ASU Electronic Theses and Dissertations
This collection includes most of the ASU Theses and Dissertations from 2011 to present. ASU Theses and Dissertations are available in downloadable PDF format; however, a small percentage of items are under embargo. Information about the dissertations/theses includes degree information, committee members, an abstract, supporting data or media.
In addition to the electronic theses found in the ASU Digital Repository, ASU Theses and Dissertations can be found in the ASU Library Catalog.
Dissertations and Theses granted by Arizona State University are archived and made available through a joint effort of the ASU Graduate College and the ASU Libraries. For more information or questions about this collection contact or visit the Digital Repository ETD Library Guide or contact the ASU Graduate College at gradformat@asu.edu.
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- All Subjects: Biology
- Creators: Sweazea, Karen
- Creators: LaBaer, Joshua
Description
Type 1 diabetes (T1D) is a chronic autoimmune disease characterized by progressive autoimmune destruction of insulin-producing pancreatic β-cells. Genetic, immunological and environmental factors contribute to T1D development. The focus of this dissertation is to track the humoral immune response in T1D by profiling autoantibodies (AAbs) and anti-viral antibodies using an innovative protein array platform called Nucleic Acid Programmable Protein Array (NAPPA).
AAbs provide value in identifying individuals at risk, stratifying patients with different clinical courses, improving our understanding of autoimmune destructions, identifying antigens for cellular immune response and providing candidates for prevention trials in T1D. A two-stage serological AAb screening against 6,000 human proteins was performed. A dual specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2) was validated with 36% sensitivity at 98% specificity by an orthogonal immunoassay. This is the first systematic screening for novel AAbs against large number of human proteins by protein arrays in T1D. A more comprehensive search for novel AAbs was performed using a knowledge-based approach by ELISA and a screening-based approach against 10,000 human proteins by NAPPA. Six AAbs were identified and validated with sensitivities ranged from 16% to 27% at 95% specificity. These two studies enriched the T1D “autoantigenome” and provided insights into T1D pathophysiology in an unprecedented breadth and width.
The rapid rise of T1D incidence suggests the potential involvement of environmental factors including viral infections. Sero-reactivity to 646 viral antigens was assessed in new-onset T1D patients. Antibody positive rate of EBV was significantly higher in cases than controls that suggested a potential role of EBV in T1D development. A high density-NAPPA platform was demonstrated with high reproducibility and sensitivity in profiling anti-viral antibodies.
This dissertation shows the power of a protein-array based immunoproteomics approach to characterize humoral immunoprofile against human and viral proteomes. The identification of novel T1D-specific AAbs and T1D-associated viruses will help to connect the nodes in T1D etiology and provide better understanding of T1D pathophysiology.
AAbs provide value in identifying individuals at risk, stratifying patients with different clinical courses, improving our understanding of autoimmune destructions, identifying antigens for cellular immune response and providing candidates for prevention trials in T1D. A two-stage serological AAb screening against 6,000 human proteins was performed. A dual specificity tyrosine-phosphorylation-regulated kinase 2 (DYRK2) was validated with 36% sensitivity at 98% specificity by an orthogonal immunoassay. This is the first systematic screening for novel AAbs against large number of human proteins by protein arrays in T1D. A more comprehensive search for novel AAbs was performed using a knowledge-based approach by ELISA and a screening-based approach against 10,000 human proteins by NAPPA. Six AAbs were identified and validated with sensitivities ranged from 16% to 27% at 95% specificity. These two studies enriched the T1D “autoantigenome” and provided insights into T1D pathophysiology in an unprecedented breadth and width.
The rapid rise of T1D incidence suggests the potential involvement of environmental factors including viral infections. Sero-reactivity to 646 viral antigens was assessed in new-onset T1D patients. Antibody positive rate of EBV was significantly higher in cases than controls that suggested a potential role of EBV in T1D development. A high density-NAPPA platform was demonstrated with high reproducibility and sensitivity in profiling anti-viral antibodies.
This dissertation shows the power of a protein-array based immunoproteomics approach to characterize humoral immunoprofile against human and viral proteomes. The identification of novel T1D-specific AAbs and T1D-associated viruses will help to connect the nodes in T1D etiology and provide better understanding of T1D pathophysiology.
ContributorsBian, Xiaofang (Author) / LaBaer, Joshua (Thesis advisor) / Mandarino, Lawrence (Committee member) / Chang, Yung (Committee member) / Arizona State University (Publisher)
Created2015
Description
For animals that experience annual cycles of gonad development, the seasonal timing (phenology) of gonad growth is a major adaptation to local environmental conditions. To optimally time seasonal gonad growth, animals use environmental cues that forecast future conditions. The availability of food is one such environmental cue. Although the importance of food availability has been appreciated for decades, the physiological mechanisms underlying the modulation of seasonal gonad growth by this environmental factor remain poorly understood.
Urbanization is characterized by profound environmental changes, and urban animals must adjust to an environment vastly different from that of their non-urban conspecifics. Evidence suggests that birds adjust to urban areas by advancing the timing of seasonal breeding and gonad development, compared to their non-urban conspecifics. A leading hypothesis to account for this phenomenon is that food availability is elevated in urban areas, which improves the energetic status of urban birds and enables them to initiate gonad development earlier than their non-urban conspecifics. However, this hypothesis remains largely untested.
My dissertation dovetailed comparative studies and experimental approaches conducted in field and captive settings to examine the physiological mechanisms by which food availability modulates gonad growth and to investigate whether elevated food availability in urban areas advances the phenology of gonad growth in urban birds. My captive study demonstrated that energetic status modulates reproductive hormone secretion, but not gonad growth. By contrast, free-ranging urban and non-urban birds did not differ in energetic status or plasma levels of reproductive hormones either in years in which urban birds had advanced phenology of gonad growth or in a year that had no habitat-related disparity in seasonal gonad growth. Therefore, my dissertation provides no support for the hypothesis that urban birds begin seasonal gonad growth because they are in better energetic status and increase the secretion of reproductive hormones earlier than non-urban birds. My studies do suggest, however, that the phenology of key food items and the endocrine responsiveness of the reproductive system may contribute to habitat-related disparities in the phenology of gonad growth.
Urbanization is characterized by profound environmental changes, and urban animals must adjust to an environment vastly different from that of their non-urban conspecifics. Evidence suggests that birds adjust to urban areas by advancing the timing of seasonal breeding and gonad development, compared to their non-urban conspecifics. A leading hypothesis to account for this phenomenon is that food availability is elevated in urban areas, which improves the energetic status of urban birds and enables them to initiate gonad development earlier than their non-urban conspecifics. However, this hypothesis remains largely untested.
My dissertation dovetailed comparative studies and experimental approaches conducted in field and captive settings to examine the physiological mechanisms by which food availability modulates gonad growth and to investigate whether elevated food availability in urban areas advances the phenology of gonad growth in urban birds. My captive study demonstrated that energetic status modulates reproductive hormone secretion, but not gonad growth. By contrast, free-ranging urban and non-urban birds did not differ in energetic status or plasma levels of reproductive hormones either in years in which urban birds had advanced phenology of gonad growth or in a year that had no habitat-related disparity in seasonal gonad growth. Therefore, my dissertation provides no support for the hypothesis that urban birds begin seasonal gonad growth because they are in better energetic status and increase the secretion of reproductive hormones earlier than non-urban birds. My studies do suggest, however, that the phenology of key food items and the endocrine responsiveness of the reproductive system may contribute to habitat-related disparities in the phenology of gonad growth.
ContributorsDavies, Scott (Author) / Deviche, Pierre (Thesis advisor) / Sweazea, Karen (Committee member) / McGraw, Kevin (Committee member) / Orchinik, Miles (Committee member) / Warren, Paige (Committee member) / Arizona State University (Publisher)
Created2014
Description
While exercising mammalian muscle increasingly relies on carbohydrates for fuel as aerobic exercise intensity rises above the moderate range, flying birds are extraordinary endurance athletes and fuel flight, a moderate-high intensity exercise, almost exclusively with lipid. In addition, Aves have long lifespans compared to weight-matched mammals. As skeletal muscle mitochondria account for the majority of oxygen consumption during aerobic exercise, the primary goal was to investigate differences in isolated muscle mitochondria between these species and to examine to what extent factors intrinsic to mitochondria may account for the behavior observed in the intact tissue and whole organism. First, maximal enzyme activities were assessed in sparrow and rat mitochondria. Citrate synthase and aspartate aminotransferase activity were higher in sparrow compared to rat mitochondria, while glutamate dehydrogenase activity was lower. Sparrow mitochondrial NAD-linked isocitrate dehydrogenase activity was dependent on phosphate, unlike the mammalian enzyme. Next, the rate of oxygen consumption (JO), electron transport chain (ETC) activity, and reactive oxygen species (ROS) production were assessed in intact mitochondria. Maximal rates of fat oxidation were lower than for carbohydrate in rat but not sparrow mitochondria. ETC activity was higher in sparrows, but no differences were found in ROS production between species. Finally, fuel selection and control of respiration at three rates between rest and maximum were assessed. Mitochondrial fuel oxidation and selection mirrored that of the whole body; in rat mitochondria the reliance on carbohydrate increased as the rate of oxygen consumption increased, whereas fat dominated under all conditions in the sparrow. These data indicate fuel selection, at least in part, can be modulated at the level of the mitochondrial matrix when multiple substrates are present at saturating levels. As an increase in matrix oxidation-reduction potential has been linked to a suppression of fat oxidation and high ROS production, the high ETC activity relative to dehydrogenase activity in avian compared to mammalian mitochondria may result in lower matrix oxidation-reduction potential, allowing fatty acid oxidation to proceed while also resulting in low ROS production in vivo.
ContributorsKuzmiak, Sarah (Author) / Willis, Wayne T (Thesis advisor) / Mandarino, Lawrence (Committee member) / Sweazea, Karen (Committee member) / Harrison, Jon (Committee member) / Gadau, Juergen (Committee member) / Arizona State University (Publisher)
Created2012
Description
Birds have shown promise as models of diabetes due to health and longevity despite naturally high plasma glucose concentrations, a condition which in diabetic humans leads to protein glycation and various complications. Research into mechanisms that protect birds from high plasma glucose have shown that some species of birds have naturally low levels of protein glycation. Some hypothesize a diet rich in carotenoids and other antioxidants protects birds from protein glycation and oxidative damage. There is little research, however, into the amount of protein glycation in birds of prey, which consume a high protein, high fat diet. No studies have examined the potential link between the diet of carnivorous birds and protein glycation. The overall purpose of this study was to evaluate whether birds of prey have higher protein glycation given their high protein, high fat diet in comparison to chickens, which consume a diet higher in carbohydrates. This was accomplished through analyses of serum samples from select birds of prey (bald eagle, red-tailed hawk, barred owl, great horned owl). Serum samples were obtained from The Raptor Center at the University of Minnesota where the birds of prey consumed high protein, high fat, non-supplemented diets that consisted of small animals and very little to no carbohydrate. Serum was also obtained from one chicken for a control, which consumed a higher carbohydrate and antioxidant-rich diet. Glucose, native albumin glycation and antioxidant concentrations (uric acid, vitamin E, retinol and several carotenoids) of each sample was measured. Statistical analyses showed significant between group differences in percent protein glycation amongst the birds of prey species. Glycation was significantly higher (p < 0.001) in bald eagles (23.67 ± 1.90%) and barred owls (24.28 ± 1.43%) compared to red-tailed hawks (14.31 ± 0.63%). Percent glycation was higher in all birds of prey compared to the chicken sample and literature values for chicken albumin glycation. Levels of the carotenoid lutein were significantly higher in bald eagles and barred owls compared to great horned owls and red-tailed hawks and the carotenoids beta-cryptoxanthin and beta-carotene were significantly greater in bald eagles compared to red-tailed hawks and great horned owls.
ContributorsIngram, Tana (Author) / Sweazea, Karen (Thesis advisor) / Johnston, Carol (Committee member) / Lespron, Christy (Committee member) / Arizona State University (Publisher)
Created2017
Description
Male reproductive dysfunction accounts for almost half of male infertility cases, yet the signaling mechanisms involved in the male reproductive system remain unclear. Although the exact cause of male reproductive dysfunction varies, obtaining a better understanding of the modulators of smooth muscle contractions may provide new targets for the treatment of male reproductive conditions. The male reproductive tract, consisting of the testes, epididymis, vas deferens, and penis, is lined with innervated smooth muscle fibers that transport spermatozoa through the system. Contractions of these smooth muscle fibers can be modulated by neurotransmitters and hormones, like dopamine and norepinephrine, as well as biogenic amines. The focus of this study is on the biogenic amine tyramine, which is produced by the breakdown of tyrosine via decarboxylation. Tyramine has been shown to modulate vasoconstriction and increase blood pressure due to its effect on smooth muscle contractions. This study has found that tyramine localizes in male reproductive tissues and modulates smooth muscle contractions. Age and environment were also found to play a significant role in the expression of tyramine and its associated receptor, TAAR1.
ContributorsSteadman, Solange (Author) / Baluch, Debra (Thesis advisor) / Roberson, Robert (Committee member) / Sweazea, Karen (Committee member) / Arizona State University (Publisher)
Created2023
Description
This feasibility study explored the use of an evolutionary mismatch narrative in nutritional education intervention aiming to reduce ultra-processed foods in the diets of veterans with type 2 diabetes and improve diabetic outcomes. Ultra-processed foods are foods that are primarily manufactured through industrial processes. These foods are high in calories but low in nutritional content. Diets high in these foods have been linked to increased health risks. One of the major health risks is type 2 diabetes. Type 2 diabetes is a chronic disease that is developed when cells become unable to properly utilize insulin. Over time this may lead to additional health conditions such as nerve damage, cardiovascular disease, and renal disease. Evolutionary mismatch narrative nutritional intervention offers a different approach to nutritional education to help reduce ultra-processed foods in diets. This study was a randomized controlled feasibility study at the Phoenix VA. Eleven participants were enrolled and randomly selected to be given either an evolutionary mismatch narrative education intervention or general nutritional education about ultra-processed foods. 24-hour diet recalls and blood chemistry were collected and analyzed. Blood chemistry provided diabetes related measurements which included glucose, HbA1c, insulin, HOMA-IR, and C-reactive protein. Statistically significant findings in this study included percentage of ultra-processed foods decreasing for both control and experimental groups from week 0 to week 4 (p=0.014), and C-reactive protein levels between the control and experimental groups (p=0.042). However, baseline C-reactive protein concentrations were lower in the experimental group such that normalizing for group differences at baseline revealed no significant difference in C-reactive protein change between interventions (p = 1.000). There were no other statistically significant values regarding diabetes related measurements. The results from this study suggest that nutritional education in general may help decrease ultra-processed food consumption.
ContributorsLiang, Nathan Adam (Author) / Sweazea, Karen (Thesis advisor) / Basile, Anthony J (Committee member) / Johnston, Carol (Committee member) / Arizona State University (Publisher)
Created2023
Description
Human preterm labor is the single most significant issue in modern obstetrics andgynecology, affecting ten percent of pregnancies, constituting the leading cause of infant death, and contributing significantly to chronic childhood disease. Obstetricians and reproductive scientists are faced with the major challenge of trying to increase the understanding of the complex molecular and cellular signals that regulate uterine activity during human pregnancy and labor. Even though preterm labor accounts for a large portion of perinatal mortality and morbidity, there still is not an effective therapeutic strategy for the treatment or prevention of preterm labor. This dissertation presents tyramine as an alternative modulator of uterine activity. In this dissertation the aims were as follows: 1) to investigate the localization of tyramine and trace amine associated receptor 1 (TAAR1) in the mouse uterine horn using immunohistochemistry as well as confirm the presence of tyramine in the uterine tissue using high performance liquid chromatography, 2) identify which TAAR 1-9 subtypes were present in the mouse uterine horn using RT-qPCR, 3) investigate ultrastructural differences in the mouse uterine horn following tyramine and dopamine treatment using transmission electron microscopy and 4) investigate pinopod ultrastructure as well as pinopod ultrastructural differences following tyramine and dopamine treatment. The research presented in this dissertation showed: 1) tyramine has very specific localization in the mouse endometrium, mainly in the uterine glands, TAAR1 is localized all throughout the perimetrium, myometrium and endometrium, and that tyramine was confirmed and quantified using HPLC, 2) TAAR 1- 9 genes are expressed in trace levels in the mouse uterine horn, 3) tyramine influences changes in endometrial ultrastructure, and 4) tyramine influences changes in pinopod ultrastructure. Ultimately these findings can help with identifying novel treatment options not only for spontaneous preterm labor contractions but also for other uterine related disorders.
ContributorsObayomi, SM Bukola (Author) / Baluch, Debra P (Thesis advisor) / Roberson, Robert (Thesis advisor) / Sweazea, Karen (Committee member) / Brent, Colin (Committee member) / Arizona State University (Publisher)
Created2023
Description
Emerging pathogens present several challenges to medical diagnostics. Primarily, the exponential spread of a novel pathogen through naïve populations require a rapid and overwhelming diagnostic response at the site of outbreak. While point-of-care (PoC) platforms have been developed for detection of antigens, serologic responses, and pathogenic genomes, only nucleic acid diagnostics currently have the potential to be developed and manufactured within weeks of an outbreak owing to the speed of next-generation sequencing and custom DNA synthesis. Among nucleic acid diagnostics, isothermal amplification strategies are uniquely suited for PoC implementation due to their simple instrumentation and lack of thermocycling requirement. Unfortunately, isothermal strategies are currently prone to spurious nonspecific amplification, hindering their specificity and necessitating extensive empirical design pipelines that are both time and resource intensive. In this work, isothermal amplification strategies are extensively compared for their feasibility of implementation in outbreak response scenarios. One such technology, Loop-mediated Amplification (LAMP), is identified as having high-potential for rapid development and PoC deployment. Various approaches to abrogating nonspecific amplification are described including a novel in silico design tool based on coarse-grained simulation of interactions between thermophilic DNA polymerase and DNA strands in isothermal reaction conditions. Nonspecific amplification is shown to be due to stabilization of primer secondary structures by high concentrations of Bst DNA polymerase and a mechanism of micro-complement-mediated cross-priming is demonstrated as causal via nanopore sequencing of nonspecific reaction products. The resulting computational model predicts primer set background in 64% of 67 test assays and its usefulness is illustrated further by determining problematic primers in a West Nile Virus-specific LAMP primer set and optimizing primer 3’ nucleotides to eliminate micro-complements within the reaction, resulting in inhibition of background accumulation. Finally, the emergence of Orthopox monkeypox (MPXV) as a recurring threat is discussed and SimCycle is utilized to develop a novel technique for clade-specific discrimination of MPXV based on bridging viral genomic rearrangements (Bridging LAMP). Bridging LAMP is implemented in a 4-plex microfluidic format and demonstrates 100% sensitivity in detection of 100 copies of viral lysates and 45 crude MPXV-positive patient samples collected during the 2022 Clade IIb outbreak.
ContributorsKnappenberger, Mark Daniel (Author) / Anderson, Karen S (Thesis advisor) / LaBaer, Joshua (Committee member) / Roberson, Robert (Committee member) / Lindsay, Stuart (Committee member) / Arizona State University (Publisher)
Created2023
Description
According to the World Health Organization, cancer is one of the leading causes of death around the world. Although early diagnostics using biomarkers and improved treatments with targeted therapy have reduced the rate of cancer related mortalities, there remain many unknowns regarding the contributions of the tumor microenvironment to cancer progression and therapeutic resistance. The tumor microenvironment plays a significant role by manipulating the progression of cancer cells through biochemical and biophysical signals from the surrounding stromal cells along with the extracellular matrix. As such, there is a critical need to understand how the tumor microenvironment influences the molecular mechanisms underlying cancer metastasis to facilitate the discovery of better therapies. This thesis described the development of microfluidic technologies to study the interplay of cancer cells with their surrounding microenvironment. The microfluidic model was used to assess how exposure to chemoattractant, epidermal growth factor (EGF), impacted 3D breast cancer cell invasion and enhanced cell motility speed was noted in the presence of EGF validating physiological cell behavior. Additionally, breast cancer and patient-derived cancer-associated fibroblast (CAF) cells were co-cultured to study cell-cell crosstalk and how it affected cancer invasion. GPNMB was identified as a novel gene of interest and it was shown that CAFs enhanced breast cancer invasion by up-regulating the expression of GPNMB on breast cancer cells resulting in increased migration speed. Lastly, this thesis described the design, biological validation, and use of this microfluidic platform as a new in vitro 3D organotypic model to study mechanisms of glioma stem cell (GSC) invasion in the context of a vascular niche. It was confirmed that CXCL12-CXCR4 signaling is involved in promoting GSC invasion in a 3D vascular microenvironment, while also demonstrating the effectiveness of the microfluidic as a drug screening assay. Taken together, the broader impacts of the microfluidic model developed in this dissertation include, a possible alternative platform to animal testing that is focused on mimicking human physiology, a potential ex vivo platform using patient-derived cells for studying the interplay of cancer cells with its surrounding microenvironment, and development of future therapeutic strategies tailored toward disrupting key molecular pathways involved in regulatory mechanisms of cancer invasion.
ContributorsTruong, Danh, Ph.D (Author) / Nikkhah, Mehdi (Thesis advisor) / LaBaer, Joshua (Committee member) / Smith, Barbara (Committee member) / Mouneimne, Ghassan (Committee member) / Vernon, Brent (Committee member) / Arizona State University (Publisher)
Created2018
Description
Lipolysis or hydrolysis of triglyceride (TG) stored within intracellular lipid droplets (LD), is vital to maintaining metabolic homeostasis in mammals. Regulation of lipolysis and subsequent utilization of liberated fatty acids impacts cellular and organismal functions including body fat accumulation and thermogenesis. Adipose triglyceride lipase (ATGL) is the intracellular rate-limiting enzyme responsible for catalyzing hydrolysis of TG to diacylglycerol (DAG), the initial step of the lipolytic reaction. G0/G1 switch gene-2 (G0S2) and hypoxia-inducible gene-2 (HIG2) are selective inhibitors of ATGL. G0S2 facilitates accumulation of TG in the liver and adipose tissue, while HIG2 functions under hypoxic conditions. Sequence analysis and mutagenesis were used to confirm the presence of conserved domains between these proteins, and that these domains are required for efficient binding and inhibition of ATGL. Further analysis revealed a Positive sequence (Pos-Seq)-LD binding motif in G0S2 but not HIG2. The Pos-Seq mediated ATGL-independent localization to LD and was required for achieving maximal inhibition of ATGL activity by G0S2. Identification and mutational analysis of this motif revealed distinct mechanisms for HIG2 and G0S2 LD association. In addition to molecular characterization of known protein inhibitors of lipolysis, an intracellular member of the apolipoprotein L (ApoL) family, ApoL6, was also identified as a LD and mitochondria associated protein expressed in adipose tissue. Brown adipose tissue uses fatty acids as fuel for increasing its energy output as heat during acute responses to cold exposure. A Comprehensive Lab Animal Monitoring System was used to compare heat production at room temperature (RT) and 4oC in transgenic animals overexpressing ApoL6 in brown adipose tissue. Overexpression of ApoL6 delayed utilization of long-chain fatty acids (LCFAs) as a fuel source while promoting an enhanced thermogenic response during initial cold exposure. ApoL6 mediated inhibition of LCFA utilization results from binding of ApoL6 to Mitochondrial Trifunctional Protein (MTP/TFP), which catalyzes mitochondrial β-oxidation. Indirect calorimetry and fasting acute cold exposure experiments suggest the augmented thermogenic profile of ApoL6 transgenic animals is a result of enhanced utilization of medium-chain fatty acids (MCFAs), glucose, and amino acids as fuel sources. Cumulatively these results indicate multiple mechanisms for regulation lipolysis and fatty acid utilization.
ContributorsCampbell, Latoya E (Author) / Lake, Douglas (Thesis advisor) / Liu, Jun (Committee member) / Folmes, Clifford (Committee member) / Sweazea, Karen (Committee member) / Baluch, Debra (Committee member) / Arizona State University (Publisher)
Created2021