Chemical and Biomolecular Engineering, Department of
First Advisor
Rajib Saha
Committee Members
Vitali Alexandrov, Nicole Iverson
Date of this Version
12-2024
Document Type
Thesis
Citation
A thesis presented to the faculty of the Graduate College at the University of Nebraska in partial fulfillment of requirements for the degree of Master of Science
Major: Chemical Engineering
Under the supervision of Professor Rajib Saha
Lincoln, Nebraska, December 2024
Abstract
The highly plastic nature of alveolar macrophage (AM) plays a crucial role in the defense against inhaled particulates and pathogens in the lungs. Depending on the signal, AM acquires either the classically activated M1 phenotype or the alternatively activated M2 phenotype. In this study, we investigate the metabolic shift in the activated phases of AM (M1 and M2 phases) by reconstructing context specific genome-scale metabolic (GSM) models. Metabolic pathways such as pyruvate metabolism, arachidonic acid metabolism, chondroitin/heparan sulfate biosynthesis, and heparan sulfate degradation are found to be important driving forces in the development of the M1/M2 phenotypes. Additionally, we formulated a bilevel optimization framework named MetaShiftOptimizer to identify minimal modifications that shift one activated state (M1/M2) to the other. The identified reactions involve metabolites such as glycogenin, L-carnitine, 5-hydroperoxyeicosatetraenoic acid, and leukotriene B4, which show potential to be further investigated as significant factors for developing efficient therapy targets for severe respiratory disorders in the future. Overall, our study contributes to the understanding of the metabolic capabilities of M1 and M2 phenotype of AM and identifies pathways and reactions that can be potential targets for polarization shift and also be used as therapeutic strategies against respiratory diseases.
Advisor: Rajib Saha
Comments
Copyright 2024, Sunayana Malla. Used by permission