Theses and Dissertations from UMD
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New submissions to the thesis/dissertation collections are added automatically as they are received from the Graduate School. Currently, the Graduate School deposits all theses and dissertations from a given semester after the official graduation date. This means that there may be up to a 4 month delay in the appearance of a give thesis/dissertation in DRUM
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Item Effects of exercise and inflammation on circulating microparticles(2024) Heilman, James; Prior, Steven J.; Kinesiology; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Circulating microparticles (MPs), a subset of extracellular vesicles, have been implicated as novel biomarkers connected to vascular dysfunction. As such, they may contribute to atherosclerosis, hypertension, and other conditions leading to cardiovascular disease. MPs are involved in cell-to-cell communication in response to apoptosis and activation of the immune and inflammatory response, transferring their contents to nearby cells and effectively spreading each condition. The objective of this dissertation was to explore how circulating MP number and function are affected by stimuli such as diet and exercise. Our first study examined how post-prandial inflammation caused by a high-fat meal affects circulating MP number and function in young, healthy adults. We determined that a high fitness level may have a protective effect against the inflammatory load posed by a high-fat meal. The second study determined the effects of acute high-intensity interval aerobic exercise versus acute moderate intensity continuous aerobic exercise on circulating MP number and function in overweight versus lean recreationally active adults. We found that MPs and arterial stiffness in overweight individuals are differentially impacted by the type of acute exercise. Our findings suggest that overweight individuals undergo a greater inflammatory response following high-intensity exercise compared to lean. The third study investigated the effects of a 6-month aerobic exercise training program on circulating MP counts and function in previously sedentary older adults. While we found no effect of the exercise training program on MPs, we provide insight into how improvements in cardiovascular fitness as well as higher exercise intensities may be needed to see changes in MP number and function following aerobic exercise training in older adults. For the first time, we have shown that both dietary inflammation and acute exercise can significantly impact MP function. Furthermore, we have shown that fitness status and body composition play important roles in determining MP number and function after each stimulus. Our findings provide novel insight into how MPs contribute to various types of inflammation as well as how they may be used as biomarkers to measure the progression of cardiovascular disease.Item Metabolic Profiling of Brain Microvascular Endothelial Cells: Investigating the Role of Sex, Stress, APOE Genotype, and Exercise in Alzheimer's Disease Risk(2024) Weber, Callie; Clyne, Alisa M; Bioengineering; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Alzheimer’s disease (AD) is the 7th leading cause of death in the United States, yet there are still no effective treatments to prevent or slow the progression of the disease. AD develops from a combination of genetic and lifestyle risk factors including female sex, elevated stress hormone exposure, the apolipoprotein (APOE) ε4 genotype, and a sedentary lifestyle. In order to better identify the manifestations of AD, it is vital to understand how each of these risk factors impact brain health and lead to neurological dysfunction associated with AD. Brain microvascular endothelial cells (BMEC) line the blood vessels of the brain and have specialized tight junctions designed to strictly regulate nutrient and waste transfer between the blood and the brain. Two of the early indicators of AD development are breakdown of the tight junctions and whole brain glucose hypometabolism. Since BMEC form the first line of defense for the brain against neurotoxic compounds in the blood and are responsible for glucose transport to the rest of the brain, the overarching goal of this thesis is to understand how female sex, elevates stress hormone exposure, the APOE ε4 genotype, and a sedentary lifestyle induce breakdown of tight junction proteins and glucose hypometabolism in BMEC. I first demonstrate that female sex exacerbates endothelial dysfunction in response to high levels of a stress hormone, Angiotensin II (AngII). Specifically, I show that in response to AngII, female endothelial cells increase oxidative stress and inflammatory responses while male endothelial cells do not. Next, I used CRISPR/Cas9 to generate a set of induced pluripotent stem cells (iPSC) homozygous for the APOE ε3 and ε4 genotype and differentiated them into BMEC (hiBMEC). Using the hiBMEC I showed the APOE ε4 genotype induces barrier deficiencies that are partially mediated through reduced levels of protein deacetylase Sirtuin 1 (SIRT1), and that the APOE ε4 genotype causes glucose hypometabolism through decreased insulin signaling. Finally, by adding serum from sedentary and exercise trained individuals to genotype-matched hiBMEC, I show that APOE ε3 and ε4 hiBMEC have divergent responses to treatment with serum from sedentary and exercise trained individuals. Treatment with exercise trained serum increases SIRT1 and glycolytic enzymes compared to sedentary serum, while exercise trained serum decreases SIRT1 and glycolytic enzymes in APOE ε4 hiBMEC compared to sedentary serum. The work described in this thesis gives a fundamental, mechanistic understanding to the roles of female sex, stress hormone exposure, the APOE ε4 genotype, and a sedentary lifestyle in BMEC dysfunction and hypometabolism, giving insight into how these factors contribute to AD development and progression.Item ACUTE EXERCISE INDUCED MICROSTRUCTURAL AND FUNCTIONAL CHANGES IN THE HIPPOCAMPUS OF OLDER ADULTS(2023) Callow, Daniel; Carson, Jerome J; Neuroscience and Cognitive Science; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Declining memory function is a common complaint of aging adults and a primary symptom of mild cognitive impairment (MCI) and Alzheimer’s disease (AD). The hippocampus is often the first brain area to exhibit noticeable deficits in age and pathologically-related cognitive decline and is a necessary structure for proper memory function. More specifically, the dentate gyrus (DG) and the third cornu ammonis area (CA3) of the hippocampus directly support mnemonic discrimination (MD), which is the process of reducing interference among new representations and distinctly encoding them as independent memories. Poor MD is associated with age and is a presymptomatic biomarker of cognitive decline and is believed to result from reduced neurogenesis, angiogenesis, and synaptogenesis within the DG/CA3 subregion of the hippocampus. While causes and treatments for memory decline remain elusive, lifestyle interventions, especially physical activity, have received attention as cost-effective and safe means of ameliorating and potentially preventing cognitive decline in a growing aging population. Animal and human studies suggest exercise benefits the hippocampal structure, preserving neurogenesis and angiogenesis in aging rodents and macrostructure and memory in older adults. However, the mechanisms by which exercise affects the human hippocampus remains a significant knowledge gap in the field and is a critical aspect in understanding the long-term impact exercise has on the aging hippocampus. To better address this gap, researchers have begun implementing acute exercise studies, which allow for greater control of non-exercise-related factors, are cheaper and more time efficient to conduct than training studies, and can predict and inform training-related adaptations. Unfortunately, limitations in the study designs, population tested, specificity of cognitive tasks, and spatial resolution of human imaging techniques have posed significant barriers to our understanding of how acute exercise relates to healthy brain aging at the functional and microstructural levels. Therefore, the objective of this dissertation was to expand our understanding of how acute aerobic exercise alters the function and microstructure of the aging hippocampus. Three within-subject studies were conducted comparing the relationship between a 30-minute bout of moderate to vigorous intensity aerobic exercise vs seated rest on MD performance, hippocampal microstructure, and high-resolution hippocampal-subfield microstructure and functional activity in healthy older adults. In study one, acute exercise preserved MD performance compared to decrements exhibited after seated rest in a pre and post-condition study design. In study two, a post-condition-only study design, acute exercise elevated microstructural diffusion within the hippocampus, indicative of a hippocampal neuroinflammatory response and upregulation of neurotrophic factors. Finally, in study three, a post-condition-only study design, we found that acute exercise resulted in lower MD, suppressed MD-related DG/CA3 network hyperactivity (indicative of healthier network function), and led to higher DG/CA3 extracellular diffusion. However, these neuroimaging-based correlates of hippocampal neuroplasticity and network function were not associated with differences in MD performance. These findings suggest that higher-intensity acute exercise can alter memory performance and stimulate neuroplasticity and neurotrophic cascades within the hippocampus and the DG/CA3 subfield, potentially via different mechanisms. Furthermore these results give insight into the immediate neurotrophic and behavioral effects of acute moderate to vigorous intensity aerobic exercise in older adults and provide new methods and tools for better understanding if and how exercise promotes healthy brain aging. Finally, these initial findings lay a foundation for optimizing exercise prescription and identifying future effective exercise treatments.Item Sex- and Race-Based Differences in the Effects of Acute and Chronic Exercise on Vascular Function and Circulating MicroRNA(2021) Sapp, Ryan M; Hagberg, James M; Kinesiology; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Cardiovascular disease (CVD) is the leading global cause of death. Disparities in CVD development exist, with greater rates observed in men than women and in African Americans (AA) than Caucasian Americans (CA). It is crucial to determine the molecular mechanisms underlying these disparities in order to formulate preventative strategies. Regular aerobic exercise reduces CVD risk, while acute exercise is a useful stimulus to reveal impairments in cardiovascular function not apparent at rest. This dissertation utilizes approaches to identify sex- and race-based differences in vascular function within young, healthy individuals, indicative of future CVD risk, including the use of acute exercise as a cardiovascular stimulus and the exercise-trained individual as a model of superior cardiovascular health. Aim #1 shows that exercise training is associated with beneficial effects of the circulating factors in serum on vascular endothelial cells, in a sex-specific manner, suggesting that circulating factors are differently affected by exercise training in men and women. Aim #2 shows that endothelial function and central arterial stiffness respond similarly to acute exercise in AA and CA. Carotid arterial compliance, however, is increased only in CA during exercise recovery. MicroRNAs (miRs) are epigenetic modulators of gene expression implicated in CVD development. Blood-borne circulating miRs (ci-miRs) are paracrine/endocrine molecules and preclinical biomarkers, yet sex- and race-based differences in ci-miRs are understudied. Additionally, ci-miRs are altered with exercise and may mediate training-induced vascular adaptations. Aim #3 of this dissertation reveals that the resting concentrations of select vascular-related ci-miRs differ based on sex and exercise training status, but not race. In response to acute exercise however, several anti-inflammatory ci-miRs increased significantly in CA, but not AA. Additionally, the changes in one anti-inflammatory ci-miR exhibited race-specific correlations with the changes in carotid arterial compliance identified in Aim #2. Aim #4 investigates the hypothesis that exercise elicits endothelial integral damage, and that this may mediate changes in vascular function and endothelial-derived ci-miRs. By measuring different endothelial-derived circulating factors, we show that exercise likely does not cause endothelial cell detachment or apoptosis. Thus, ci-miR are likely released via a selective method of secretion, rather than passively leaking from damaged endothelium.Item Understanding and Retraining the Causal Attributions for Exercise Intenders(2019) Singpurwalla, Darius; Iso-Ahola, Seppo E; Kinesiology; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Given that ~50% of all exercise intenders will fall into the intention-behavior gap (i.e., a situation where people fail to act on their intentions), it is necessary to identify the constructs and/or theories that can explain the discord between intention and behavior (i.e., the intention-behavior gap). For this purpose, the present research was conducted through two studies that were designed to test the efficacy of causal attributions as a means to reduce the intention-behavior discord. The first study collected information from 952 individuals on their exercise behavior and their associated causal attributions over a six-week period. The findings from this study included: (1) those individuals who fell into the intention-behavior gap made self-serving attributions for their exercise failure; (2) Weiner’s model accurately predicted several of the affective and cognitive responses to exercise behavior for the sample of exercise intenders; and (3) causal attributions were not found to be effective moderators of the intention-behavior relationship. The second study was an experiment that tested whether an attribution retraining intervention could improve exercise behavior for a sample of sedentary, exercise intenders (n=200). Results of this study were mixed as the intervention appeared to have been able to modify one of the targeted attributional dimensions (control), but the effect was not strong enough to change the exercise behavior of the participants in the experimental group. It is suggested that attributions may not be able to reduce the gap because they represent conscious deliberations of the behavior, while sustained exercise is based on nonconscious processing of relevant information to make exercise an automatic behavior.Item EXERCISE IS MEDICINE? A CRITICAL EXAMINATION OF THE PROMOTION OF EXERCISE FOR MENTAL HEALTHCARE(2018) Maier, Julie; Jette, Shannon L; Kinesiology; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Increasingly, physical activity is being promoted as a way to prevent or treat a range of chronic health conditions, including mental illness. In this dissertation, I utilize an ecological framework and draw upon feminist theories to explore why it is that physical activity is being used as a form of (mental health) therapy in this current moment, as well as the benefits and shortcomings of physical activity in preventing or treating mental illness. In particular, I focus on the ways in which gendered discourses and norms shape the physical activity experiences of women with mental illness. The project entails three separate, yet related, phases: 1) Extensive review of popular and academic literature to contextualize the “exercise is medicine” movement; 2) Assessment of the American College of Sports Medicine and American Medical Association’s “Exercise is Medicine” initiative; and 3) In-depth qualitative interviews with women with obsessive compulsive disorder (OCD). The results of my three empirical examinations suggest that physical activity can be a beneficial form of mental health treatment, or a valued part of one’s life and identity more generally. However, too often the limits to physical activity’s effectiveness in treating particular mental illnesses is downplayed, as is attention to the potential harms that can come from being physically active. At times, exercise is even positioned as a “cure”, or superior to psychopharmaceuticals in treating mental illnesses, such as depression. Such enthusiasm toward exercise’s potential therapeutic value can be seen to be, in part, the result of the current neoliberal, healthist moment in which individual responsibility, hard work, and natural remedies are valued over that which is considered easy, quick, or synthetic (Crawford, 1980, Lupton, 1995, Fullagar, 2017). This is not to suggest that physical activity cannot play a vital role in helping people with mental illness, but better messages and more resources are needed to make it accessible, safe, and meaningful to this population. I conclude the dissertation by providing suggestions as to how this can be accomplished.Item Exercise training-associated differences in circulating microRNAs and serum-induced endothelial cell migration rate(2015) Sapp, Ryan M.; Hagberg, James M; Kinesiology; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Cardiovascular Diseases (CVDs) are the primary source of global mortality and morbidity. The initial steps of CVD development occur in the endothelium. MicroRNAs (miRNAs) have recently emerged as novel regulators of cardiovascular physiology and pathology. Interestingly, regular aerobic exercise acts to prevent CVDs and also regulates miRNAs in the circulation (ci-miRNAs). The purpose of this study was to determine the effects of serum from highly active and sedentary, young, healthy individuals on migration rate of endothelial cells in vitro. Secondarily, CVD-associated ci-miRNAs in serum were compared between groups. The results of this study represent a novel way by which sedentary behavior may act as an early risk for CVD development before the appearance of other classic risk factors. RT-qPCR array analysis identified nine ci-miRNAs as > 4-fold differentially expressed in serum of trained versus inactive subjects, though more subjects are needed before any conclusions about ci-miRNA differences can be made.Item Breast Cancer Type 1 Susceptibility Protein is a Critical Regulator of Skeletal Muscle Lipid Metabolism(2013) Jackson, Kathryn Campbell; Spangenburg, Espen E; Kinesiology; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)This dissertation research consists of three investigations in an effort to determine how circulating estrogens affect skeletal muscle lipid metabolism. Loss of circulating estrogens results in significant increases in visceral fat mass and intramuscular lipids (IMCL). These increases in lipid storage are strongly associated with an elevated risk of developing type 2 diabetes. The first investigation examined how the loss of circulating estrogens alters skeletal muscle metabolic function. Ovariectomy (OVX) resulted in significantly higher visceral fat mass and fatty acid sarcolemmal transporter content, which corresponded with elevated IMCL. Skeletal muscle in the OVX group exhibited lower acyl carnitine species suggesting impaired lipid flux through the mitochondria. Lastly, mitochondrial oxygen consumption rates were impaired in OVX skeletal muscle fibers. The results from this study gave rise to a search to identify an estrogen- sensitive mechanism that regulated lipid transport into the mitochondria. Study two determined for the first time that the BRCA1 protein, which is encoded by an estrogen-sensitive gene, is present and functions as an integral regulator of lipid metabolism in skeletal muscle. Specifically, BRCA1 binds to acetyl CoA carboxylase in response to acute exercise. The in vitro induction of decreases in BRCA1 expression resulted in higher IMCL content, reduced mitochondrial oxygen consumption rates, and elevated reactive oxygen species production. Surprisingly, no differences in BRCA1 content were detected between males and females. In the final study, an inducible, skeletal-muscle specific, BRCA1 KO mouse was developed. Ablation of BRCA1 in skeletal muscle resulted in exercise intolerance and the development of kyphosis. Contrary to our hypothesis, loss of functional BRCA1 in skeletal muscle attenuated the negative metabolic consequences of chronic high fat diet exposure. Collectively, these data provide strong rationale that BRCA1 is an important regulator of skeletal muscle metabolic function and further provide evidence that BRCA1 function is critical in multiple tissues across the body.Item Effects of chronic exercise on global DNA methylation and epigenetic factors in sperm and testes of mice.(2012) Marini, Michael Paul; Roth, Stephen M; Kinesiology; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)Epigenetic alterations of DNA affect DNA transcription and translation. These alterations occur frequently, however environmental exposures induce epigenetic changes to DNA that would otherwise remain in autoregulatory stasis. This study aimed to look at exercise as a possible environmental factor causing epigenetic change. The study also assessed global DNA methylation in sperm, which may transmit such epigenetic changes via the paternal germ line. Measurements were compared between groups of mice that engaged in chronic exercise or remained sedentary. This study also examined enzymes causing methylation shifts in sperm by comparing levels of mRNA expression of genes responsible for new DNA methylation - DNMT3A, DNMT3B and DNMT3L - in testes. These results were compared between exercise and sedentary cohorts, and in progeny to assess heritability of epigenetic change. The results showed a significant difference in global methylation in the sperm between exercise and sedentary cohorts and a concomitant increase in gene expression in multiple DNMT3 genes.Item TELOMERE DYNAMICS AND REGULATION: EFFECTS OF CHRONIC EXERCISE, ACUTE EXERCISE, AND OXIDATIVE STRESS(2011) Ludlow, Andrew Todd; Roth, Stephen M; Kinesiology; Digital Repository at the University of Maryland; University of Maryland (College Park, Md.)This dissertation research is comprised of three studies each examining the effects of chronic exercise, acute exercise, or oxidative stress on telomere biology. Exercise training and physical activity have previously been associated with telomere maintenance, but the underlying mechanisms of this association are unclear. The majority of studies to date have been performed in immune cells; however, the findings from these cells may not reflect telomere biology in other tissues. Since exercise is a multi-organ stimulus we sought to describe the effect of exercise on telomere biology in multiple tissues, with a particular focus on skeletal muscle. Study #1 showed that the effect of chronic voluntary exercise on telomere length in CAST/Ei mice is tissue specific. Exercise was `telo-protective' (i.e., maintained telomere length) in cardiac and liver tissues, while telomere shortening was observed in skeletal muscle of exercised animals compared to sedentary and young mice. Study #2 was performed to elucidate the responses to acute exercise that could underlie the paradoxical response of telomere length in skeletal muscle to exercise training. This study revealed that the MAPK pathway appears to be related to the expression of telomere binding proteins in response to acute exercise. In skeletal muscle, p38 MAPK mediated a decrease in gene expression of telomere binding proteins, providing insight into a possible mechanism for eventual telomere shortening in response to chronic exercise. The results of study #2 indicate that the early cellular responses to exercise may accumulate (i.e., repeat bout effect) and underlie the shortened telomere length in skeletal muscle. Study #3 sought to determine if reactive oxygen species were a plausible mechanism of telomere shortening in adult skeletal muscle fibers, as no mechanism to date has been elucidated for telomere shortening in this tissue. Study #3 showed that oxidative stress is a potent telomere- shortening stimulus in skeletal muscle fibers of mice and that telomere binding protein expression was also significantly affected by oxidative stress. In total these results indicate that although chronic exercise attenuates telomere shortening in most tissues, skeletal muscle demonstrates a unique contradictory response likely due to its reaction to oxidative stress.