Theses and Dissertations at Montana State University (MSU)

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Study of diverse host immune responses to viral and bacterial pathogens
(Montana State University - Bozeman, College of Agriculture, 2023) Plewa, Jack Bruno; Chairperson, Graduate Committee: Mark Jutila; This is a manuscript style paper that includes co-authored chapters.
Brucella abortus is the bacterium that causes brucellosis, an infection transmitted from cattle to people, often through consumption of raw milk and contact with aborted materials. With antibiotic resistance on the rise, phage therapy for bacterial infection may become a useful approach. The direct effects of phage on mammalian cells is important to understand, yet understudied. In vivo delivery of low phage MOI to the mouse lung was more effective at diminishing Brucella burden than higher doses of phage. In an in vitro model of intracellular Brucella infection, low phage MOI was capable of minimizing human THP-1 monocyte infection, but, unexpectedly, use of higher phage MOI diminished this effect. We hypothesized that recognition of these phage preparations may induce an antiviral immune suppressive response that may counteract their anti-bacterial effects. Indeed, when the type I IFN signaling pathway was disrupted in mice, phage treatment was more effective. However, when attempting to induce type I IFN in vitro using both human monocyte and mouse macrophage cell lines, we were unable to stimulate expression of type I IFN with Brucella phage, including in response to a combination of phage and bacteria. We then examined the effect of phage treatment on macrophage cell surface markers that are indicative of activation/differentiation. Interestingly, while Brucella LPS induced expression of CD71 and CD206, the addition of phage suppressed upregulation of these markers. Our discovery of immune suppressive effects of Brucella bacteriophage is an important consideration for using phage as a treatment.
Virus-like particle surface toll-like receptor signaling modulates host response to bacterial infection
(Montana State University - Bozeman, College of Agriculture, 2022) Hatton, Alexis Alexandria; Chairperson, Graduate Committee: Mark T. Quinn; This is a manuscript style paper that includes co-authored chapters.
Innate immune recognition of viruses is critical for the rapid response and subsequent clearance of an infection. The primary focus of virus innate immune recognition is the recognition of viral nucleic acids post-infection. However, innate pattern recognition receptors (PRRs) have been demonstrated to recognize viral proteins independent of infection. One group of PRRs associated with viral recognition are Toll-like Receptors (TLRs). With the discovery of TLRs in the late 1990's, over two decades of research have endeavored to identify if cell surface TLRs recognize viral proteins and if so, understand whether surface TLR-viral recognition benefits the host or the virus. To the benefit of the host, it was previously determined that host-recognition of viral proteins protects mice from bacterial infection early post-virus exposure, independent of viral nucleic acids (virus-like particle; VLP). This suggested that early viral protein recognition could protectively prime the host against bacterial infection. Our investigation here attempts to address the generality of surface TLR-virus recognition independent of infection, how viral protein recognition alters the subsequent signaling response to bacterial infection, and finally, if/how expression system-associated variables interfere with the interpretation of our study. We utilized macrophage deficient in surface TLRs and TLR-associated signaling proteins to address the TLR signaling pathway responsible for the general response to VLPs that results in reduced bacterial burden. We found that different surface TLRs were responsible for reducing bacterial burden, resulting in the activation of different signaling pathways dependent upon the VLP macrophages were exposed to. In addition, our results demonstrate how expression system-associated variables alter the interpretation of signaling pathways activated by surface TLRs.
Scoping out intestinal epithelium differentiation, proliferation, and homeostasis through the lenses of interleukin-10 and aryl hydrocarbon receptor signaling pathways
(Montana State University - Bozeman, College of Agriculture, 2020) Jenkins, Brittany Rene; Co-Chairs, Graduate Committee: Douglas Kominsky and Seth Walk; Nathan A. Blaseg, Heather M. Grifka-Walk, Benjamin Deuling, Steve D. Swain, Eric L. Campbell, Seth T. Walk and Douglas J. Kominsky were co-authors of the article, 'Loss of interleukin-10 receptor disrupts intestinal epithelial cell proliferation and skews differentiation towards the goblet cell fate' submitted to the journal 'The Federation of American Societies for Experimental Biology (FASEB) journal' which is contained within this dissertation.; Heather M. Grifka-Walk, Steve D. Swain, Trevor R. Zahl, Andrew Gentry, Seth T. Walk and Douglas J. Kominsky were co-authors of the article, 'Aryl hydrocarbon receptor modulation of intestinal epithelial cell fate is sex-dependent and exhibits variability among allelic variants' which is contained within this dissertation.; Dissertation contains two articles of which Brittany Rene Jenkins is not the main author.
Intestinal epithelial cells (IEC) are crucial for maintaining proper digestion and overall homeostasis of the gut mucosa. IEC proliferation and differentiation are tightly regulated by well described pathways, however, relatively little is known about the influence of interleukin (IL)-10 and aryl hydrocarbon receptor (AHR) signaling pathways on these processes or whether AHR can regulate IL-10R expression in IECs. IL-10 signaling suppresses inflammation. AHR is a ligand activated transcription factor largely known for downstream activation of xenobiotic-metabolizing enzymes but also exerts a diverse range of responses in the host that can be modulated by gut microbe metabolites. Both IL-10 and AHR signaling are shown to promote IEC barrier function, and thus, they may also regulate other critical homeostatic functions like IEC lineage fate and regenerative capacity. These gaps in knowledge were addressed in Chapters 2 and 3. Techniques such as reverse-transcription quantitative polymerase chain reaction (RT-qPCR), western blotting, and histology staining techniques were used to assess changes in expression of target genes and proteins between control and either IL-10R- or AHR-deficient models. Loss of IL-10R or AHR demonstrated substantial impacts exhibiting nearly opposite patterns on lineage fate outcomes and on the proliferative compartment. In Chapter 4, we showed that activation of AHR by microbe-derived tryptophan metabolites increased IL-10R1 expression in IECs, and these metabolites ameliorated disease in a murine model of colitis. Findings from Chapters 2-4 add to a growing body of evidence for the importance of IL-10R and AHR signaling pathways in inflammatory bowel disease (IBD) and gastrointestinal (GI) cancers. Organoid models provide an additional study system to test these gaps in the field and hold great promise for advancing disease research. However, limitations exist for accessing the luminal surface to recapitulate the GI environment. In Chapter 5, we developed the GOFlowChip to solve this problem. This platform applies long-term, steady-state flow through to the organoid and can be modified to serve different research goals. These studies culminate in a deeper understanding of how IEC homeostasis is maintained and how innovative technologies can be developed for advancing this field of research.
Quantitative 1 H NMR analyses of immunometabolic modulation in human macrophages
(Montana State University - Bozeman, College of Letters & Science, 2019) Fuchs, Amanda Lee; Chairperson, Graduate Committee: Valerie Copie; Sage M. Schiller was an author and Wyatt J. Keegan, Mary Cloud B. Ammons, Brian Eilers, Brian Tripet and Valerie Copie were co-authors of the article, 'Quantitative 1 H NMR metabolomics reveals distinct metabolic adaptations in human macrophages following differential activation' in the journal 'Metabolites' which is contained within this dissertation.; Sage M. Schiller was an author and Isaac R. Miller, Mary Cloud B. Ammons, Brian Eilers, Brian Tripet and Valerie Copie were co-authors of the article, 'Pseudomonas aeruginosa planktonic- and biofilm-conditioned media elicit divergent responses in human macrophages' submitted to the journal 'PLoS pathogens' which is contained within this dissertation.
Macrophages are innate immune cells that are found ubiquitously in nearly all human tissues, where they support host innate and adaptive immune responses in an effort to maintain systemic homeostasis. They are inherently plastic in nature and can dramatically modulate their functional phenotype according to pathogen and microenvironmental stimuli. Previous studies have shown that macrophages are particularly important for the resolution of inflammation in acute wound healing, which is marked by a phenotypic transition of wound macrophages from pro-inflammatory to anti-inflammatory. Chronic, or non-healing, wounds, such as diabetic, pressure, and venous leg ulcers, feature a prolonged host inflammatory response due in part to aberrant wound macrophage behavior. Non-healing in chronic wounds has also been shown to be dependent upon the establishment of pathogenic biofilms, which are more resistant to host defense mechanisms than planktonic, or free-floating, bacteria. Therefore, investigating macrophage dysregulation in the presence of bacterial biofilms has gained considerable interest. Here, 1D 1 H NMR-based metabolomics was utilized to identify metabolic pathways that are differentially modulated following primary human monocyte-derived macrophage activation with pro-inflammatory or anti-inflammatory stimuli relative to resting macrophages. Metabolic profiling of inflammatory macrophages indicated a substantial increase in oxidative stress as well as a decrease in mitochondrial respiration. These metabolic profiles also provided evidence that inflammatory macrophages divert metabolites from de novo glycerophospholipid synthesis to inhibit oxidative phosphorylation. In addition, we investigated which metabolic pathways are differentially modulated following primary human monocyte-derived macrophage exposure to Pseudomonas aeruginosa planktonic- and biofilm-conditioned media. Metabolic profiling of PCM- and BCM-exposed macrophages indicated a significant depletion of intracellular glucose without elevation of downstream glycolytic products. These metabolic patterns suggest that PCM- and BCM-exposed macrophages potentially divert glycolytic intermediates towards inositol phosphate metabolism. Overall, our studies provide additional support to previous findings, generate novel results regarding metabolic modulation of human macrophages following activation and exposure to planktonic- vs. biofilm-conditioned media, and contribute new insight to the field of immunometabolism.
Gastrointestinal organoid structure and transport
(Montana State University - Bozeman, College of Engineering, 2019) Sidar, Barkan; Chairperson, Graduate Committee: James Wilking; Thomas A. Sebrell was an author and Rachel Bruns, Royce A. Wilkinson, Blake Wiedenheft, Paul J. Taylor, Brian A. Perrino, Linda C. Samuelson, James N. Wilking and Diane Bimczok were co-authors of the article, 'Live imaging analysis of human gastric epithelial spheroids reveals spontaneous rupture, rotation, and fusion events' in the journal 'Cell and tissue research' which is contained within this dissertation.; Thomas A. Sebrell, Bengisu Kilic, David Brown, Mert Aytac, Brian A. Perrino, Linda C. Samuelson, Henry Fu, Diane Bimzcok, James N. Wilking were co-authors of the article, 'Rupturing of human gastric organoids' which is contained within this dissertation.; Brittany R. Jenkins, Sha Huang, Jason R. Spence, Seth T. Walk and James N. Wilking were co-authors of the article, 'Flow through human intestinal organoids with the gut organoid flow chip (GOFlowChip)' submitted to the journal 'Lab on a Chip' which is contained within this dissertation.; Dissertation contains two articles of which Barkan Sidar is not the main author.
Organoids are three-dimensional (3D) self-assembled, mammalian tissue cultures derived from stem cells that differentiate to contain multiple cell types. These cells spatially organize within the 3D structure and are capable of recapitulating the structure and function of a particular organ. Organoids offer a variety of existing and potential applications in medicine and biotechnology, including drug formulation testing, regenerative medicine, and microbiome research. Despite their value, knowledge of how organoid structure impacts dynamics, mechanics, and transport is lacking. This is particularly true for gastrointestinal organoids, which are composed of a monolayer-thick epithelial sheet wrapped into a closed sphere. The primary goals of this dissertation are to understand the impact of gastrointestinal organoid structure on organoid function, develop a millifluidic chip platform to improve their viability and reliability as a model system and to explore their uses as model co-culture systems. To achieve this, we use a combination of time-lapse microscopy, image analysis, modeling, and fluidics fabrication techniques to develop an understanding of organoid growth and development in addition to expanding current uses as model systems. Our observations revealed that human gastric organoid growth was associated with cyclic rupture of the epithelial shell, rotational movement around their axes within the Matrigel matrix and luminal fusion by adjacent organoids. Furthermore, the rupture events are an indirect result of osmotic swelling carried out by the diffusion of water due to osmolyte concentration regulation by the epithelial shell. To overcome the advection limitation due to the topologically closed spherical structure of the organoids, we developed a millifluidic device called the Gut Organoid Flow Chip (GOFlowChip). This represents the first demonstration of established liquid flow through the luminal space of a gastrointestinal organoid. Given that organoids show great potential as model systems, established co-culture system consisting of dendritic cells (DC) with infected human gastric organoids shows the gastric epithelium actively recruits DCs for immunosurveillance with increased recruitment upon active Helicobacter pylori infection. Finally, investigation on CD103 attachment protein in gastric DCs revealed that CD103 engages in DC-epithelial cell interactions upon contact with epithelial E-cadherin but is not a significant driver of DC adhesion to gastrointestinal epithelia.
Disruption of neutrophil reactive oxygen species production by Staphylococcus aureus
(Montana State University - Bozeman, College of Letters & Science, 2018) Guerra, Fermin Ernesto; Chairperson, Graduate Committee: Jovanka Voyich-Kane; Timothy R. Borgogna, Delisha M. Patel, Eli W. Sward and Jovanka M. Voyich were co-authors of the article, 'Epic immune battles of history: neutrophils vs. Staphylococcus aureus' in the journal 'Frontiers in Cellular and Infection Microbiology' which is contained within this dissertation.; Conrad B. Addisson, Nienke W. M. de Jong, Joseph Azzolino, Kyler B. Pallister, Jos (A. G.) van Strijp and Jovanka M. Voyich were co-authors of the article, 'Staphylococcus aureus SaeR/S-regulated factors reduce human neutrophil reactive oxygen species production' in the journal 'Journal of Leukocyte Biology' which is contained within this dissertation.; Kyler B. Pallister, Tyler K. Nygaard, Mark T. Quinn, and Jovanka M. Voyich were co-authors of the article, 'Staphylococcus aureus leukocidins modulate human neutrophil reactive oxygen species production' which is contained within this dissertation.
Staphylococcus aureus (S. aureus) is a bacterial pathogen that causes a wide range of human disease, from skin infections to invasive endocarditis. Neutrophils are the most abundant white blood cell in the human body, and the first line of defense following S. aureus infection. Even though neutrophils are equipped with an arsenal of bactericidal mechanisms, S. aureus survives neutrophil encounter. The mechanisms used by S. aureus to survive neutrophil killing remain unresolved. Previous studies have shown that the S. aureus SaeR/S two-component gene regulatory system is essential to survive neutrophil killing. Herein, we tested the hypothesis that S. aureus uses SaeR/S-dependent mechanisms to reduce neutrophil bactericidal mechanisms. First, we determined that S. aureus uses genes under the regulation of SaeR/S to inhibit neutrophil reactive oxygen species (ROS) production independent of previously defined mechanisms. Subsequently, we helped characterize a novel S. aureus SaeR/S-regulated virulence factor that inhibits human myeloperoxidase (MPO) activity to prevent formation of the highly bactericidal agent hypochlorous acid. Thus, S. aureus SaeR/S-regulated factors disrupt the neutrophil bactericidal mechanism with most efficacy against it, which is killing by oxidative mechanisms. We then focused on the role of S. aureus SaeR/S-regulated secreted leukocidins on neutrophil ROS production. While S. aureus leukocidins show redundancy inducing neutrophil pore formation, we determined that the surface receptors engaged by leukocidins induce distinct signaling pathways leading to ROS production. We showed that specific kinases are required for the differential production of neutrophil ROS induced by the S. aureus leukocidins LukGH and Panton-Valentine leukocidin (PVL). Importantly, the signaling pathways induced by S. aureus leukocidins through neutrophil surface receptors differ from the signals induced by physiological ligands through the same surface receptors. These results suggest S. aureus leukocidins 'shortcircuit' neutrophil signals to induce aberrant ROS production. In conclusion, S. aureus SaeR/S-regulated factors prevent proper bacterial clearance by disrupting neutrophil ROS production. These data provide us with a better understanding of the specific mechanisms used by S. aureus to survive neutrophil killing leading to pathogenesis.
Redox homeostasis and stress in mouse livers lacking the NADPH-dependent disulfide reductase systems
(Montana State University - Bozeman, College of Letters & Science, 2019) Miller, Colin Gregory; Chairperson, Graduate Committee: Mary J. Cloninger; Edward E. Schmidt (co-chair); Arne Holmgren, Elias S.J. Arner and Edward E. Schmidt were co-authors of the article, 'Introduction --NADPH dependent and --independent disulfide reductase systems' in the journal 'Free radical biology and medicine' which is contained within this thesis.; Edward E. Schmidt was a co-author of the article, 'Disulfide reductase systems in the liver' in the journal 'British journal of pharmacology' which is contained within this thesis.; Jean A. Kundert, Justin R. Prigge, Julie Amato, Allison E. Perez and Edward E. Schmidt were co-authors of the article, 'Supplemental ascorbate compromises hepatocyte survival and increases risk of acute liver failure during severe oxidative stress' submitted to the journal 'Antioxidant' which is contained within this thesis.; Dissertation contains two articles of which Colin Gregory Miller is not the main author.
This thesis includes two reviews that cover the background of cellular disulfide reduction, from its earliest form in hydrothermal vents and its evolution to the current, multifaceted systems that maintain cellular redox homeostasis, to the roles of the disulfide reductase systems in different subcellular compartments, as well as provide a current status for many of the unkown roles disulfide reductase enzymes play. Furthermore, this thesis includes two published research articles, both relating changes in the NADPH-dependent disulfide reductase systems to altered physiology and the possible impacts of these changes to human health (ie cancer, acetaminophen overdose or toxic arsenic exposure.) A third research paper is also included in this thesis, which demonstrates the pro-oxidant effects of administration of the antioxidant ascorbate to TrxR1/Gsr-null livers. This paper is potentially valuable both in a clinical aspect, where ascorbate might be prescribed to counter the effects of excess oxidants, but also to the general public, as ascorbate is one of the most commonly taken over-the-counter supplements. The final chapter of this thesis is fundamental groundwork for future projects aimed at identifying how cells manage accumulation of oxidants/compromised disulfide reductase systems. The two isotopically labled amino acids, L-(^34 S)Met and L-(^34 S)cystine, are valuable tools to monitor S-metabolism, both in the TrxR1/Gsr-null livers but also in other disease states, such as those mentioned above. L-(^34 S)cystine is of particular interest to one of our collaborators, Dr. Gina DeNicola, who plans to use L-(^34 S)cystine to monitor S-metabolism in pancreatic organoids to study pancreatic adenocarcinoma.
Mechanisms of CRISPR-mediated immunity in Escherichia coli
(Montana State University - Bozeman, College of Letters & Science, 2019) van Erp, Paul Bertram Geert; Chairperson, Graduate Committee: Blake Wiedenheft; Gary Bloomer, Royce Wilkinson and Blake Wiedenheft were co-authors of the article, 'The history and market impact of CRISPR RNA-guided nucleases' in the journal 'Current opinion in virology' which is contained within this thesis.; Ryan N. Jackson and Joshua Carter were authors and Sarah M. Golden, Scott Bailey and Blake Wiedenheft were co-authors of the article, 'Mechanism of CRISPR-RNA guided recognition of DNA targets in Escherichia coli' in the journal 'Nucleic acids research' which is contained within this thesis.; Angela Patterson was an author and Ravi Kant, Luke Berry, Sarah M. Golden, Brittney L. Forsman, Joshua Carter, Ryan N. Jackson, Brian Bothner, and Blake Wiedenheft were co-authors of the article, 'Conformational dynamics of DNA binding and CAS3 recruitment by the CRISPR RNA-guided cascade complex' in the journal 'ACS chemical biology' which is contained within this thesis.; Tanner Wiegand, Royce A. Wilkinson, Laina Hall, Dominick Faith and Blake Wiedenheft were co-authors of the article, 'Protein overexpression reduces specific phage infectivity in prokaryotic argonaute screen' which is contained within this thesis.; Dissertation contains three articles of which Paul Bertram Geert van Erp is not the main author.
Prokaryotes are under constant threat from foreign genetic elements such as viruses and plasmids. To defend themselves against these genetic invaders prokaryotes have evolved extensive defense mechanisms. In this thesis I explore two such defense systems: prokaryotic Argonautes and CRISPR-systems. CRISPR-systems acquire short sequences derived from foreign genetic elements and store them in the CRISPR locus. In subsequent rounds of infection these stored sequences are used as guides by Cas proteins to target the invaders. Escherichia coli K-12 contains a type I-E CRISPR system, consisting of two CRISPR loci and eight cas genes. five of these cas genes, together with and 61-nucleotide CRISPR-RNA guide form the RNA-guided surveillance complex Cascade. This complex finds and binds foreign DNA targets that are complementary to its RNA guide. After target binding the helicase/nuclease Cas3 is recruited to the Cascade-DNA complex for destruction of the target. The goal of this research is to understand the molecular mechanisms that lead to target recognition and destruction in the type I-E CRISPR systems. Atomic resolution structures of the proteins involved in these CRISPR systems provide the blueprints of these proteins machines. Structure guided mutational analysis coupled with in vivo and in vitro biochemical experiments are used to investigate the underlying molecular mechanisms of this CRISPR system. Together, these results explain the rules of target recognition and Cas3 recruitment. Prokaryotic Argonautes have been hypothesized to defend against mobile genetic elements such as plasmids and viruses through guided nuclease activity. To test this hypothesis, we overexpressed 8 phylogenetically diverse prokaryotic Argonautes proteins in Escherichia coli and challenged them with seven bacteriophages. This resulted in robust protection against phage Lambda and phage P1 by four of the tested Argonautes, while little impact on phage infectivity was observed for the other phages tested. However, control experiments with a nuclease inactive Argonaute mutant and expression of an unrelated control protein showed similar protection against phage Lambda and phage P1. Collectively, our data suggest that protein overexpression in general, rather than Argonaute expression in particular, results in protection against 2 specific phages.
Safety improvement in biologic therapy for patients with moderate to severe plaque psoriasis: a pilot project and quantitative analysis
(Montana State University - Bozeman, College of Nursing, 2016) Addison, Kara Marie; Chairperson, Graduate Committee: Jennifer Sofie
Biologic Response Modifier (BRM) medications are indicated for moderate to severe psoriasis and demonstrate high efficacy for disease reduction. Although BRM medications are considered the most effective therapy in the treatment of moderate to severe plaque psoriasis, their side effect profile can be severe. Using BRMs may increase the risk of infections, demyelinating disease, and malignancy (Reich, Burden, Eaton, & Hawkins, 2012). With such established risks, baseline assessments and monitoring have been recommended. However, no standardized guidelines exist for the monitoring of BRM medications (Hanson, Gannon, Khamo, Sodhi, Orr, & Stubbings, 2013). Therefore, the objective of this scholarly project was to implement a BRM monitoring protocol into the Electronic Medical Record (EMR) of a Montana dermatology clinic to improve provider monitoring compliance and therefore improve psoriasis patient outcomes, safety, and education. Monitoring criteria were developed based on recommendations from the University of Illinois Medical Center Clinical Care Guidelines and the American Academy of Dermatologists Biologic Monitoring guidelines. A BRM Electronic Medical Record (EMR) template was then created to utilize such guidelines to improve clinical compliance and patient safety. Seven main criteria were measured for completion including laboratory studies, physical assessment, patient education, follow up, psoriasis severity scale, immunizations, and vital signs. Side effects experienced and patient comorbidities were also recorded. Completion rates of the protocol were analyzed using before and after comparisons, the paired t-test, and McNemar's test. Before the intervention was implemented, 54% of charts had completion of all seven categories and after the intervention 98% of charts were completed, illustrating a 44% improvement in provider compliance and monitoring. The paired t-test illustrated an average difference of 0.43 with a standard error of .029. The McNemar's test established a positive association between implementation of the BRM protocol and improvement in provider compliance. 40% of patients experienced co-morbidities associated with psoriasis and 25% of patients experienced side effects related to BRM therapy. These project findings demonstrated the efficacy of a BRM monitoring template for improving provider-monitoring compliance and improving patient safety through early identification of comorbidities and side effects.
From immunology to MRI data anlysis : problems in mathematical biology
(Montana State University - Bozeman, College of Letters & Science, 2015) Waters, Ryan Samuel; Chairperson, Graduate Committee: Tomas Gedeon
This thesis represents a collection of four distinct biological projects rising from immunology and metabolomics that required unique and creative mathematical approaches. One project focuses on understanding the role IL-2 plays in immune response regulation and exploring how these effects can be altered. We developed several dynamic models of the receptor signaling network which we analyze analytically and numerically. In a second project focused also on MS, we sought to create a system for grading magnetic resonance images (MRI) with good correlation with disability. The goal is for these MRI scores to provide a better standard for large-scale clinical drug trials, which limits the bias associated with differences in available MRI technology and general grader/participant variability. The third project involves the study of the CRISPR adaptive immune system in bacteria. Bacterial cells recognize and acquire snippets of exogenous genetic material, which they incorporate into their DNA. In this project we explore the optimal design for the CRISPR system given a viral distribution to maximize its probability of survival. The final project involves the study of the benefits for colocalization of coupled enzymes in metabolic pathways. The hypothesized kinetic advantage, known as 'channeling', of putting coupled enzymes closer together has been used as justification for the colocalization of coupled enzymes in biological systems. We developed and analyzed a simple partial differential equation of the diffusion of the intermediate substrate between coupled enzymes to explore the phenomena of channeling. The four projects of my thesis represent very distinct biological problems that required a variety of techniques from diverse areas of mathematics ranging from dynamical modeling to statistics, Fourier series and calculus of variations. In each case, quantitative techniques were used to address biological questions from a mathematical perspective ultimately providing insight back to the biological problems which motivated them.

Theses and Dissertations at Montana State University (MSU)

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