Life history traits are closely associated with metabolic processes. For example, in the model organism C. elegans, changing the diet from one bacterial species to another or perturbations in certain metabolic genes can significantly change fecundity, life span, and the rate of development. Therefore, C. elegans is an excellent animal model for understanding the relationship between metabolically mediated phenotypes and dietary or genetic manipulations. Gaining such understanding requires a systems-level reconstruction of its metabolic network as well as an experimental platform to monitor its conversion of nutrients to biomass and energy. Global metabolic network models are available for more than 50 organisms, mostly prokaryotes but also eukaryotes such as Saccharomyces cerevisiae, Arabidopsis thaliana and Homo sapiens. In prokaryotes and yeast, reconstructions have been combined with experimental measurements and predictions of growth rates and other phenotypes in bioreactors. Most intact multicellular organisms cannot be grown under precisely controlled conditions that mimic a prokaryotic bioreactor. C. elegans, however, has several distinctive properties that uniquely enable this, including short life span, hermaphroditic reproduction, and simple morphology. In this project, we will first reconstruct a genome-scale metabolic network model for C. elegans and subsequently calibrate and validate this model experimentally. We will initiate the compartmentalization of the model into three parts: the intestine (the major metabolic organ), the germline (the reproductive organ that generates biomass), and the other somatic tissues. We will calibrate the model with experimental parameters, including biomass composition, food uptake rates, and maintenance ATP to define growth in liquid cultures. Finally, we will validate our model with independent tests, including dietary and genetic manipulations with expected phenotypes that are to be predicted by the model via biomass production and other metabolic rates. The worm model proposed in this study, together with the quantitative liquid culturing techniques, will serve as a unique toolbox for the analysis and genetic engineering of C. elegans and create opportunities for a broad array of applications at a systems level.
All organisms need to metabolize nutrients to generate energy and produce biomass. Metabolism can be regarded as a network of biochemical reactions that are catalyzed by enzymes associated with metabolic genes. Missing links or abnormal regulations of the network cause serious diseases such as defective glycogen storage, diabetes, and obesity. Systematic studies of the relationships between metabolic disorders and phenotypes are greatly facilitated by using relatively simple, yet multicellular organisms that have a short life span and that can be grown under controlled conditions. The proposed study will establish the first such animal model, by first reconstructing the metabolic network model of the soil dwelling nematode Caenorhabditis elegans, and then calibrating this model with the organism's life in a bioreactor.
| Yilmaz, L Safak; Walhout, Albertha Jm (2017) Metabolic network modeling with model organisms. Curr Opin Chem Biol 36:32-39 |
| Yilmaz, L Safak; Walhout, Albertha J M (2016) A Caenorhabditis elegans Genome-Scale Metabolic Network Model. Cell Syst 2:297-311 |
| Yilmaz, Lutfu Safak; Walhout, Albertha J M (2014) Worms, bacteria, and micronutrients: an elegant model of our diet. Trends Genet 30:496-503 |
