Modeling of the metabolic network of Caenorhabditis elegans

描述（由申请人提供）：生活史特征与代谢过程密切相关。例如，在模式生物秀丽隐杆线虫中，将饮食从一种细菌种类改为另一种细菌种类或扰动某些代谢基因可以显着改变繁殖力、寿命和发育速度。因此，线虫是了解代谢介导的表型与饮食或遗传操作之间关系的绝佳动物模型。要获得这样的理解，需要对其代谢网络进行系统级重建，并建立一个实验平台来监测其营养物质向生物质和能量的转化。全球代谢网络模型适用于 50 多种生物体，其中大部分是原核生物，但也有真核生物，如酿酒酵母、拟南芥和智人。在原核生物和酵母中，重建已与生物反应器中生长速率和其他表型的实验测量和预测相结合。大多数完整的多细胞生物体不能在模拟原核生物反应器的精确控制条件下生长。然而，线虫有几个独特的特性，可以独特地实现这一点，包括寿命短、雌雄同体 繁殖和简单的形态。在这个项目中，我们将首先重建线虫基因组规模的代谢网络模型，然后通过实验校准和验证该模型。我们将把模型分为三个部分：肠道（主要代谢器官）、种系（产生生物量的生殖器官）和其他体细胞组织。我们将使用实验参数校准模型，包括生物量组成、食物摄取率和维持 ATP，以定义液体培养物中的生长。最后，我们将通过独立测试验证我们的模型，包括饮食和遗传操作以及模型通过生物量产生和其他代谢率预测的预期表型。本研究中提出的蠕虫模型，与定量液体培养技术一起，将作为线虫分析和基因工程的独特工具箱，并为系统水平的广泛应用创造机会。

DESCRIPTION (provided by applicant): 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.