Recent breakthroughs in genetic sequencing technology have set the stage for an unprecedented wide understanding of all microbial life. Previously, automated methods for the creation of genome-scale metabolic models (MMs) have been developed and applied by this group. These methods have since been applied to thousands of microbial genomes in freely available online software systems. While the MMs are yielding unprecedented insights into microbial metabolism, the next great challenge is to capture gene regulatory information in order to more accurately model the metabolic response of an organism to its environment. Anticipating this need, ongoing efforts by the group have set the stage for integrating a wide range of alternative data sources with the thousands of MMs. The group is now uniquely positioned to develop enhanced MMs through the integration of regulatory information into the models, yielding integrated metabolic, regulatory models (iMRMs). To date, little methodological effort has been directed toward the wide-scale development of iMRMs due, in part, to the lack of sufficient and integrated data for most organisms. This project will (1) develop new and improved iMRMs by addressing methodological weaknesses in current approaches, (2) develop methods to utilize iMRMs to predict conditions for wet-lab experiments to generate and test novel biological hypotheses, (3) develop novel approaches to use thousands of models to better understand metabolic and regulatory diversity, and (4) fully incorporate undergraduate and high school students in all aspects of the research. Thus, the project will substantially advance the capacity to construct integrated metabolic regulatory models through the development and evaluation of methods for the incorporation of regulatory data, produce tools for researchers to assess the diversity of existing gene expression data sets for their organisms of interest, validate proposed methods via targeted wet lab experiments, and address fundamental questions about metabolic and regulatory diversity across the microbial tree of life.
Broader Impacts All methodological advancements will be integrated into an open-source software environment for modeling microbial life. At least 21 undergraduate and at least 60 high school students will be integrally involved in the research, providing them with training, experience and exposure to the interdisciplinary field of quantitative approaches for predictive systems biology.
