Abstract
In 1977, the Food and Drug Administration recommended that phase I and II clinical trials do not include women of childbearing age. While this decision was reversed in 1986, women are still underrepresented in clinical trials, even for diseases that disproportionately affect women, and in basic research, where a majority of animal and cell populations are sourced from male populations or do not report sex at all. We intend to close this gap in knowledge by exploring how sex impacts metabolism across several contexts. Here, we use genome-scale metabolic models (GEMs) to computationally create sex-specific models with which to simulate metabolism in response to various perturbations. In this dissertation, we compare male- and female-specific metabolism in hepatocytes and analyze how these sex-specific metabolic pathways are perturbed by drugs known to be toxic in the liver. Then, we study how sex impacts metabolism in pediatric Crohn’s disease, predict inflammation-causing metabolic subsystems, and find a treatment which decreases inflammatory cytokines in vitro. Next, we observe how metabolic sex differences manifest differently in colonic and ileal Crohn’s disease. Finally, we create a new method, MediaBlitz, which can predict the extracellular metabolic environment of a cell from its transcriptome and suggest how this technique could be used to explore sex-specific extracellular environments. Overall, we investigate sexual dimorphism through the synthesis of omics data and metabolic modeling, representing a novel application for this combination of in silico techniques that provides additional insight into how the context of sex results in differential metabolism. We hope that these findings aid future work toward the development of patient-specific treatments across many populations and that, ultimately, these precision interventions yield more positive patient outcomes.
