Developing Computational Approaches for Integration of Metabolomics into Systems Biology

代谢组学是对生物系统中存在的所有化学物质和代谢物(即代谢组)的综合研究。代谢组既包括内源性代谢产物，也包括来自食物、肠道微生物、化学暴露等的外源化合物，代表受宿主遗传和环境影响的复杂生物事件的最终产物。代谢组学越来越多地被应用于研究复杂的疾病、植物生理学、动物营养、宿主-肠道微生物区系相互作用以及环境监测。生物信息学在代谢组学中发挥着至关重要的作用--从原始数据处理到生物学解释。目前，代谢组学面临着三个主要的计算挑战：i)由于高分辨率质谱学(MS)系统的日益使用而带来的光谱处理挑战，ii)由于从哺乳动物肠道微生物区系(即代谢组)等复杂环境中产生代谢组学数据而带来的功能解释挑战，以及iii)将代谢组学数据与其他组学数据相结合以进行全面生物学理解的挑战。迫切需要新的计算方法来满足这些需求。我的研究计划的长期目标是开发一个集成的、全面的和可预测的系统生物学框架，以帮助解释由于不同环境扰动而导致的代谢组变化。短期目标是开发生物信息学方法，在宿主-肠道微生物区系代谢相互作用的背景下解决目前的数据处理和整合挑战。为此，我将开发创新的计算算法来改进基于MS的代谢组学数据处理和注释；整合基因组挖掘方法来全面描述肠道代谢组；最后通过社区规模的代谢网络来模拟肠道代谢组的变异。将使用公共数据集以及内部和通过协作产生的数据集来评估这些工具的性能。研究成果，包括工具、数据库和算法，将通过最新的网络技术和基于云计算的平台公开提供。拟议的研究计划解决了当前代谢组学中的主要瓶颈，并通过识别新的生物标志物、发现关键联系和开发预测模型，为翻译应用提供了巨大的潜力。本建议所述的研究活动将使HQP能够在跨学科的环境中进行有效的培训和安置。

Metabolomics is the comprehensive study of all chemicals and metabolites (i.e. the metabolome) present in a biological system. The metabolome includes both endogenous metabolites and exogenous compounds from food, gut microbes, chemical exposures, etc., representing the final products of complex biological events governed by host genetics and environmental influences. Metabolomics is increasingly applied to study complex diseases, plant physiology, animal nutrition, host-gut microbiota interactions as well as environmental monitoring. Bioinformatics plays an essential role in metabolomics - from raw data processing to biological interpretation. Currently, metabolomics is facing three main computational challenges: i) the spectral processing challenge due to the increasing use of high-resolution mass spectrometry (MS) systems, ii) the functional interpretation challenge due to the generation of metabolomics data from complex environments such as the mammalian gut microbiota (i.e. meta-metabolome), and iii) the challenge for integrating metabolomics data with other omics data for comprehensive biological understanding. Novel computational approaches are urgently needed to address these needs. The long-term goal of my research program is to develop an integrated, comprehensive and predictive systems-biology framework to help explain metabolome variations due to different environmental perturbations. The short-term objective is to develop bioinformatics approaches to address the current data processing and integration challenges within the context of host-gut microbiota metabolic interactions. To this end, I will develop innovative computational algorithms to improve MS-based metabolomics data processing and annotation; integrate with genome mining approaches for comprehensive gut metabolome characterization; and finally model the variations of gut metabolome through community-scale metabolic networks. The performance of these tools will be evaluated using the public data sets as well as the data sets generated in-house and through collaborations. The research results, including tools, databases and algorithms will be publicly available through the latest web technologies and cloud-based computing platforms. The proposed research program addresses the major bottlenecks in current metabolomics, and offers great potential for translational applications through the identification of novel biomarkers, the discovery of key connections and the development of predictive models. The research activities described in this proposal will enable effective training and placement of HQP in a cross-disciplinary environment.