Matching Items (14)

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The Effect of Glucocorticoids on Insulin Resistance in Rat Skeletal Muscle via TXNIP

Description

Glucocorticoids are a class of corticosteroids that bind to glucocorticoid receptors
within cells that result in changes in the metabolism of carbohydrates and immune functions.
Ingesting glucocorticoids has

Glucocorticoids are a class of corticosteroids that bind to glucocorticoid receptors
within cells that result in changes in the metabolism of carbohydrates and immune functions.
Ingesting glucocorticoids has also been linked to insulin resistance, a main feature of Type 2
diabetes. Experiments including polymerase chain reaction, western blotting, and glycogen
synthase analysis were conducted to determine if exposure to higher doses of dexamethasone, a
glucocorticoid, induces insulin resistance in cultured rat skeletal muscle via interaction with
thioredoxin-interacting protein (TXNIP). Treatment with dexamethasone was shown to cause
mild increases in TXNIP while a definitive increase or decrease in insulin signaling was unable
to be determined.

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Agent

Created

Date Created
  • 2020-05

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The role of corticosterone in stress-induced suppression of innate immunity in the male house sparrow

Description

In wild birds, the stress response can inhibit the activity of the innate immune system, which serves as the first line of defense against pathogens. By elucidating the mechanisms which

In wild birds, the stress response can inhibit the activity of the innate immune system, which serves as the first line of defense against pathogens. By elucidating the mechanisms which regulate the interaction between stress and innate immunity, researchers may be able to predict when birds experience increased susceptibility to infections and can target specific mediators to mitigate stress-induced suppression of innate immune activity. Such elucidation is especially important for urban birds, such as the House Sparrow (Passer domesticus), because these birds experience higher pathogen prevalence and transmission when compared to birds in rural regions. I investigated the role of corticosterone (CORT) in stress-induced suppression of two measures of innate immune activity (complement- and natural antibody-mediated activity) in male House Sparrows. Corticosterone, the primary avian glucocorticoid, is elevated during the stress response and high levels of this hormone induce effects through the activation of cytosolic and membrane-bound glucocorticoid receptors (GR). My results demonstrate that CORT is necessary and sufficient for stress-induced suppression of complement-mediated activity, and that this relationship is consistent between years. Corticosterone, however, does not inhibit complement-mediated activity through cytosolic GR, and additional research is needed to confirm the involvement of membrane-bound GR. The role of CORT in stress-induced inhibition of natural antibody-mediated activity, however, remains puzzling. Stress-induced elevation of CORT can suppress natural antibody-mediated activity through the activation of cytosolic GR, but the necessity of this mechanism varies inter-annually. In other words, both CORT-dependent and CORT-independent mechanisms may inhibit natural antibody-mediated activity during stress in certain years, but the causes of this inter-annual variation are not known. Previous studies have indicated that changes in the pathogen environment or food availability can alter regulation of innate immunity, but further research is needed to test these hypotheses. Overall, my dissertation demonstrates that stress inhibits innate immunity through several mechanisms, but environmental pressures may influence this inhibitory relationship.

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Agent

Created

Date Created
  • 2017

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Targeted proteomics studies: design, development and translation of mass spectrometric immunoassays for diabetes and kidney disease

Description

In an effort to begin validating the large number of discovered candidate biomarkers, proteomics is beginning to shift from shotgun proteomic experiments towards targeted proteomic approaches that provide solutions to

In an effort to begin validating the large number of discovered candidate biomarkers, proteomics is beginning to shift from shotgun proteomic experiments towards targeted proteomic approaches that provide solutions to automation and economic concerns. Such approaches to validate biomarkers necessitate the mass spectrometric analysis of hundreds to thousands of human samples. As this takes place, a serendipitous opportunity has become evident. By the virtue that as one narrows the focus towards "single" protein targets (instead of entire proteomes) using pan-antibody-based enrichment techniques, a discovery science has emerged, so to speak. This is due to the largely unknown context in which "single" proteins exist in blood (i.e. polymorphisms, transcript variants, and posttranslational modifications) and hence, targeted proteomics has applications for established biomarkers. Furthermore, besides protein heterogeneity accounting for interferences with conventional immunometric platforms, it is becoming evident that this formerly hidden dimension of structural information also contains rich-pathobiological information. Consequently, targeted proteomics studies that aim to ascertain a protein's genuine presentation within disease- stratified populations and serve as a stepping-stone within a biomarker translational pipeline are of clinical interest. Roughly 128 million Americans are pre-diabetic, diabetic, and/or have kidney disease and public and private spending for treating these diseases is in the hundreds of billions of dollars. In an effort to create new solutions for the early detection and management of these conditions, described herein is the design, development, and translation of mass spectrometric immunoassays targeted towards diabetes and kidney disease. Population proteomics experiments were performed for the following clinically relevant proteins: insulin, C-peptide, RANTES, and parathyroid hormone. At least thirty-eight protein isoforms were detected. Besides the numerous disease correlations confronted within the disease-stratified cohorts, certain isoforms also appeared to be causally related to the underlying pathophysiology and/or have therapeutic implications. Technical advancements include multiplexed isoform quantification as well a "dual- extraction" methodology for eliminating non-specific proteins while simultaneously validating isoforms. Industrial efforts towards widespread clinical adoption are also described. Consequently, this work lays a foundation for the translation of mass spectrometric immunoassays into the clinical arena and simultaneously presents the most recent advancements concerning the mass spectrometric immunoassay approach.

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Agent

Created

Date Created
  • 2011

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Investigating the influence of food on reproductive physiology and gonad growth: urbanization as a natural experiment

Description

For animals that experience annual cycles of gonad development, the seasonal timing (phenology) of gonad growth is a major adaptation to local environmental conditions. To optimally time seasonal gonad growth,

For animals that experience annual cycles of gonad development, the seasonal timing (phenology) of gonad growth is a major adaptation to local environmental conditions. To optimally time seasonal gonad growth, animals use environmental cues that forecast future conditions. The availability of food is one such environmental cue. Although the importance of food availability has been appreciated for decades, the physiological mechanisms underlying the modulation of seasonal gonad growth by this environmental factor remain poorly understood.

Urbanization is characterized by profound environmental changes, and urban animals must adjust to an environment vastly different from that of their non-urban conspecifics. Evidence suggests that birds adjust to urban areas by advancing the timing of seasonal breeding and gonad development, compared to their non-urban conspecifics. A leading hypothesis to account for this phenomenon is that food availability is elevated in urban areas, which improves the energetic status of urban birds and enables them to initiate gonad development earlier than their non-urban conspecifics. However, this hypothesis remains largely untested.

My dissertation dovetailed comparative studies and experimental approaches conducted in field and captive settings to examine the physiological mechanisms by which food availability modulates gonad growth and to investigate whether elevated food availability in urban areas advances the phenology of gonad growth in urban birds. My captive study demonstrated that energetic status modulates reproductive hormone secretion, but not gonad growth. By contrast, free-ranging urban and non-urban birds did not differ in energetic status or plasma levels of reproductive hormones either in years in which urban birds had advanced phenology of gonad growth or in a year that had no habitat-related disparity in seasonal gonad growth. Therefore, my dissertation provides no support for the hypothesis that urban birds begin seasonal gonad growth because they are in better energetic status and increase the secretion of reproductive hormones earlier than non-urban birds. My studies do suggest, however, that the phenology of key food items and the endocrine responsiveness of the reproductive system may contribute to habitat-related disparities in the phenology of gonad growth.

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Agent

Created

Date Created
  • 2014

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Dose and delivery method impact cognitive outcome of Ethinyl Estradiol administration in the surgically menopausal rat

Description

Ethinyl estradiol, (EE) a synthetic, orally bio-available estrogen, is the most commonly prescribed form of estrogen in oral contraceptives (Shively, C., 1998), and is found in at least 30 different

Ethinyl estradiol, (EE) a synthetic, orally bio-available estrogen, is the most commonly prescribed form of estrogen in oral contraceptives (Shively, C., 1998), and is found in at least 30 different contraceptive formulations currently prescribed to women (Curtis et al., 2005). EE is also used in hormone therapies prescribed to menopausal women, such as FemhrtTM (Simon et al., 2003). Thus, EE is prescribed clinically to women at ages ranging from puberty through reproductive senescence. Here, in two separate studies, the cognitive effects of cyclic or tonic EE administration following ovariectomy (Ovx) were evaluated in young, female rats. Study I assessed the cognitive effects of low and high doses of EE, delivered tonically via a subcutaneous osmotic pump. Study II evaluated the cognitive effects of low, medium, and high doses of EE administered via a daily subcutaneous injection. For these studies, the low and medium doses correspond to the range of doses currently used in clinical formulations, and the high dose corresponds to the range of doses prescribed to a generation of women between 1960 and 1970, when oral contraceptives first became available. For each study, cognition was evaluated with a battery of maze tasks tapping several domains of spatial learning and memory. At the highest dose, EE treatment impaired multiple domains of spatial memory relative to vehicle treatment, regardless of administration method. When given cyclically at the low and medium doses, EE did not impact working memory, but transiently impaired reference memory during the learning phase of testing. Of the doses and regimens tested here, only EE at the highest dose impaired several domains of memory; this was seen for both cyclic and tonic regimens. Cyclic and tonic delivery of low EE, a dose that corresponds to doses used in the clinic today, resulted in transient and null impairments, respectively, on cognition.

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Agent

Created

Date Created
  • 2012

Investigation of DNA methylation in obesity and its underlying insulin resistance

Description

Obesity and its underlying insulin resistance are caused by environmental and genetic factors. DNA methylation provides a mechanism by which environmental factors can regulate transcriptional activity. The overall goal of

Obesity and its underlying insulin resistance are caused by environmental and genetic factors. DNA methylation provides a mechanism by which environmental factors can regulate transcriptional activity. The overall goal of the work herein was to (1) identify alterations in DNA methylation in human skeletal muscle with obesity and its underlying insulin resistance, (2) to determine if these changes in methylation can be altered through weight-loss induced by bariatric surgery, and (3) to identify DNA methylation biomarkers in whole blood that can be used as a surrogate for skeletal muscle.

Assessment of DNA methylation was performed on human skeletal muscle and blood using reduced representation bisulfite sequencing (RRBS) for high-throughput identification and pyrosequencing for site-specific confirmation. Sorbin and SH3 homology domain 3 (SORBS3) was identified in skeletal muscle to be increased in methylation (+5.0 to +24.4 %) in the promoter and 5’untranslated region (UTR) in the obese participants (n= 10) compared to lean (n=12), and this finding corresponded with a decrease in gene expression (fold change: -1.9, P=0.0001). Furthermore, SORBS3 was demonstrated in a separate cohort of morbidly obese participants (n=7) undergoing weight-loss induced by surgery, to decrease in methylation (-5.6 to -24.2%) and increase in gene expression (fold change: +1.7; P=0.05) post-surgery. Moreover, SORBS3 promoter methylation was demonstrated in vitro to inhibit transcriptional activity (P=0.000003). The methylation and transcriptional changes for SORBS3 were significantly (P≤0.05) correlated with obesity measures and fasting insulin levels. SORBS3 was not identified in the blood methylation analysis of lean (n=10) and obese (n=10) participants suggesting that it is a muscle specific marker. However, solute carrier family 19 member 1 (SLC19A1) was identified in blood and skeletal muscle to have decreased 5’UTR methylation in obese participants, and this was significantly (P≤0.05) predicted by insulin sensitivity.

These findings suggest SLC19A1 as a potential blood-based biomarker for obese, insulin resistant states. The collective findings of SORBS3 DNA methylation and gene expression present an exciting novel target in skeletal muscle for further understanding obesity and its underlying insulin resistance. Moreover, the dynamic changes to SORBS3 in response to metabolic improvements and weight-loss induced by surgery.

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Agent

Created

Date Created
  • 2017

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iDECIDE: An Evidence-based Decision Support System for Improving Postprandial Blood Glucose by Accounting for Patient’s Preferences

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

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.

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Created

Date Created
  • 2017

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Diffuse Brain Injury Incites Sexual Differences and Hypothalamic-Pituitary-Adrenal Axis Disruptions

Description

Of the 2.87 million traumatic brain injuries (TBI) sustained yearly in the United States, 75% are diffuse injuries. A single TBI can have acute and chronic influences on the neuroendocrine

Of the 2.87 million traumatic brain injuries (TBI) sustained yearly in the United States, 75% are diffuse injuries. A single TBI can have acute and chronic influences on the neuroendocrine system leading to hypothalamic-pituitary-adrenal axis (HPA) dysregulation and increased affective disorders. Preliminary data indicate TBI causes neuroinflammation in the hippocampus, likely due to axonal damage, and in the paraventricular nucleus of the hypothalamus (PVN), where no axonal damage is apparent. Mechanisms regulating neuroinflammation in the PVN are unknown. Furthermore, chronic stress causes HPA dysregulation and glucocorticoid receptor (GR)-mediated neuroinflammation in the PVN. The goal of this project was to evaluate neuroinflammation in the HPA axis and determine if GR levels change at 7 days post-injury (DPI).

Adult male and female Sprague Dawley rats were subjected to midline fluid percussion injury. At 7 DPI, half of each brain was post-fixed for immunohistochemistry (IBA-1) and half biopsied for gene/protein analysis. IBA-1 staining was analyzed for microglia activation via skeleton analysis in the hypothalamus and hippocampus. Extracted RNA and protein were used to quantify mRNA expression and protein levels for GRs. Data indicate increased microglia cell number and decreased endpoints/cell and process length in the PVN of males, but not females. In the dentate gyrus, both males and females have an increased microglia cell number after TBI, but there is also an interaction between sex and injury in microglia presentation, where males exhibit a more robust effect than females. Both sexes have significant decreases of endpoints/cell and process length. In both regions, GR protein levels decreased for injured males, but in the hippocampus, GR levels increased for injured females. Data indicate that diffuse TBI causes alterations in microglia morphology and GR levels in the hypothalamus and hippocampus at 7 DPI, providing a potential mechanism for HPA axis dysregulation at a sub-acute time point.

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Agent

Created

Date Created
  • 2019

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On the cognitive impact of endogenous and exogenous hormone exposures across the lifespan

Description

Women are exposed to numerous endogenous and exogenous hormones across the lifespan. In the last several decades, the prescription of novel hormonal contraceptives and hormone therapies (HTs) have resulted in

Women are exposed to numerous endogenous and exogenous hormones across the lifespan. In the last several decades, the prescription of novel hormonal contraceptives and hormone therapies (HTs) have resulted in aging women that have a unique hormone exposure history; little is known about the impact of these hormone exposures on short- and long- term brain health. The goal of my dissertation was to understand how lifetime hormone exposures shape the female cognitive phenotype using several innovative approaches, including a new human spatial working memory task, the human radial arm maze (HRAM), and several rodent menopause models with variants of clinically used hormone treatments. Using the HRAM (chapter 2) and established human neuropsychological tests, I determined males outperformed females with high endogenous or exogenous estrogen levels on visuospatial tasks and the spatial working memory HRAM (chapter 3). Evaluating the synthetic estrogen in contraceptives, ethinyl estradiol (EE), I found a high EE dose impaired spatial working memory in ovariectomized (Ovx) rats, medium and high EE doses reduced choline-acetyltransferace-immunoreactive neuron population estimates in the basal forebrain following Ovx (chapter 4), and low EE impaired spatial cognition in ovary-intact rats (chapter 5). Assessing the impact of several clinically-used HTs, I identified a window of opportunity around ovarian follicular depletion outside of which the HT conjugated equine estrogens (CEE) was detrimental to spatial memory (chapter 6), as well as therapeutic potentials for synthetic contraceptive hormones (chapter 9) and bioidentical estradiol (chapter 7) during and after the transition to menopause. Chapter 6 and 7 findings, that estradiol and Ovx benefitted cognition after the menopause transition, but CEE did not, are perhaps due to the negative impact of ovarian-produced, androstenedione-derived estrone; indeed, blocking androstenedione’s conversion to estrone prevented its cognitive impairments (chapter 8). Finally, I determined that EE combined with the popular progestin levonorgestrel benefited spatial memory during the transition to menopause, a profile not seen with estradiol, levonorgestrel, or EE alone (chapter 9). This work identifies several cognitively safe, and enhancing, hormonal treatment options at different time points throughout female aging, revealing promising avenues toward optimizing female health.

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Agent

Created

Date Created
  • 2015

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Novel biomarkers and genetic variants for type 2 diabetes in Latinos

Description

The shape of glucose response and one hour (1-hr) glucose during an oral glucose tolerance test (OGTT) are emerging biomarkers for type 2 diabetes. The purpose of this study was

The shape of glucose response and one hour (1-hr) glucose during an oral glucose tolerance test (OGTT) are emerging biomarkers for type 2 diabetes. The purpose of this study was two-fold: (1) to investigate the utility of these novel biomakers to differentiate type 2 diabetes risk in Latino youth, and (2) to examine the genetic determinants in a Latino population.

Data from the ASU Arizona Insulin Registry (AIR) registry and the USC Study of Latino Adolescents at Risk for diabetes project were used to test the cross-sectional and prospective utility of novel biomarkers to identify youth at risk for type 2 diabetes. Pediatric and adult data from the ASU AIR registry were assessed to examine the association of single nucleotide polymorphisms (SNPs) with type 2 diabetes risk. Three KCNQ1 SNPs (rs151290; rs2237892; rs2237895) were examined as novel genetic variants for type 2 diabetes in Latinos.

Latino youth with a biphasic response in the AIR registry exhibited significantly better β-cell function (P < 0.05) compared to youth with a monophasic response. Additionally, Latino youth with a 1-hr glucose ≥155 mg/dL exhibited a significantly greater decline in β-cell function over 8 years compared with the <155 mg/dL group (β=-327.8±126.2, P = 0.01). Moreover, a 1-hr glucose ≥155 mg/dL was associated with a 2.5 times greater risk for developing prediabetes over time (P = 0.0001). 1-hr glucose was the most powerful predictor of prediabetes (area under the receiver operating characteristic curve=0.73) when compared to the traditional biomarkers including HbA1c (0.58), fasting (0.67), and 2-hr glucose (0.64). Two KCNQ1 SNPs (rs151290 and rs2237892) exhibited significant associations with type 2 diabetes risk factors. For the novel glycemic markers, 15 SNPs were associated with the glucose response curve, while 18 SNPs were associated with 1-hr glucose.

These data suggest that glucose response curve and 1-hr glucose during an OGTT independently differentiate type 2 diabetes risk among Latino youth. Furthermore, it was successful to replicate the association of type 2 diabetes risk with 2 KCNQ1 SNPs in a Latino population. Data suggest that novel glycemic biomarkers are influenced by genetic background in this high-risk population.

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Agent

Created

Date Created
  • 2015