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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
In the United States, many new cases of type I diabetes appear among youth. Upon diagnosis, many patients experience psychosocial issues in addition to physical issues, including depression, anxiety, and poor self-esteem. Diabetes educators have found that it is important to form interpersonal connections and trust with their adolescent patients. One tool that may be particularly useful for diabetes educators to implement is art therapy, which combines creativity and problem solving in a practical manner. Art therapy may be particularly helpful for individuals with type 1 diabetes because of the great cognitive and emotional changes, which occur during adolescence. In order for caretakers and educators to implement tenants of art therapy, it is helpful to have a medium, such as an art journal, which provides a foundation on which to process the emotions and thoughts the adolescent is experiencing as they process diabetes and their feelings throughout diagnosis. Keywords: art therapy, type I diabetes
ContributorsFowle, Mikaelah Jenee (Author) / Bodman, Denise (Thesis director) / Rogers, Jennifer (Committee member) / Barrett, The Honors College (Contributor) / T. Denny Sanford School of Social and Family Dynamics (Contributor)
Created2015-05
Description
Type 1 diabetes (T1D) is a chronic disease that affects 1.25 million people in the United States. There is no known cure and patients must self-manage the disease to avoid complications resulting from blood glucose (BG) excursions. Patients are more likely to adhere to treatments when they incorporate lifestyle preferences. Current technologies that assist patients fail to consider two factors that are known to affect BG: exercise and alcohol. The hypothesis is postprandial blood glucose levels of adult patients with T1D can be improved by providing insulin bolus or carbohydrate recommendations that account for meal and alcohol carbohydrates, glycemic excursion, and planned exercise. I propose an evidence-based decision support tool, iDECIDE, to make recommendations to improve glucose control by taking into account meal and alcohol carbohydrates, glycemic excursion and planned exercise. iDECIDE is deployed as a low-cost and easy to disseminate smartphone application.
A literature review was conducted on T1D and the state-of-the-art in diabetes technology. To better understand self-management behaviors and guide the development of iDECIDE, several data sources were collected and analyzed: surveys, insulin pump paired with glucose monitoring, and self-tracking of exercise and alcohol. The analysis showed variability in compensation techniques for exercise and alcohol and that patients made unaided decisions, suggesting a need for better decision support.
The iDECIDE algorithm can make insulin and carbohydrate recommendations. Since there were no existing in-silico methods for assessing bolus calculators, like iDECIDE, I proposed a novel methodology to retrospectively compare insulin pump bolus calculators. Application of the methodology shows that iDECIDE outperformed the Medtronic insulin pump bolus calculator and could have improved glucose control.
This work makes contributions to diabetes technology researchers, clinicians and patients. The iDECIDE app provides patients easy access to a decision support tool that can improve glucose control. The study of behaviors from diabetes technology and self-report patient data can inform clinicians and the design of future technologies and bedside tools that integrate patient’s behaviors and perceptions. The comparison methodology provides a means for clinical informatics researchers to identify and retrospectively test promising insulin blousing algorithms using real-life data.
A literature review was conducted on T1D and the state-of-the-art in diabetes technology. To better understand self-management behaviors and guide the development of iDECIDE, several data sources were collected and analyzed: surveys, insulin pump paired with glucose monitoring, and self-tracking of exercise and alcohol. The analysis showed variability in compensation techniques for exercise and alcohol and that patients made unaided decisions, suggesting a need for better decision support.
The iDECIDE algorithm can make insulin and carbohydrate recommendations. Since there were no existing in-silico methods for assessing bolus calculators, like iDECIDE, I proposed a novel methodology to retrospectively compare insulin pump bolus calculators. Application of the methodology shows that iDECIDE outperformed the Medtronic insulin pump bolus calculator and could have improved glucose control.
This work makes contributions to diabetes technology researchers, clinicians and patients. The iDECIDE app provides patients easy access to a decision support tool that can improve glucose control. The study of behaviors from diabetes technology and self-report patient data can inform clinicians and the design of future technologies and bedside tools that integrate patient’s behaviors and perceptions. The comparison methodology provides a means for clinical informatics researchers to identify and retrospectively test promising insulin blousing algorithms using real-life data.
ContributorsGroat, Danielle (Author) / Grando, Maria Adela (Thesis advisor) / Kaufman, David (Committee member) / Thompson, Bithika (Committee member) / Arizona State University (Publisher)
Created2017
Description
Type 1 diabetes (T1D) is one of the most common chronic diseases in youth and it has been shown that adolescents have the worst glycemic control of any age group. The objective of this study was to develop, test and evaluate the feasibility of an online intervention (Can-Do-Tude) that uses the principles of motivational interviewing (MI) to deliver tailored diabetes self-management education to adolescents with T1D. Bandura’s efficacy belief system was used to guide the design of this study.
The study used a multi-phase, multi-method approach. The first phase (alpha) of this study was a qualitative descriptive design to examine the intervention’s fidelity. Evaluation of performance was conducted by experts in the fields of MI, T1D, adolescence and/or online education. The second phase (beta) was a quantitative descriptive design conducted in order to evaluate feasibility by examining the acceptability (recruitment, retention and satisfaction) and implementation (diabetes self-management self-efficacy) to determine whether the intervention was appropriate for further testing.
First phase findings showed that the intervention passed all measures with the content experts (n = 6): it was functional, accurate, usable and secure. Improvements to the intervention were made based on reviewer recommendations. For the second phase 5 adolescents between 14 and 17 were enrolled. Three adolescents completed all 4 weeks of the intervention while 2 completed only 3 weeks. Participants (n = 3) rated satisfaction on a 5-point Likert-type scale ranging from “not at all” satisfied (1) to “very much” satisfied (5). There was a positive response to the intervention (M = 4.28, SD = 0.55). Implementation was measured by a pre- and post-test for diabetes self-management self-efficacy. Participants (n = 3) demonstrated overall improvements in diabetes self-management self-efficacy (Z = -2.952, p = .007).
Implications for further Can-Do-Tude research are planned at a metropolitan diabetes center using updated technology including an application platform. Although the sample was small, findings indicate that the intervention can be conducted using a web-based format and there is initial evidence of improvement in self-efficacy for diabetes self-management.
The study used a multi-phase, multi-method approach. The first phase (alpha) of this study was a qualitative descriptive design to examine the intervention’s fidelity. Evaluation of performance was conducted by experts in the fields of MI, T1D, adolescence and/or online education. The second phase (beta) was a quantitative descriptive design conducted in order to evaluate feasibility by examining the acceptability (recruitment, retention and satisfaction) and implementation (diabetes self-management self-efficacy) to determine whether the intervention was appropriate for further testing.
First phase findings showed that the intervention passed all measures with the content experts (n = 6): it was functional, accurate, usable and secure. Improvements to the intervention were made based on reviewer recommendations. For the second phase 5 adolescents between 14 and 17 were enrolled. Three adolescents completed all 4 weeks of the intervention while 2 completed only 3 weeks. Participants (n = 3) rated satisfaction on a 5-point Likert-type scale ranging from “not at all” satisfied (1) to “very much” satisfied (5). There was a positive response to the intervention (M = 4.28, SD = 0.55). Implementation was measured by a pre- and post-test for diabetes self-management self-efficacy. Participants (n = 3) demonstrated overall improvements in diabetes self-management self-efficacy (Z = -2.952, p = .007).
Implications for further Can-Do-Tude research are planned at a metropolitan diabetes center using updated technology including an application platform. Although the sample was small, findings indicate that the intervention can be conducted using a web-based format and there is initial evidence of improvement in self-efficacy for diabetes self-management.
ContributorsPaul, Linda Louise (Author) / Komnenich, Pauline (Thesis advisor) / Spezia Faulkner, Melissa (Committee member) / Shaibi, Gabriel (Committee member) / Arizona State University (Publisher)
Created2017
Description
The pathogenesis of type 1 diabetes (T1D) is still not fully understood in the scientific community. Evidence has shown that viral infections are one of the important environmental factors associated with the disease development. Seven of the top T1D related viruses were selected to study the prevalence of viral humoral response in T1D patients using our innovative protein array platform called Nucleic Acid Programmable Protein Array (NAPPA). In this study, each viral gene was individually captured using various PCR based techniques, cloned into a protein expression vector, and assembled as the first version of T1D viral protein array. Humoral responses of IgG, IgA, and IgM were examined. Although each class of immunoglobulin generated a wide-range of reactivity, responses to various viral proteins from different proteins were observed. In summary, we captured most of the T1D related viral genes, established viral protein expression on the protein array, and displayed the serum response on the viral protein array. The successful progress will help to fulfill the long term goal of testing the viral infection hypothesis in T1D development.
ContributorsDavis, Amy Darlene (Author) / LaBaer, Joshua (Thesis director) / Qiu, Ji (Committee member) / Desi, Paul (Committee member) / Barrett, The Honors College (Contributor) / Department of Chemistry and Biochemistry (Contributor)
Created2013-05
ContributorsPerkins, Caitlin (Author) / Jacobs, Bertram (Thesis director) / Gile, Gillian (Committee member) / Barrett, The Honors College (Contributor) / School of Life Sciences (Contributor)
Created2023-05
ContributorsPerkins, Caitlin (Author) / Jacobs, Bertram (Thesis director) / Gile, Gillian (Committee member) / Barrett, The Honors College (Contributor) / School of Life Sciences (Contributor)
Created2023-05
Description
In completing this thesis project, I attempted to hypothesize the trigger in my own personal diagnosis of type 1 diabetes through literature research as well as further research on viruses and their contribution to autoimmune disorders. I had previously hypothesized that, based on my own family life, type 1 diabetes could possibly be a non-heritable disease despite its consistent inheritance pattern discovered by researchers; however, the research presented in this thesis project rejects this idea and supports the theory that I may have been previously susceptible to this disorder and would have developed type 1 diabetes naturally. There were multiple viruses discovered during the literature research conducted that could possibly have been triggers in the acceleration of my disease. The major link between enteroviruses and autoimmune disorders was discovered, as well as influenza A and SARS-COV-2 and this is explained further in this project.
ContributorsPerkins, Caitlin (Author) / Jacobs, Bertram (Thesis director) / Gile, Gillian (Committee member) / Barrett, The Honors College (Contributor) / School of Life Sciences (Contributor)
Created2023-05
Description
Type 1 diabetes (T1D) is the result of an autoimmune attack against the insulin-producing β-cells of the pancreas causing hyperglycemia and requiring the individual to rely on life-long exogenous insulin. With the age of onset typically occurring in childhood, there is increased physical and emotional stress to the child as well as caregivers to maintain appropriate glucose levels. The majority of T1D patients have antibodies to one or more antigens: insulin, IA-2, GAD65, and ZnT8. Although antibodies are detectable years before symptoms occur, the initiating factors and mechanisms of progression towards β-cell destruction are still not known. The search for new autoantibodies to elucidate the autoimmune process in diabetes has been slow, with proteome level screenings on native proteins only finding a few minor antigens. Post-translational modifications (PTM)—chemical changes that occur to the protein after translation is complete—are an unexplored way a self-protein could become immunogenic. This dissertation presents the first large sale screening of autoantibodies in T1D to nitrated proteins. The Contra Capture Protein Array (CCPA) allowed for fresh expression of hundreds of proteins that were captured on a secondary slide by tag-specific ligand and subsequent modification with peroxynitrite. The IgG and IgM humoral response of 48 newly diagnosed T1D subjects and 48 age-matched controls were screened against 1632 proteins highly or specifically expressed in pancreatic cells. Top targets at 95% specificity were confirmed with the same serum samples using rapid antigenic protein in situ display enzyme-linked immunosorbent assay (RAPID ELISA) a modified sandwich ELISA employing the same cell-free expression as the CCPA. For validation, 8 IgG and 5 IgM targets were evaluated with an independent serum sample set of 94 T1D subjects and 94 controls. The two best candidates at 90% specificity were estrogen receptor 1 (ESR1) and phosphatidylinositol 4-kinase type 2 beta (PI4K2B) which had sensitivities of 22% (p=.014) and 25% (p=.045), respectively. Receiver operating characteristic (ROC) analyses found an area under curve (AUC) of 0.6 for ESR1 and 0.58 for PI4K2B. These studies demonstrate the ability and value for high-throughput autoantibody screening to modified antigens and the frequency of Type 1 diabetes.
ContributorsHesterman, Jennifer (Author) / LaBaer, Joshua (Thesis advisor) / Borges, Chad (Committee member) / Sweazea, Karen (Committee member) / Mangone, Marco (Committee member) / Arizona State University (Publisher)
Created2022
Description
Type 1 diabetes is a metabolic disorder in which the pancreas produces little to no insulin due to the cells being destroyed by a person’s own body. A potential treatment for this disorder is the allogeneic transplantation of pancreatic beta cells. Unfortunately, this potential solution requires the use of immunosuppressants. For my project with the Weaver Lab, I will be assessing pseudoislet survival in macroencapsulation via injection molding. I will be analyzing survival and metabolic assays of the pseudoislets in the mold process. Pseudoislets in hydrogels usually undergo hypoxia-included cell death due to the diffusion distances oxygen has to travel. We will test the impact of macroencapsulation device geometry on hypoxia within encapsulated cells. I will be culturing pancreatic cells and encapsulating them in hydrogels. Macroencapsulation devices will be utilized to shield islets from the immune system and eliminate the need for immunosuppressants. In order to analyze the cells’ structure and to ensure their viability, confocal microscopy will be used. Staining for live cells will be done using calcein AM which produces green fluorescence and indicates live cells. Staining for dead cells on the other hand will be done using an ethidium homodimer which produces red fluorescence and indicates dead cells. To determine if the cells are metabolically active the Alamar Blue assay will be used.
ContributorsSaenz, Fidel Junior (Author) / Weaver, Jessica (Thesis director) / Emerson, Amy (Committee member) / Barrett, The Honors College (Contributor) / School of Life Sciences (Contributor)
Created2022-05