Assessment of Pathway Design Through Multi-level Modeling and Experimentation

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The long-term goal of this research is to discover and understand design and operating principles of biological networks. As a first step toward this goal, the project investigates a very detailed, multi-level analysis of a small system, namely the trehalose cycle in yeast. This system is representative for many pathway systems, and because biology is often modular and hierarchical, insights gained from this small system will be crucial for rationalizing other and larger systems. Trehalose is a disaccharide that equips microorganisms with an important defense mechanism against a wide variety of stresses, including high temperature, hydrostatic pressure, desiccation, nutrient starvation, osmotic or oxidative stress, and exposure to toxic chemicals. In stressed yeast, trehalose is produced with amazing speed and in enormous quantities. Once the stress ceases, trehalose is quickly recycled to glucose. This stress response system is very interesting because it confronts the cell with the complex task of channeling material toward glycolysis, glycogen storage, or trehalose production in a manner that is efficient and most appropriate for its present environmental conditions. The cell manages this three-way decision through an intricate network of metabolic and genomic controls surrounding the critical metabolic branch point of the pathway, glucose 6-phosphate. Even though many specific properties of the trehalose cycle in stressed cells have been studied extensively, the dynamics of this highly regulated system is not well understood. Indeed, the cycle exhibits counterintuitive and so far unexplained features, such as the strong up-regulation of genes that code for trehalose-degrading enzymes at the time of greatest trehalose demand. This project elucidates the functioning of the trehalose system through dense time series measurements of the expression of all relevant genes, of the activities of all relevant enzymes, and of all pertinent metabolites. The data will provide an unprecedented opportunity for integrative analysis, which will include novel statistical and systems biological methods. Beyond yielding deeper understanding of this particular system, this project will serve as a paradigm for multi-disciplinary approaches to understanding integrated and highly regulated metabolic pathway systems. Broader ImpactsThe merging of experimental and numerical analyses within this project creates an outstanding training ground for graduate students and postdoctoral fellows, who will gain intimate familiarity with a repertoire of tools that are becoming mandatory in the systems-oriented biology of the 21st Century. The trainees will learn how to extract diverse biological information and analytical techniques from the literature, invent new techniques, and to forge data and methods into interdisciplinary tools for addressing issue they have not encountered before.