans (Gebauer et al, 2016; Yilmaz and Walhout, 2016; Ma et al, 2017) and a community-driven approach has reconciled and extended these into a consensus model (Hastings et al, 2017; Witting et al, 2018). Whole-genome metabolic models can be used to predict intracellular turnover rates (fluxes) for metabolic reactions using for instance Flux Balance Analysis (FBA), a mathematical method that uses the stoichiometry of every reaction in a whole system to derive a steady state solution by optimizing an objective function, usually growth (Orth et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

Multi-Omics and Genome-Scale Modeling Reveal a Metabolic Shift During C. elegans Aging

Hastings

Mains

Virk

et al. 2019

Front. Mol. Biosci.

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In this contribution, we describe a multi-omics systems biology study of the metabolic changes that occur during aging in Caenorhabditis elegans. Sampling several time points from young adulthood until early old age, our study covers the full duration of aging and include transcriptomics, and targeted MS-based metabolomics. In order to focus on the metabolic changes due to age we used two strains that are metabolically close to wild-type, yet are conditionally non-reproductive. Using these data in combination with a whole-genome model of the metabolism of C. elegans and mathematical modeling, we predicted metabolic fluxes during early aging. We find that standard Flux Balance Analysis does not accurately predict in vivo measured fluxes nor age-related changes associated with the Citric Acid cycle. We present a novel Flux Balance Analysis method where we combined biomass production and targeted metabolomics information to generate an objective function that is more suitable for aging studies. We validated this approach with a detailed case study of the age-associated changes in the Citric Acid cycle. Our approach provides a comprehensive time-resolved multi-omics and modeling resource for studying the metabolic changes during normal aging in C. elegans.

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Section: Introductionmentioning

confidence: 99%

Multi-Omics and Genome-Scale Modeling Reveal a Metabolic Shift During C. elegans Aging

Hastings

Mains

Virk

et al. 2019

Front. Mol. Biosci.

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“…High resolution mass spectrometry-based metabolomics has been used in several C. elegans studies (Edison et al 2015;Hastings et al 2017;Mor 2020;Witting et al 2018). The comprehensive molecular understanding of the nematode model makes it amenable to characterizing systemic biochemistry and perturbations to global metabolism as a result of genetic, environmental and toxicological perturbations.…”

Section: Discussionmentioning

confidence: 99%

Genetic or toxicant induced disruption of vesicular monoamine storage and global metabolic profiling inCaenorhabditis elegans

Bradner

Kalia

Lau

et al. 2020

Preprint

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The proper storage and release of monoamines contributes to a wide range of neuronal activity. Here, we examine the effects of altered vesicular monoamine transport in the nematode C. elegans. The gene cat-1 is responsible for the encoding of the vesicular monoamine transporter (VMAT) in C. elegans and is analogous to the mammalian vesicular monoamine transporter 2 (VMAT2). Our laboratory has previously shown that reduced VMAT2 activity confers vulnerability on catecholamine neurons in mice. The purpose of this paper was to determine whether this function is conserved and to determine the impact of reduced VMAT activity in C. elegans. Here we show that deletion of cat-1/VMAT increases sensitivity to the neurotoxicant 1-methyl-4-phenylpyridinium (MPP+) as measured by enhanced degeneration of dopamine neurons. Reduced cat-1/VMAT also induces changes in dopamine-mediated behaviors. High-resolution mass spectrometry-based metabolomics in the whole organism reveals changes in amino acid metabolism, including tyrosine metabolism in the cat-1/VMAT mutants. Treatment with MPP+ disrupted tryptophan metabolism. Both conditions altered glycerophospholipid metabolism, suggesting a convergent pathway of neuronal dysfunction. Our results demonstrate the evolutionarily conserved nature of monoamine function in C. elegans and further suggest that HRMS-based metabolomics can be used in this model to study environmental and genetic contributors to complex human disease

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“…For example, important progress has already been made in establishing the necessary computational tools [83] and reconstructing metabolic models of bacterial strains from the human microbiota [84]. There is also a community effort to develop the first metabolic model of a multicellular organism -C. elegans, which will incorporate the metabolic contribution of gut commensals [85]. In the future, such approaches might provide valuable insights when transitioning from animal testing to human trials.…”

Section: Discussionmentioning

confidence: 99%

Pharmacology in the age of the holobiont

Norvaišas

Cabreiro

2018

Current Opinion in Systems Biology

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Highlights Pharmacomicrobiomics -new frontier in pharmacology  Holobiont -the physiological unit of host and microbes as a drug target  Drugs and drug targets are re-defined in the context of the holobiont  New holistic approach in drug research using holobiont animal models  Exciting new prospects for microbiota-based personalised medicine Glossary:Holobiont -Supra-organism of host and its microbes.Pharmacogenomics -Field of research which combines pharmacology and genomics to study how the genetic make-up of an individual modulates its response to therapeutic drugs [1].Pharmacometabolomics -Field of research which combines pharmacology and metabolomics to study how the metabolome shaped by environment and genetics influence the response of an individual to therapeutic drugs [2].Xenobiotics -An exogenously produced chemical compound found inside an organism. This broad term encompasses therapeutic drugs and dietary metabolites. AbstractDespite the widely acknowledged fact that the microbiota regulates many aspects of human health, the dynamics and factors that govern these interactions remain mostly unknown. Pharmacomicrobiomics is a new research frontier in pharmacology that studies the interaction between drugs and the microbiota. This discipline, by including the microbiota as a key regulator of host health, calls for a redefinition of what constitutes a drug target and ultimately what is a drug or drug therapy. This is supported by recent evidence showing that host physiology can no longer be studied in separation from its microbial ecology and the environmental factors that shape it, as the combination of these elements forms the physiological unit of study -the holobiont. Here we discuss both the novel challenges and untapped opportunities that this new framework creates. On one hand, a more complete understanding of the physiology of the host imposes the development/adaptation of new animal models to address these interactions. In particular, we focus on the advantages and disadvantages of C. elegans as a host organism. On the other hand -a complete understanding of the effects of the microbiota and xenobiotics (e.g. drugs and dietary metabolites) on host health opens new prospects for personalized therapy. Pharmacology has come a long way since the inception of "magic bullet" drugs at the beginning of the 20th century. Intelligent drug design still holds the promise of devising new compounds that specifically affect a disease target yet are harmless to the functioning of the entire organism. The lack of success in achieving such gold standards, associated with high failure of new drugs in clinical trials has led to an increasing interest for drug repurposing [3,4]. Developments in molecular and cellular biology have revealed a number of new drug targets and factors that may affect efficacy and/or side-effects. As a consequence, new branches of pharmacology emerged, like pharmacogenomics and pharmacometabolomics, which aim at understanding how the genetics and the metabolism of an individual can modu...

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WormJam: A consensusC. elegansMetabolic Reconstruction and Metabolomics Community and Workshop Series

Cited by 14 publications

References 14 publications

Multi-Omics and Genome-Scale Modeling Reveal a Metabolic Shift During C. elegans Aging

Multi-Omics and Genome-Scale Modeling Reveal a Metabolic Shift During C. elegans Aging

Genetic or toxicant induced disruption of vesicular monoamine storage and global metabolic profiling inCaenorhabditis elegans

Pharmacology in the age of the holobiont

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