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- Creators: Arizona State University
- Creators: Hackney Price, Jennifer
- Member of: Theses and Dissertations
- Member of: Barrett, The Honors College Thesis/Creative Project Collection
Description
ABSTRACT Despite significant advancements in drug therapy, cardiovascular disease (CVD) is still the leading cause of death in the United States. Given this, research has begun to seek out alternative approaches to reduce CVD risk. One of these alternative approaches is Vitamin D supplementation. Current research has shown a link between Vitamin D status and CVD risk in both healthy and diseased populations. Among the possible mechanisms is a positive effect of Vitamin D on vascular endothelial function, which can be measured with noninvasive techniques such as flow-mediated dilation (FMD) of conduit vessels using high-resolution ultrasound. This dissertation is comprised of two studies. The first examines whether Vitamin D supplementation can improve FMD in older adults within a time period (two weeks) associated with peak increases in plasma Vitamin D concentrations after a single-dose supplementation. The second examines the effect of Vitamin D supplementation in people with Rheumatoid Arthritis (RA). The reason for looking at an RA population is that CVD is the leading cause of early mortality in people with RA. In the first study 29 Post-Menopausal Women received either 100,000 IU of Vitamin D3 or a Placebo. Their FMD was measured at baseline and 2 weeks after supplementation. After 2 weeks there was a significant increase in FMD in the Vitamin D group (6.19 + 4.87 % to 10.69 + 5.18 %) as compared to the Placebo group (p=.03). In the second study, 11 older adults with RA were given 100,000 IU of Vitamin D or a Placebo. At baseline and one month later their FMD was examined as well as plasma concentrations of Vitamin D and tumor necrosis factor-alpha; (TNF-alpha;). They also filled out a Quality of Life Questionnaire and underwent a submaximal exercise test on the treadmill for estimation of maximum oxygen uptake (VO2max). There was no significant change in FMD in Vitamin D group as compared to the Placebo group (p=.721). Additionally, there was no significant improvement in either plasma Vitamin D or TNF-alpha; in the Vitamin D group. There was however a significant improvement in predicted VO2max from the submaximal exercise test in the group receiving Vitamin D (p=.003). The results of these studies suggest that a single 100,000 IU dose of Vitamin D can enhance FMD within two week in older adults, but that a similar dose may not be sufficient to increase FMD or plasma Vitamin D levels in older adults with RA. A more aggressive supplementation regimen may be required in this patient population.
ContributorsRyan, Dana Meredith (Author) / Gaesser, Glenn A (Thesis advisor) / Rizzo, Warren (Committee member) / Martin, Keith (Committee member) / Larkey, Linda (Committee member) / Chisum, Jack (Committee member) / Arizona State University (Publisher)
Created2012
Description
This study examined whether cognitive behavioral therapy and mindfulness interventions affect positive (PA) and negative affect (NA) reports for patients with rheumatoid arthritis (RA) before, during, and after stress induction. The study also investigated the effects of a history of recurrent depression on intervention effects and testing effects due to the Solomon-6 study design utilized. The 144 RA patients were assessed for a history of major depressive episodes by diagnostic interview and half of the participants completed a laboratory study before the intervention began. The RA patients were randomly assigned to 1 of 3 treatments: cognitive behavioral therapy for pain (P), mindfulness meditation and emotion regulation therapy (M), or education only attention control group (E). Upon completion of the intervention, 128 of the RA patients participated in a laboratory session designed to induce stress in which they were asked to report on their PA and NA throughout the laboratory study. Patients in the M group exhibited dampened negative and positive affective reactivity to stress, and sustained PA at recovery, compared to the P and E groups. PA increased in response to induced stress for all groups, suggesting an "emotional immune response." History of recurrent depression increased negative affective reactivity, but did not predict reports of PA. RA patients who underwent a pre-intervention laboratory study showed less reactivity to stressors for both NA and PA during the post-intervention laboratory study. The M intervention demonstrated dampened emotional reactions to stress and lessened loss of PA after stress induction, displaying active emotion regulation in comparison to the other groups. These findings provide additional information about the effects of mindfulness on the dynamics of affect and adaptation to stress in chronic pain patients.
ContributorsArewasikporn, Anne (Author) / Zautra, Alex J (Thesis advisor) / Davis, Mary C. (Committee member) / Karoly, Paul (Committee member) / Arizona State University (Publisher)
Created2012
Description
The role of climate change, as measured in terms of changes in the climatology of geophysical variables (such as temperature and rainfall), on the global distribution and burden of vector-borne diseases (VBDs) remains a subject of considerable debate. This dissertation attempts to contribute to this debate via the use of mathematical (compartmental) modeling and statistical data analysis. In particular, the objective is to find suitable values and/or ranges of the climate variables considered (typically temperature and rainfall) for maximum vector abundance and consequently, maximum transmission intensity of the disease(s) they cause.
Motivated by the fact that understanding the dynamics of disease vector is crucial to understanding the transmission and control of the VBDs they cause, a novel weather-driven deterministic model for the population biology of the mosquito is formulated and rigorously analyzed. Numerical simulations, using relevant weather and entomological data for Anopheles mosquito (the vector for malaria), show that maximum mosquito abundance occurs when temperature and rainfall values lie in the range [20-25]C and [105-115] mm, respectively.
The Anopheles mosquito ecology model is extended to incorporate human dynamics. The resulting weather-driven malaria transmission model, which includes many of the key aspects of malaria (such as disease transmission by asymptomatically-infectious humans, and enhanced malaria immunity due to repeated exposure), was rigorously analyzed. The model which also incorporates the effect of diurnal temperature range (DTR) on malaria transmission dynamics shows that increasing DTR shifts the peak temperature value for malaria transmission from 29C (when DTR is 0C) to about 25C (when DTR is 15C).
Finally, the malaria model is adapted and used to study the transmission dynamics of chikungunya, dengue and Zika, three diseases co-circulating in the Americas caused by the same vector (Aedes aegypti). The resulting model, which is fitted using data from Mexico, is used to assess a few hypotheses (such as those associated with the possible impact the newly-released dengue vaccine will have on Zika) and the impact of variability in climate variables on the dynamics of the three diseases. Suitable temperature and rainfall ranges for the maximum transmission intensity of the three diseases are obtained.
Motivated by the fact that understanding the dynamics of disease vector is crucial to understanding the transmission and control of the VBDs they cause, a novel weather-driven deterministic model for the population biology of the mosquito is formulated and rigorously analyzed. Numerical simulations, using relevant weather and entomological data for Anopheles mosquito (the vector for malaria), show that maximum mosquito abundance occurs when temperature and rainfall values lie in the range [20-25]C and [105-115] mm, respectively.
The Anopheles mosquito ecology model is extended to incorporate human dynamics. The resulting weather-driven malaria transmission model, which includes many of the key aspects of malaria (such as disease transmission by asymptomatically-infectious humans, and enhanced malaria immunity due to repeated exposure), was rigorously analyzed. The model which also incorporates the effect of diurnal temperature range (DTR) on malaria transmission dynamics shows that increasing DTR shifts the peak temperature value for malaria transmission from 29C (when DTR is 0C) to about 25C (when DTR is 15C).
Finally, the malaria model is adapted and used to study the transmission dynamics of chikungunya, dengue and Zika, three diseases co-circulating in the Americas caused by the same vector (Aedes aegypti). The resulting model, which is fitted using data from Mexico, is used to assess a few hypotheses (such as those associated with the possible impact the newly-released dengue vaccine will have on Zika) and the impact of variability in climate variables on the dynamics of the three diseases. Suitable temperature and rainfall ranges for the maximum transmission intensity of the three diseases are obtained.
ContributorsOkuneye, Kamaldeen O (Author) / Gumel, Abba B (Thesis advisor) / Kuang, Yang (Committee member) / Smith, Hal (Committee member) / Thieme, Horst (Committee member) / Nagy, John (Committee member) / Arizona State University (Publisher)
Created2018
Description
Bexarotene is a commercially produced drug commonly known as Targetin presecribed to treat cutaneous T-cell lymphoma (CTCL). Bex mimics the actions of natural 9-cis retinoic acid in the body, which are derived from Vitamin A in the diet and boost the immune system. Bex has been shown to be effective in the treatment of multiple types of cancer, including lung cancer. However, the disadvantages of using Bex include increased instances of hypothyroidism and excessive concentrations of blood triglycerides. If an analog of Bex can be developed which retains high affinity RXR binding similar to the 9-cis retinoic acid while exhibiting less interference for heterodimerization pathways, it would be of great clinical significance in improving the quality of life for patients with CTCL. This thesis will detail the biological profiling of additional novel (Generation Two) analogs, which are currently in submission for publication, as well as that of Generation Three analogs. The results from these studies reveal that specific alterations in the core structure of the Bex "parent" compound structure can have dramatic effects in modifying the biological activity of RXR agonists.
ContributorsYang, Joanna (Author) / Jurutka, Peter (Thesis director) / Wagner, Carl (Committee member) / Hibler, Elizabeth (Committee member) / Barrett, The Honors College (Contributor)
Created2012-05
Description
Bexarotene (Bex) is a FDA-approved drug used to treat cutaneous T-cell lymphoma (CTCL). It binds with high affinity to the retinoid-X-receptor (RXR), a nuclear receptor implicated in numerous biological pathways. Bex may have the potential to attenuate estrogenic activity by acting as an estrogen receptor alpha (ERα) signaling antagonist, and can therefore be used to treat ERα-positive cancers, such as breast cancer. Using dual luciferase reporter assays, real-time qRT-PCR, and metabolic proliferation assays, the anti-estrogenic properties of Bex were ascertained. However, since Bex produces numerous contraindications, select novel RXR drug analogs were also evaluated. Results revealed that, in luciferase assays, Bex could significantly (P < 0.01) inhibit the transcriptional activity of ERα, so much so that it rivaled ER pan-antagonist ZK164015 in potency. Bex was also able to suppress the proliferation of two breast cancer cell models, MCF-7 and T-47D, and downregulate the expression of an estrogen receptor target gene (A-myb), which is responsible for cell proliferation. In addition, novel analogs A30, A33, A35, and A38 were evaluated as being more potent at inhibiting ERE-mediated transcription than Bex at lower concentrations. Analogs A34 and A35 were able to suppress MCF-7 cell proliferation to a degree comparable to that of Bex. Inhibition of T-47D cell proliferation, by contrast, was best achieved by analogs A34 and A36. For those with ERα – positive breast cancer who are refractory to current chemotherapeutics used to treat breast cancer, Bex and its analogs may prove to be useful alternative options.
ContributorsBains, Supreet (Author) / Jurutka, Peter (Thesis director) / Hackney Price, Jennifer (Committee member) / School of Life Sciences (Contributor) / Barrett, The Honors College (Contributor)
Created2016-12
Description
Bexarotene is a Food and Drug administration (FDA)-approved therapeutic used in the treatment of cutaneous T-cell lymphoma (CTCL). However, bexarotene therapy causes significant side effects like hyperlipidemia and hypothyroidism due to crossover activity with retinoic acid receptor (RAR), thyroid hormone receptor (TR), and liver X receptor (LXR) signaling, respectively. More recently bexarotene has shown promise to reverse neurodegeneration, improve cognition and decrease levels of amyloid- β in transgenic mice expressing familial Alzheimer’s disease (AD) mutations. Bexarotene is a high affinity ligand for the retinoid X receptor (RXR) that heterodimerizes with the liver- X- receptors (LXR) and with peroxisome proliferator-activated receptor-gamma (PPARϒ) to control cholesterol efflux, inflammation, and transcriptionally upregulates the production of apolipoprotein (ApoE) in the brain. Enhanced ApoE expression may promote clearance of soluble Aβ peptides from the brain and reduce Aβ plaques, thus resolving both amyloid pathology and cognitive deficits. The present study assessed the potential of bexarotene and a group of 62 novel rexinoids to bind and activate RXR using a series of biological assays and screening methods, including: 1) a mammalian two-hybrid system (M2H) and an 2) Retinoid X Receptor response element (RXRE)-mediated reporter assays in cultured human cells. Moreover, Liver X Receptor response element (LXRE)-mediated luciferase assays were performed to analyze the ability of the novel analogs to activate LXRE - directed transcription, and to induce ApoE messenger ribonucleic acid (mRNA) in U87 glial cells. Furthermore, the most potent analogs were analyzed via quantitative polymerase chain reaction (qPCR) to determine efficacy in modulating expression of two critical tumor suppressor genes, activating transcription factor 3 (ATF3) and early growth response 3 (EGR3). Results from these multiple assays indicate that the panel of RXR ligands contains compounds with a range of activities, with some analogs capable of binding to RXR with higher affinity than others, and in some cases upregulating ApoE expression to a greater extent than bexarotene. The data suggests that minor modifications to the bexarotene core chemical structure may yield novel analogs possessing an equal or greater capacity to activate RXR and may be useful as therapeutic agents against CTCL and Alzheimer’s disease.
ContributorsReshi, Sabeeha Mushtaq (Author) / Jurutka, Peter (Thesis advisor) / Wagner, Carl (Committee member) / Marshall, Pamela (Committee member) / Arizona State University (Publisher)
Created2023
Description
Autoimmunity develops when the immune system targets self-antigens within the body. Rheumatoid arthritis (RA) is a common autoimmune disease, and its progression is characterized by pro-inflammatory immune cells rapidly proliferating, migrating, and infiltrating joint tissue to provoke inflammation. In order to fulfill this taxing autoreactive response, an increase in energy metabolism is required by immune cells, such as dendritic cells (DCs). Therefore, a shift in DC energy reliance from the Krebs cycle toward glycolysis occurs. This metabolic shift phenotypically transitions DCs from anti-inflammatory properties toward an aggressive pro-inflammatory phenotype, in turn activating pro-inflammatory T cells and promoting RA pathogenesis. If the disease persists uncontrollably, further complications and eventual joint dysfunction can occur. Although, clinically approved drugs can prevent RA progression, they require frequent administration for temporary symptom relief. Furthermore, current approved biological products for RA are not known to have a direct modulatory effect on immunometabolism. Given that cellular metabolism controls immune cell function, this work aims to harness perturbations within RA immune cell energy metabolism and utilizes it as a therapeutic target by reprogramming immune cell metabolism via the delivery of metabolite-based particles. The two-time delivery of these particles reduced RA inflammation in a RA collagen-induced arthritis (CIA) mouse model and generated desired responses with long-term effects. Specifically, this work was achieved by:
Aim 1 – developing and delivering metabolite-based polymeric microparticles synthesized from the Krebs cycle metabolite, alpha-ketoglutarate (aKG; termed paKG MPs) to DCs to modulate their energy metabolism and promote anti-inflammatory properties (in context of RA).
Aim 2 – exploiting the encapsulation ability of paKG MPs to inhibit DC glycolysis in the presence of the CIA self-antigen (collagen type II (bc2)) for the treatment of RA in CIA mice. Herein, paKG MPs encapsulating a glycolytic inhibitor and bc2 induce an anti-inflammatory DC phenotype in vitro and generate suppressive bc2-specific T cell responses and reduce paw inflammation in CIA mice.
ContributorsMangal, Joslyn Lata (Author) / Acharya, Abhinav P (Thesis advisor) / Florsheim, Esther B (Committee member) / Wu, Hsin-Jung Joyce (Committee member) / Anderson, Karen (Committee member) / Arizona State University (Publisher)
Created2022
Description
Since its isolation from a rhesus monkey in the Zika forest of Uganda in 1947, Zika virus (ZIKV) has spread into many parts of the world, causing major epidemics, notably in the Americas and some parts of Europe and Asia. The flavivirus ZIKV is primarily transmitted to humans via the bite of infectious adult female Aedes mosquitoes. In the absence of effective treatment or a safe and effective vaccine against the disease, control efforts are focused on effective vector management to reduce the mosquito population and limit human exposure to mosquito bites. The work in this thesis is based on the use of a mathematical model for gaining insight into the transmission dynamics of ZIKV in a population. The model, which takes the form of a deterministic system of nonlinear differential equations, is rigorously analyzed to gain insight into its basic qualitative features. In particular, it is shown that the disease-free equilibrium of the model is locally-asymptotically stable whenever a certain epidemiological quantity (known as the reproduction number, denoted by R0) is less than unity. The epidemiological implication of this result is that a small influx of ZIKV-infected individuals or vectors into the community will not generate a large outbreak if the anti-ZIKV control strategy (or strategies) adopted by the community can reduce and maintain R0 to a value less than unity. Numerical simulations of the model, using data relevant to ZIKV transmission dynamics in Puerto Rico, shows that a control strategy that solely focuses on killing immature mosquitoes (using highly efficacious larvicides) can lead to the elimination of ZIKV if the larvicide coverage (i.e., proportion of breeding sites treated with larvicides) is high enough (over 90%). Such elimination is also feasible using a control strategy that solely focuses on the use of insect repellents (as a means of personal protection against mosquito bites) if the coverage level of the insect repellent usage in the community is high enough (at least 70%). However, it is also shown that although the use of adulticides (i.e., using insecticides to kill adult mosquitoes) can reduce the reproduction number (hence, disease burden), it fails to reduce it to a value less than unity, regardless of coverage level. Thus, unlike with the use of larvicide-only or repellent-only strategies, the population-wide implementation of an adulticide-only strategy is unable to lead to ZIKV elimination. Finally, it is shown that the combined (integrated pest management) strategy, based on using all three aforementioned strategies, is the most effective approach for combatting ZIKV in the population. In particular, it is shown that even a moderately-effective level of this strategy, which entails using only 50% coverage of both larvicides and adulticides, together with about 45% coverage for a repellent strategy, will lead to ZIKV elimination. This moderately-effective combined strategy seems attainable in Puerto Rico.
ContributorsUrcuyo, Javier (Author) / Gumel, Abba (Thesis director) / Hackney Price, Jennifer (Committee member) / School of Mathematical and Natural Sciences (Contributor, Contributor) / Barrett, The Honors College (Contributor)
Created2019-05
Description
Rheumatoid Arthritis (RA) is an autoimmune disorder where the body mistakenly attacks healthy joints. This in turn causes inflammation resulting in pain and swelling. It is very important to get RA accurately diagnosed and treated as early as possible. Similarly, with any disease: the longer it is left untreated, the more damage it can cause. RA can cause irreversible joint damage leading to disability. The purpose of this study is to determine if oral microbiome can be used as an additional criterion to aid in diagnosing RA. Several oral microbes have already been identified as biomarkers for RA in saliva. In this study, 10 participants were recruited: 6 diagnosed with RA and 4 Healthy as a control. Two subgroups of RA were done within this study; those diagnose with a positive Rheumatoid Factor (RF) and those diagnose with a negative RF. These subgroups were then compared in order to determine the validity of using certain microbes as biomarkers for RA even when different diagnostic criteria were met. The microbe Parahaemolyticus had the largest measure of effect, showing the greatest potential for statistically significant results with a larger sample size. If we can work narrow to down specific microbes to be undoubtedly higher in abundance with already diagnosed RA patients when comparing to healthy participants, this will be a gamechanger. Not only could we give a higher sense of confidence with the diagnosis of RA, but this could streamline RA diagnosis.
ContributorsNunez, Celeste (Author) / Marshall, Pamela (Thesis director) / Hackney Price, Jennifer (Committee member) / Kizer, Elizabeth (Committee member) / College of Health Solutions (Contributor) / Barrett, The Honors College (Contributor)
Created2020-12