Theses and Dissertations at Montana State University (MSU)
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Item 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.Item The roles of interleukin-1 and leukotriene-B4 in the innate immune response to pulmonary Aspergillus fumigatus infection(Montana State University - Bozeman, College of Letters & Science, 2017) Caffrey-Carr, Alayna Katherine; Chairperson, Graduate Committee: Mark T. Quinn; Margaret M. Lehmann, Julianne M. Zickovich, Vanessa Espinosa, Kelly M. Shepardson, Christopher P. Watschke, Kimberly M. Hilmer, Arsa Thammahong, Bridget M. Barker, Amariliz Rivera, Robert A. Cramer and Joshua J. Obar were co-authors of the article, 'IL-1A signaling is critical for leukocyte recruitment after pulmonary Aspergillus fumigatus challenge' in the journal 'PLoS pathogens' which is contained within this thesis.; Joshua J. Obar was a co-author of the article, 'Alarmin(G) the innate immune system to invasive fungal infections' in the journal 'Current opinion in microbiology' which is contained within this thesis.; Caitlin H. Kowalski, Sarah R. Beattie, Nate A. Blaseg, Chanell R. Upshaw, Arsa Thammahong, Hannah E. Lust, Yi-Wei Tang, Tobias M. Hohl, Robert A. Cramer, Joshua J. Obar were co-authors of the article, 'IL-1A signaling is critical for resistance against highly virulent Aspergillus fumigatus strains' submitted to the journal 'Infection and Immunity' which is contained within this thesis.; Kimberly M. Hilmer and Joshua J. Obar were co-authors of the article, 'Host-derived leukotriene B4 is critical for resistance against invasive pulmonary Aspergillosis' submitted to the journal 'Microbes and Infection Short Communication' which is contained within this thesis.Aspergillus fumigatus is a ubiquitous environmental mold, and even though most individuals are regularly exposed to fungal spores, clinical invasive disease is a rare manifestation. However, in the growing population of individuals with weakened immune systems, for example due to prolonged corticosteroid treatment or chemotherapeutic interventions, A. fumigatus exposure can cause severe, invasive aspergillosis (IA). Overall, invasive fungal infections are estimated to kill at least 1.5 million people annually (Brown et al. 2012), with IA being the most common and deadly invasive respiratory fungal infection. Thus, it is critical to better understand the host-pathogen interactions after A. fumigatus exposure in order to develop novel treatment options which harness the power of the host's immune response. Defining key immunological events that are needed for the prevention of Aspergillus growth within the pulmonary environment of immune competent individuals is an essential step toward a better understanding of how the immune response is altered within the immune compromised populations that are at risk of developing IA. Utilizing an immune competent murine model of IA, we have shown that signaling through both the Interleukin-1 receptor, type I (IL-1RI) and the Leukotriene B4 receptor (BLT1) are both critical pathways for host resistance against IA through timely neutrophil recruitment which ultimately control fungal germination. More recently, we have found that different environmental and clinical strains of A. fumigatus lead to different inflammatory profiles as well as different disease pathology. Strains that are able to germinate within the lung environment are more virulent, and lead to enhanced lung damage, vascular leakage and inflammation. Furthermore, the more virulent strains induce neutrophil recruitment and subsequent fungal clearance that is dependent on the alarmin IL-1alpha, while clearance of the less virulent strains are independent of IL-1alpha signaling. With this research we will better understand the fungal component(s) that are important in virulence determination, which immune pathways are contributing to the different disease pathologies observed, as well as understand the mechanism through which a healthy immune system can resist A. fumigatus exposure on a daily basis.Item Modulation of adherent bovine neutrophil responses by extracellular matrix proteins(Montana State University - Bozeman, College of Agriculture, 2002) Borgquist, Jessica James DavantItem Toxoplasma inhibitory factor and interleukin 2 : assessment of their effects on toxoplasma gondii replication within a continuous macrophage-like cell line(Montana State University - Bozeman, College of Agriculture, 1982) Hagemo, Anita SusanItem The consistency of inflammatory responses and muscle damage to high-force eccentric exercise(Montana State University - Bozeman, College of Education, Health & Human Development, 2006) Andring, Jan Marie; Chairperson, Graduate Committee: Mary P. Miles.High-force eccentric exercise causes muscle damage and leads to inflammation resulting in increased levels of C-reactive protein (CRP) and interleukin-6 (IL-6). Indicators of muscle damage are creatine kinase (CK), decreased maximal isometric strength, muscle soreness (SOR) and swelling. This study investigated rank ordering of eccentric exercise of the non-dominant (ND) and dominant (D) elbow flexors. Rank ordering is determined by the magnitude and duration of the inflammatory response indicated by CRP, IL-6 and IL-10. Twelve subjects enrolled in the study, nine subjects performed high-force eccentric exercise on each arm, 3 weeks apart, consisting of 3x15 reps in the ND and D elbow flexors. Blood samples were taken at pre-exercise (0h), 4h, 8h, 12h, 24h and 120h post-exercise. Two subjects were eliminated from the data analysis because of elevated baseline IL-6 levels and insufficient strength losses. A Spearman rank order correlation was used to determine the consistency of the inflammatory response. A repeated measures ANOVA was used to detect significant changes over time and between arms as well as to determine an arm by time interaction. For CRP, no significant rank order correlation was detected and a RM ANOVA detected no significant differences. For IL-6, no significant rank order correlation was detected, but a trend (p = 0.071) was found. Also, a RM ANOVA detected a trend (p = 0.107) for IL-6 with a peak increase at 8h post-exercise. A significant rank order correlation was detected for CK (p < 0.05). A RM ANOVA detected a trend (p = 0.099) for a higher response in the ND arm. A significant rank order correlation was detected for maximal isometric strength (p < 0.05). A RM ANOVA detected significant strength decreases (p < 0.001) immediately post-exercise for both the ND and D arms. No significant rank order correlation was found for muscle soreness. A significant increase (p < 0.001) in soreness was detected at 24h post-exercise. For swelling, no significant rank order correlation was detected and no significant changes occurred. The consistency of the inflammatory response after high-force eccentric exercise in the ND and D elbow flexors is undetermined at this time.