Date of Award

Fall 2022

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Cellular and Molecular Physiology

First Advisor

Perry, Rachel

Abstract

The breakdown, synthesis, and interconversion of macronutrients is essential to sustaining life and driving pathological mechanisms rooted in disease. With attempts to combat the metabolic underpinnings of disease, it has become clear that focus on individual metabolites, proteins, or genes cannot fully explain the complexity of dysregulated metabolism in systemic conditions such as obesity, cancer, and sepsis. With the advent of accessible Omics techniques and hordes of open access data it has become possible to study metabolism as a whole—at the level of gene transcription, translation, and metabolism. A major goal of this PhD thesis was to integrate isotope tracing techniques with an omics-informed approach to identify systemic metabolic patterns in complex disease states. We explored cancer’s manipulation of metabolic programs, the adaptation to nutrient or inflammatory stress, and the generation and accumulation of potentially toxic metabolic intermediates during the maintenance of homeostasis. We examine the metabolic process that nature exerts substantial metabolic control over during evolution, determine the interactions between obesity and exercise capacity on tumor metabolism and progression, and explore the systemic metabolic reprogramming that occurs in humans and rodents during sepsis.The analysis of existing datasets represents an opportunity to yield new insight in a relatively efficient manner and maximizes the benefits that can be gleaned from the donation of patient’s tissues/samples to science. We hope that our attempt to combine computational and experimental approaches to understand the metabolic response to disease will serve as a launching pad for the growing field of translational systems metabolism. I consider this work a “systems” view of metabolism in multiple senses of the term: the study of conditions where multiple organ systems are involved and reprogrammed, and the use of computational techniques to elucidate systemic patterns that are not apparent by examining molecules at the individual level. All the code and data that has been generated will be published publicly to enhance the reproducibility of science and increase access to data, ideas, and analytical methods across the world.

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