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.

Displaying 1 - 10 of 31
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The majority of chronic myeloid leukemia (CML) and some of acute lymphocytic leukemia (ALL) cases are associated with possessing the BCR-Abl fusion protein from an oncogenic translocation, resulting in a constantly active form of Abl and rapid proliferation. CML and ALL cells that possess the BCR-Abl fusion protein are known

The majority of chronic myeloid leukemia (CML) and some of acute lymphocytic leukemia (ALL) cases are associated with possessing the BCR-Abl fusion protein from an oncogenic translocation, resulting in a constantly active form of Abl and rapid proliferation. CML and ALL cells that possess the BCR-Abl fusion protein are known as Philadelphia chromosome positive (Ph+). Currently, Imatinib (selective Abl inhibitor) is used as therapy against CML and ALL. However, some patients may have malignancies which show resistance to Imatinib. Previous work displays that the transformation of progenitor B cells with the v-Abl oncogene of Abelson murine leukemia virus results in cell cycle progression, rapid proliferation, and potentially malignant transformation while preventing any further differentiation. Progenitor B cells transformed with the temperature-sensitive form of the v-Abl oncogene have served as a model to study cellular response to Imatinib treatment. After some manipulation, very few cells were forced to progress to malignancy, forming tumor in vivo. These cells were no long sensitive to v-Abl inactivation, resembling the Imatinib resistant ALL. Autophagy is the process by which proteins and organelles are broken-down and recycled within the eukaryotic cell and has been hypothesized to play a part in cancer cell survival and drug-resistance. LC3 processing is a widely accepted marker of autophagy induction and progression. It has also been shown that Imatinib treatment of Ph+ leukemia can induce autophagy. In this study, we examined the autophagy induction in response to v-Abl inactivation in a Ph+-B-ALL cell model that shows resistance to Imatinib. In particular, we wonder whether the tumor cell line resistant to v-Abl inactivation may acquire a high level of autophagy to become resistant to apoptosis induced by v-Abl inactivation, and thus become addicted to autophagy. Indeed, this tumor cell line displays a high basal levels of LC3 I and II expression, regardless of v-Abl activity. We further demonstrated that inhibition of the autophagy pathway enhances the tumor line's sensitivity to Imatinib, resulting in cell cycle arrest and massive apoptosis. The combination of autophagy and Abl inhibitions may serve as an effective therapy for BCR-Abl positive CML.
ContributorsArkus, Nohea (Author) / Chang, Yung (Thesis advisor) / Kusumi, Kenro (Committee member) / Lake, Douglas (Committee member) / Jacobs, Bertram (Committee member) / Arizona State University (Publisher)
Created2011
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Description
Infertility has become an increasing problem in developed countries and in many cases can be attributed to compromised sperm quality. Assessment of male fertility typically utilizes semen analysis which mainly examines sperm morphology, however many males whose sperm appear normal are sub- or infertile, suggesting that sperm from these males

Infertility has become an increasing problem in developed countries and in many cases can be attributed to compromised sperm quality. Assessment of male fertility typically utilizes semen analysis which mainly examines sperm morphology, however many males whose sperm appear normal are sub- or infertile, suggesting that sperm from these males may be deficient in a protein or suite of proteins. To date, very little is known about the composition of sperm or the complex maturation process that confers motility and fertilization competency to sperm. Chapter 1 discusses the use of whole cell mass spectrometry to identify 1247 proteins comprising the Rhesus macaque (Macaca mulatta) sperm proteome, a commonly used model of human reproduction. This study provides a more robust proxy of human sperm composition than was previously available and facilitates studies of sperm using the rhesus macaque as a model. Chapters 2 & 3 provide a systems level overview of changes in sperm proteome composition that occurs during epididymal transit. Chapter 2 reports the proteomes of sperm collected from the caput, corpus and cauda segments of the mouse epididymis, identifying 1536, 1720 and 1234 proteins respectively. Chapter 3 reports the sperm proteome from four distinct segments of the Rhesus macaque epididymis, including the caput, proximal corpus, distal corpus and cauda, identifying 1951, 2014, 1764 and 1423 proteins respectively. These studies identify a number of proteins that are added and removed from sperm during epididymal transit which likely play an important role in the sperm maturation process. To date no comparative evolutionary studies of sperm proteomes have been undertaken. Chapter 4 compares four mammalian sperm proteomes including the human, macaque, mouse and rat. This study identified 98 proteins common to all four sperm proteomes, 82 primate and 90 rodent lineage-specific proteins and 494, 467, 566, and 193 species specific proteins in the human, macaque, mouse and rat sperm proteomes respectively and discusses how differences in sperm composition may ultimately lead to functional differences across species. Finally, chapter 5 uses sperm proteome data to inform the preliminary design of a rodent contraceptive vaccine delivered orally using recombinant attenuated Salmonella vaccine vectors.
ContributorsSkerget, Sheri Jo (Author) / Karr, Timothy L. (Thesis advisor) / Lake, Douglas (Committee member) / Petritis, Konstantinos (Committee member) / Arizona State University (Publisher)
Created2013
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Description
Host organisms have evolved multiple mechanisms to defend against a viral infection and likewise viruses have evolved multiple methods to subvert the host's anti-viral immune response. Vaccinia virus (VACV) is known to contain numerous proteins involved in blocking the cellular anti-viral immune response. The VACV E3L protein is

Host organisms have evolved multiple mechanisms to defend against a viral infection and likewise viruses have evolved multiple methods to subvert the host's anti-viral immune response. Vaccinia virus (VACV) is known to contain numerous proteins involved in blocking the cellular anti-viral immune response. The VACV E3L protein is important for inhibiting the anti-viral immune response and deletions within this gene lead to a severe attenuation. In particular, VACV containing N-terminal truncations in E3L are attenuated in animal models and fail to replicate in murine JC cells. Monkeypox virus (MPXV) F3L protein is a homologue of the VACV E3L protein, however it is predicted to contain a 37 amino acid N-terminal truncation. Despite containing an N-terminal truncation in the E3L homologue, MPXV is able to inhibit the anti-viral immune response similar to wild-type VACV and able to replicate in JC cells. This suggests that MPXV has evolved another mechanism(s) to counteract host defenses and promote replication in JC cells. MPXV produces less dsRNA than VACV during the course of an infection, which may explain why MPXV posses a phenotype similar to VACV, despite containing a truncated E3L homologue. The development of oncolytic viruses as a therapy for cancer has gained interest in recent years. Oncolytic viruses selectively replicate in and destroy cancerous cells and leave normal cells unharmed. Many tumors possess dysregulated anti-viral signaling pathways, since these pathways can also regulate cell growth. Creating a mutation in the N-terminus of the VACV-E3L protein generates an oncolytic VACV that depends on dysregulated anti-viral signaling pathways for replication allowing for direct targeting of the cancerous cells. VACV-E3Ldel54N selectively replicates in numerous cancer cells lines and not in the normal cell lines. Additionally, VACV-E3Ldel54N is safe and effective in causing tumor regression in a xenograph mouse model. Lastly, VACV-E3Ldel54N was capable of spreading from the treated tumors to the untreated tumors in both a xenograph and syngeneic mouse model. These data suggest that VACV-E3Ldel54N could be an effective oncolytic virus for the treatment of cancer.
ContributorsArndt, William D (Author) / Jacobs, Bertram (Thesis advisor) / Curtiss Iii, Roy (Committee member) / Chang, Yung (Committee member) / Lake, Douglas (Committee member) / Arizona State University (Publisher)
Created2010
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Description
IOsteosarcoma is the most common bone cancer and typically affects patients in the second decade of life. Current treatment methods have not proven effective for treating reoccurring or metastatic osteosarcoma (mOS) given the 5-year survival rate of 15-30%. Previous work showed that using the immune system to fight the cancer

IOsteosarcoma is the most common bone cancer and typically affects patients in the second decade of life. Current treatment methods have not proven effective for treating reoccurring or metastatic osteosarcoma (mOS) given the 5-year survival rate of 15-30%. Previous work showed that using the immune system to fight the cancer significantly improved survival of mOS in mice, but approximately 40-50% of treated mice still succumbed to disease. To further improve immunotherapy, I analyzed immune cells in the tumor bed and observed high numbers of a rare T cell subtype: CD4hiCD8αhi, or double positive (DP), T cells. While previous literature found mature DP T cells in chronic diseases, the associations and functions of this rare T cell subtype varied between studies and were unknown for mOS. Controlling for age, chronicity of disease, and environmental exposure, I found DP T cells composed a higher percentage of T cells in the cancer as tumor burden increased. I then tested whether the DP cells were pro- or anti-tumor. I found that DP cells produced the cytokines IFNγ and IL-2 when exhaustion was overcome. They also expressed FasL for cytotoxic function, although the target is unknown. These findings suggest DP T cells have multifunctionality, which could be advantageous when responding to high antigen load. II Course-based undergraduate research experiences (CUREs) offer students opportunities to engage in critical thinking and problem solving. However, quantitating the impact that incorporating research into undergraduate courses has on student learning has been difficult since most CUREs lack a comparable traditional course as a control. Because the overall class structure remained unaltered when our upper division immunology course transitioned to a CURE class, we realized retrospectively that we were in a unique position to quantitate the impact of incorporating research on student performance. I then analyzed the summative assessments used to assess student learning and found that students in the CURE format class performed significantly better on quizzes, exams, and reports. There were no significant differences in academic levels, degree programs, or grade point averages, suggesting improved performance was due to increased engagement of students in research.
ContributorsAppel, Nicole (Author) / Blattman, Joseph (Thesis advisor) / Anderson, Karen (Committee member) / Lake, Douglas (Committee member) / Hingorani, Pooja (Committee member) / Arizona State University (Publisher)
Created2022
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Description
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19) that emerged from a zoonotic host at the end of 2019 and caused a public health crisis. In this collection of studies, Nicotiana benthamiana plants are used to set the foundation for producing monoclonal

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19) that emerged from a zoonotic host at the end of 2019 and caused a public health crisis. In this collection of studies, Nicotiana benthamiana plants are used to set the foundation for producing monoclonal antibodies (mAbs) with homogeneous glycosylation to neutralize SARS-CoV-2 and potentially address the immunopathology often observed with severe COVID-19. Specifically, a mAb against the human interleukin (IL)-6 receptor (sarilumab) was generated and evaluated in vitro for its potential to reduce IL-6 signaling that has been shown to be associated with more severe cases of COVID-19. Furthermore, multiple mAbs that bind to the receptor-binding domain (RBD) of SARS-CoV-2 and efficiently neutralize the virus were developed using plant-based expression. Several of these mAbs are from different classes of RBD-binding mAbs that have distinct binding sites from one another. Several mAbs from different classes showed synergy in neutralizing the ancestral strain of SARS-CoV-2 and a smaller subset showed synergy when tested against the highly mutated Omicron (B.1.1.529) variant. Of interest, a novel RBD-binding mAb, termed 11D7, that was raised against the ancestral strain and derived from a hybridoma, appears to have an epitope on the RBD that contributes more synergy to a mAb combination that efficiently neutralizes the B.1.1.529 variant of SARS-CoV-2. This epitope was partially mapped by competitive binding and shows that it overlaps with another known antibody that binds a cryptic, distal epitope, away from the receptor binding site, giving insight into the potential mechanism by which 11D7 neutralizes SARS-CoV-2, as well as potentially allowing it to resist SARS-CoV-2 immune evasion more efficiently. Furthermore, this mAb carries a highly homogeneous glycan pattern when expressed in N. benthamiana, that may contribute to enhanced effector function and provides a tool to elucidate the precise role of crystallizable fragment (Fc)-mediated protection in SARS-CoV-2 infection. Ultimately, these studies provide evidence of the utility of plant-made mAbs to be used as cocktail members, giving clarity to the use of less potent mAbs as valuable cocktail components which will spur further investigations into how mAbs with unique epitopes work together to efficiently neutralize SARS-CoV-2.
ContributorsJugler, Collin (Author) / Chen, Qiang (Thesis advisor) / Lake, Douglas (Committee member) / Steele, Kelly (Committee member) / Mason, Hugh (Committee member) / Arizona State University (Publisher)
Created2022
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Description
Monkeypox virus (MPXV) is an orthopoxvirus that causes smallpox-like disease and has up to a 10% mortality rate, depending on the infectious strain. The global eradication of the smallpox virus has led to the decrease in smallpox vaccinations, which has led to a drastic increase in the number of human

Monkeypox virus (MPXV) is an orthopoxvirus that causes smallpox-like disease and has up to a 10% mortality rate, depending on the infectious strain. The global eradication of the smallpox virus has led to the decrease in smallpox vaccinations, which has led to a drastic increase in the number of human MPXV cases. MPXV has been named the most important orthopoxvirus to infect humans since the eradication of smallpox and has been the causative agent of the 2022 world-wide MPXV outbreak. Despite being highly pathogenic, MPXV contains a natural truncation at the N-terminus of its E3 homologue. Vaccinia virus (VACV) E3 protein has two domains: an N- terminus Z-form nucleic acid binding domain (Z-BD) and a C-terminus double stranded RNA binding domain (dsRBD). Both domains are required for pathogenesis, interferon (IFN) resistance, and protein kinase R (PKR) inhibition. The N-terminus is required for evasion of Z-DNA binding protein 1 (ZBP1)-dependent necroptosis. ZBP1 binding to Z- form deoxyribonucleic acid/ribonucleic acid (Z-DNA/RNA) leads to activation of receptor-interacting protein kinase 3 (RIPK3) leading to mixed lineage kinase domain- like (MLKL) phosphorylation, aggregation and cell death. This study investigated how different cell lines combat MPXV infection and how MPXV has evolved ways to circumvent the host response. MPXV is shown to inhibit necroptosis in L929 cells by degrading RIPK3 through the viral inducer of RIPK3 degradation (vIRD) and by inhibiting MLKL aggregation. Additionally, the data shows that IFN treatment efficiently inhibits MPXV replication in a ZBP1-, RIPK3-, and MLKL- dependent manner, but independent of necroptosis. Also, the data suggests that an IFN inducer with a pancaspase or proteasome inhibitor could potentially be a beneficial treatment against MPXV infections. Furthermore, it reveals a link between PKR and pathogen-induced necroptosis that has not been previously described.
ContributorsWilliams, Jacqueline (Author) / Jacobs, Bertram (Thesis advisor) / Langland, Jeffrey (Committee member) / Lake, Douglas (Committee member) / Varsani, Arvind (Committee member) / Arizona State University (Publisher)
Created2022
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Description
Human papillomavirus (HPV) infection has a large burden on society. It is a causal agent of 99.7% of all cervical cancer cases. The prevalence of HPV infection worldwide is high, but the burden of HPV infections lies on less developed regions. Cervical cancer is not associated with immediate symptoms, screening

Human papillomavirus (HPV) infection has a large burden on society. It is a causal agent of 99.7% of all cervical cancer cases. The prevalence of HPV infection worldwide is high, but the burden of HPV infections lies on less developed regions. Cervical cancer is not associated with immediate symptoms, screening methods are needed to detect HPV disease presence before lesions progress to cervical cancer. Protein biomarkers are a growing area of diagnostic medicine and facilitate the detection of disease at an early and treatable stage. Technologies for healthcare diagnostics often require laboratory space or expensive instrumentation, which are not feasible for point of care applications. In order for clinical diagnostics to advance in developing countries, low cost, rapid, portable, and easy to use point of care diagnostic tests are needed. The project adapts the Enzyme Linked Immunosorbent Assays (ELISA) and Nucleic Acid-Programmable Protein Array (NAPPA) to a proof of concept assay for use in magnetic bead based microfluidics. The biomarker used for analyte detection was E7, as a strong correlation has been found between presence of E7 antibodies and development of advanced cervical cancer. It is demonstrated that magnetic microfluidic assay design for rapid detection of antibodies is amenable to fluorescence detection in point of care settings. The data demonstrates that the microfluidic assay is rapid, low-cost, specific, and relevant to serology detection. The assay detects antibody responses to analytes with the point of care reader system and is realized in an on chip capacity. With the integration of anti-GST capture antibodies conjugated to the magnetic beads in the microfluidic system, many analytes can be detected without large changes to the existing assay structure, which gives the ability to adapt the system to analytes of interest rapidly.
ContributorsSnow, Kylie (Author) / Anderson, Karen (Thesis advisor) / Blain Christen, Jennifer (Committee member) / Lake, Douglas (Committee member) / Arizona State University (Publisher)
Created2022
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Description
Mucosal membranes represent a major site of pathogen transmission and cancer development. Enhancing T cell migration to mucosal surfaces could improve immune-based therapies for these diseases, yielding better clinical outcomes. All-trans-retinoic acid (ATRA) is a biologically active form of vitamin A that has been shown to increase T cell migration

Mucosal membranes represent a major site of pathogen transmission and cancer development. Enhancing T cell migration to mucosal surfaces could improve immune-based therapies for these diseases, yielding better clinical outcomes. All-trans-retinoic acid (ATRA) is a biologically active form of vitamin A that has been shown to increase T cell migration to mucosal sites, however its therapeutic use is limited by its toxicity potential and unstable nature. ATRA-related compounds with lower toxicity and higher stability were assessed for their ability to induce similar immune migration effects as ATRA, using in vitro and in vivo model systems. Chapter 2 summarizes the first project, in which synthetic, ATRA-like compounds called rexinoids were used to modulate T cell expression of mucosal homing proteins chemokine receptor 9 (CCR9) and integrin alpha 4 beta 7 (α4β7), and alter their physical migration in vitro. Several rexinoids independently mimicked the activity of ATRA to enhance protein expression and migration, while others worked synergistically with subtoxic doses of ATRA to produce similar results. Furthermore, rexinoid administration in vivo was well-tolerated by animal models, a finding not seen with ATRA. Chapter 3 focuses on the second project, where plasmids containing ATRA-synthesizing proteins were assessed for their in vivo ability to act as mucosal vaccine adjuvants and enhance T cell migration to mucosal sites during DNA vaccination. Though increased mucosal migration was seen with use of the adjuvant plasmids, these findings were not determined to be significant. Immune-mediated protection following viral challenge was also not determined to be significant in animal models receiving both vaccine and adjuvant plasmids. The data shows that several novel rexinoids may possess enhanced clinical utility compared to ATRA, lending support for their use in immunotherapeutic approaches towards mucosal maladies. While the potential mucosal vaccine adjuvants did not show great significance in enhancing T cell migration or viral protection, further optimization of the model system may produce better results. This work helps advance knowledge of immune cell trafficking to afflicted mucosal regions. It can be used as a basis for understanding migration to other body areas, as well as for the development of better immune-based treatments.
ContributorsManhas, Kavita Rani (Author) / Blattman, Joseph (Thesis advisor) / Marshall, Pamela (Committee member) / Lake, Douglas (Committee member) / Ugarova, Tatiana (Committee member) / Arizona State University (Publisher)
Created2022
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Description
To combat the global antimalarial resistance crisis effective resistance management strategies are needed. To do so, I need to gain a better understanding of the ecological interactions occurring within malaria infections. Despite the importance of the complex interplay among co-infecting strains, our current knowledge and empirical data of within-host diversity

To combat the global antimalarial resistance crisis effective resistance management strategies are needed. To do so, I need to gain a better understanding of the ecological interactions occurring within malaria infections. Despite the importance of the complex interplay among co-infecting strains, our current knowledge and empirical data of within-host diversity and malaria disease dynamics is limited. In this thesis, I explore the multifaceted dynamics of malaria infections through an ecological lens. My overall research question is: "How do ecological interactions, including niche complementarity, competition dynamics, and the cost of resistance, shape the outcomes of malaria infections, and what implications does this have on understanding and improving resistance management strategies?” In Chapter II, titled “Niche Complementarity in Malaria Infections” I demonstrate that ecological principles are observed in malarial infections by experimentally manipulating the biodiversity of rodent malaria P. chabaudi infections. I observed that some parasites experienced competitive suppression, others experienced competitive facilitation, while others were not impacted. Next, in Chapter III, titled “Determining the Differential Impact of Competition Between Genetically Distinct Plasmodium falciparum Strains” I investigate the differential effect of competition among six genetically distinct strains. The impact of competition varied between strain combinations, and both suppression and facilitation were observed, but most pairings had no competitive interactions. Lastly, in Chapter IV, titled “Assessing Fitness Costs in Malaria Parasites: A Comprehensive Review and Implications for Drug Resistance Management”, I summarize where the field currently stands and what evidence there is for the presence of a fitness cost, or lack thereof, and I highlight the current gaps in knowledge. I found that evidence from field, in vitro, and animal models are overall suggestive of the presence of a fitness cost, however, these costs were not always found. Amid the current focus on malaria eradication, it is crucial to understand the impact of biodiversity on disease severity. By incorporating an ecological approach to infectious disease systems, I can gain insights on within-host interactions and how they impact parasite fitness and transmissibility.
ContributorsSegovia, Xyonane (Author) / Huijben, Silvie (Thesis advisor) / Bean, Heather (Committee member) / Gile, Gillian (Committee member) / Hogue, Ian (Committee member) / Lake, Douglas (Committee member) / Arizona State University (Publisher)
Created2024
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Description
Peptide-based vaccines represent a promising strategy to develop personalized treatments for cancer immunotherapy. Despite their specificity and low cost of production, these vaccines have had minimal success in clinical studies due to their lack of immunogenicity, creating a need for more effective vaccine designs. Adjuvants can be incorporated to enhance

Peptide-based vaccines represent a promising strategy to develop personalized treatments for cancer immunotherapy. Despite their specificity and low cost of production, these vaccines have had minimal success in clinical studies due to their lack of immunogenicity, creating a need for more effective vaccine designs. Adjuvants can be incorporated to enhance their immunogenicity by promoting dendritic cell activation and antigen cross-presentation. Due to their favorable size and ability to incorporate peptides and adjuvants, nanoparticles represent an advantageous platform for designing peptide vaccines. One prime example is RNA origami (RNA-OG) nanostructures, which are nucleic acid nanostructures programmed to assemble into uniform shapes and sizes. These stable nanostructures can rationally incorporate small molecules giving them a wide array of functions. Furthermore, RNA-OG itself can function as an adjuvant to stimulate innate immune cells. In the following study, self-adjuvanted RNA-OG was employed as a vaccine assembly platform, incorporating tumor peptides onto the nanostructure to design RNA-OG-peptide nanovaccines for cancer immunotherapy. RNA-OG-peptide was found to induce dendritic cell activation and antigen cross-presentation, which mobilized tumor-specific cytotoxic T cells to elicit protective anti-tumor immunity in tumor-bearing mice. These findings demonstrate the therapeutic potential of RNA-OG as a stable, carrier-free nanovaccine platform. In an attempt to further enhance the efficacy by optimizing the amount of peptides assembled, RNA-OG was complexed with polylysine-linked peptides, a simple strategy that allowed peptide amounts to be varied. Interestingly, increasing the peptide load led to decreased vaccine efficacy, which was correlated with an ineffective CD8+ T cell response. On the other hand, the vaccine efficacy was improved by decreasing the amount of peptide loaded onto RNA-OG, which may have attributed to greater complex stability compared to the high peptide load. These results highlight a simple strategy that can be used to optimize vaccine efficacy by altering the load of assembled peptides. These studies advance our understanding of RNA-OG as a peptide vaccine platform and provide various strategies to improve the design of peptide vaccines for translation into cancer immunotherapy.
ContributorsYip, Theresa (Author) / Chang, Yung (Thesis advisor) / Borges Florsheim, Esther (Committee member) / Lake, Douglas (Committee member) / Yan, Hao (Committee member) / Arizona State University (Publisher)
Created2024