Medicine and Health Sciences Commons^™

Impacts Of Perinatal Oxycodone Exposed Offspring In Early Adolescence, Adrian Flores

Theses & Dissertations

The Opioid Epidemic has been a point of public health interest for the last twenty years. In this time, use of prescription opioids has grown exponentially, including use by pregnant women. The initial crisis has been focused on mitigating immediate problems such as lowering the significant loss of life in overdoses and providing support to cessation. Despite these advancements a separate phenomenon is on the rise: The rise in neonatal opioid withdrawal syndrome in neonatal care and associated challenges for these children as they age.

Currently preclinical research and epidemiological data suggests that exposed children are at risk for experiencing …

The Adaptor Protein P66shc Governs Central Nervous System Cell Metabolism And Resistance To Aβ Toxicity, Asad Lone

Electronic Thesis and Dissertation Repository

Alzheimer’s disease (AD), a progressive and irreversible neurodegenerative disorder, and is the leading cause of dementia worldwide. It has been posited that AD is caused by the gradual deposition of toxic amyloid-b (Ab) plaques in the brain- that cause oxidative stress and eventually leads to neuronal death and synaptic loss. However, multiple therapies that either interfere with the production, or enhance the removal of Ab from the brain, have ultimately failed to slow or prevent AD. With the ever-increasing burden of AD worldwide, there exists an urgent need for novel therapeutic targets. The adult human brain is an energy demanding …

Gpr75 Deficiency Attenuates High Fat Diet-Driven Obesity And Glucose Intolerance, Sakib Hossain

NYMC Student Theses and Dissertations

Recently, a collaboration between Regeneron Pharmaceuticals and the Schwartzman-Garcia labs at New York Medical College published an exome sequencing study of individuals across the United Kingdom, United States, and Mexico which concluded that individuals possessing non-functioning, truncated mutations to the orphan g protein coupled receptor (GPCR), GPR75, had lower BMI and 54% reduced likelihood of obesity. The present study was undertaken to fully characterize the metabolic phenotype of Gpr75 deficient mice when fed a high fat diet (HFD) and explore potential mechanisms by which GPR75 activation links to increased adiposity and decreased glucose tolerance. After 14 weeks of HFD-feeding we …

Utilizing Ultra-Performance Chromatography High-Resolution Mass Spectrometry To Investigate Fatty Acid Mediated Antibiotic Tolerance, Brittni Woodall

Doctoral Dissertations

The lipid membrane is the first component necessary to sustain life. To maintain homeostasis, segregate cellular machinery, provide protection from the environment, and reproduce, an organism must establish a boundary in which the processes can occur. Throughout the last two decades, research has propelled our knowledge of lipid membranes much beyond original hypotheses. Once thought of to be static and uniform, the understanding of the lipid membrane has evolved to encompass a structure that is responsive, unique, and intricately constructed by the organism itself. By chance or by choice, organisms adapt the lipid membrane according to the environment for which …

How Does The Ergogenic Benefits, Consumption, And Overall Perspective Of Caffeine Differ Between Athletes In Different Sports?, Steven Laflamme

Undergraduate Honors Theses

Caffeine has been a very popular ergogenic aid that has been widely used by athletes at all levels of sports performance (Pickering & Grgic, 2019). The effects of caffeine have shown performance-enhancing symptoms among athletes along with multiple cognitive benefits such as reaction time and overall mood during exercise. According to McArdle, Katch, and Katch (2015), caffeine acts as a stimulant for the central nervous system. It acts as a blocker for adenosine receptors and allows for more neuron firing in the brain as well as increased blood flow from the heart to other body systems. In interest of caffeine’s …

The Effects Of Sex On Zebrafish Bone Metabolism, Simon Bagatto

Williams Honors College, Honors Research Projects

I investigated the effects of diet and sex on zebrafish bone metabolism. Zebrafish were subjected to either a high-calorie or low-calorie diet over a five-week period. After this diet, zebrafish scales were used to measure alkaline phosphatase (ALP) and tartrate-resistant acid phosphatase (TRAP) enzyme activity with a fluorescent substrate. The enzyme activities were markers of the osteoblasts (ALP) and the osteoclasts (TRAP). These data were compared among sex and diet of the zebrafish using a repeated measures ANOVA statistical test. I also measured the number of resorption lacunae per scale (another indicator of osteoclast activity). The results showed higher TRAP …

Ankyrin Dependent Mitochondrial Function And Bioenergetics In The Heart, Janani Subramaniam, Janani Subramaniam

Dissertations & Theses (Open Access)

ANK2 mutations in patients are associated with numerous arrhythmias, cardiomyopathies, and other heart defects. In the heart, AnkB, the protein encoded by ANK2, clusters relevant ion channels and cell adhesion molecules in several important domains; however, its role at Mitochondria Associated ER/SR Membranes (MAMs) has yet to be investigated. MAMs are crucial to mitochondrial function and metabolism and are signaling hubs implicated in various cardiac pathologies. Among several functions, these sites mediate the direct transfer of calcium from the ER/SR to the mitochondria to modulate ATP synthesis. Given that mitochondrial function and energy production are paramount to cardiovascular heath, …

Metabolic Foundations Of Exercise-Induced Cardiac Growth., Kyle Fulghum

Electronic Theses and Dissertations

Regular aerobic exercise promotes physiological cardiac growth, which is an adaptive response thought to enable the heart to meet higher physical demands. Cardiac growth involves coordination of catabolic and anabolic activities to support ATP generation, macromolecule biosynthesis, and myocyte hypertrophy. Although previous studies suggest that exercise-induced reductions in cardiac glycolysis are critical for physiological myocyte hypertrophy, it remains unclear how exercise influences the many interlinked pathways of metabolism that support adaptive remodeling of the heart. In this thesis project, we tested the general hypothesis that aerobic exercise promotes physiological cardiac growth by coordinating myocardial metabolism to promote glucose-supported anabolic pathway …

Western Diet-Like Culture Conditions And Oxidative Stress On A Cell Model Of Non-Alcoholic Fatty Liver Disease, Celina M. Valvano

Electronic Thesis and Dissertation Repository

Non-alcoholic fatty liver disease (NAFLD) is a major health burden in the Western world, as the Western diet (WD) appears to be the driving force of this disease. However, the individual contributions of the diet and the impacts of their individual metabolism are currently ill-defined. This study used HepG2 cells to understand the impact of the individual components of WD in early NAFLD development under basal insulin levels. Specifically, nutrient-induced changes in reactive oxygen species (ROS) and signaling pathways, such as sterol regulatory element binding proteins (SREBPs), were examined to identify the root cause of steatosis development. High-fat and WD-exposed …

The Molecular Mechanisms Of Hepatic Mitochondrial Dysfunction In Growth-Restricted Offspring With Hyperlipidemia, Shelby L. Oke

Electronic Thesis and Dissertation Repository

Intrauterine growth restriction (IUGR) is a pathological condition characterized by low birth weight and poor organ development. Growth of the fetal liver is often compromised at the expense of other vital organs, thereby leading to hepatic dyslipidemia in the affected offspring. As such, epidemiological studies suggest an inverse relationship between birth weight and long-term metabolic health, while the occurrence of postnatal catch-up growth can exacerbate this relationship. Animal studies have shown that IUGR offspring exhibit impaired mitochondrial function, which likely contributes to the later development of metabolic pathologies. That said, the molecular mechanisms by which mitochondria are affected remain unknown. …

Characterizing The Roles Of Cannabinoid Receptor 1 & 2 In Zebrafish Behavior, Metabolism, And Seizure-Induced Activity, Kayci Kimmons

Honors Theses

Epileptic disorders like Dravet Syndrome require novel studies to determine the most ideal treatment. New research linking the endocannabinoid system (ECS) to epileptic disorders is arising, but there is still much to be discovered about the function and regulatory impact of the endocannabinoid system and its receptors in epilepsies like Dravet. In this study, knockout models of larval and adult zebrafish (Danio rerio) were used to investigate the roles of cannabinoid receptors 1 & 2 in behavior, brain mitochondrial metabolism, and seizure-induced activity following exposure to THC and CBD. Larval zebrafish which lacked cannabinoid receptor 1 exhibited increased …

Targeting Metabolic Adaptations To Anti-Angiogenic Therapy In Ovarian Cancer, Deanna M. Glassman, Deanna Glassman

Dissertations & Theses (Open Access)

ABSTRACT

Background: Ovarian cancer is the most lethal gynecologic malignancy. Despite modest clinical improvements with anti-VEGF antibody (AVA) therapy, adaptive resistance is nearly ubiquitous and additional therapeutic options are limited. A dependence on glutamine metabolism, via the enzyme glutaminase (GLS), is a known mechanism of adaptive resistance.

Purpose: To assess the efficacy of a glutaminase inhibitor as a means of exploiting the metabolic vulnerability of glutamine dependence that develops as a result of adaptive resistance to AVA therapy.

Experimental Design: We used a glutaminase inhibitor (GLSi) synthesized at MD Anderson Cancer Center for all in vitro and in vivo experiments. …

Severe Hypoxia Up-Regulates Gluconeogenesis In Daphnia, Morad C. Malek

Undergraduate Honors Theses

Hypoxia is a significant low oxygen state that has complex and diverse impacts on organisms. In aerobes, various adaptive responses to hypoxia are observed that vary depending on the level of oxygen depletion and previous adaptation, hence the continued attention to hypoxia as an important abiotic stressor. Adaptive responses to hypoxia are primarily governed by the hypoxia-inducible factors (HIFs), which activate downstream genetic pathways responsible for oxygen transport and metabolic plasticity. In aquatic habitats, oxygen availability can vary greatly over time and space. Therefore, aquatic organisms’ adaptation to hypoxia is likely pervasive, especially in genotypes originating from waterbodies prone to …

The Role Of Obesity In Macrophage-Mediated Mechanisms Promoting Early-Onset Colon Cancer., Katharina Marietta Scheurlen

Electronic Theses and Dissertations

Early-onset colon cancer (EOCC) is a leading cause of cancer death among people younger than 50 years of age in the United States and is associated with metabolic dysfunction and obesity. Anti-inflammatory tumor-associated macrophages (TAM) and low Peroxisome Proliferator Activated Receptor Gamma (PPARγ) gene expression in colon cancer (CC) tissue promote tumor progression and decreased patient survival. Obesity-related hormones, such as leptin and adiponectin, have the potential to affect gene expression in TAM to promote CC progression and thereby link obesity and EOCC. The aim of this project was to identify target genes in human CC and to investigate the …

Evaluation Of Hippocampal Allostatic Load-Associated Factors In Animal Models Of Post-Traumatic Stress Disorder: Relevance To Human Ptsd, Dennis Parker Kelley

LSU Doctoral Dissertations

Post-traumatic stress disorder (PTSD) is associated with elevated allostatic load, nearly double the risk for metabolic syndrome, reduced hippocampal volume, and contextual memory processing deficits. Emerging evidence suggests that these stress effects may predispose individuals to the development of PTSD, and there is a known relationship between chronic stress and metabolic dysfunction. In this work, we utilized two rat models of PTSD to explore these connections. We used an acute predator odor stressor to investigate the relationship between PTSD-like behaviors and mitochondrial dysfunction in the hippocampus of rats, and we observed that conditioned place avoidance was associated with reduced mitochondrial …

Characterization And Manipulation Of O-Glcnacylation In Granulosa Cells Of Bovine Ovarian Antral Follicles, Abigail Marie Maucieri

Graduate College Dissertations and Theses

Glucose is widely recognized as the preferred energy substrate for metabolism by granulosa cells (GCs). Yet in most cells, 2-5% of glucose is shunted through the hexosamine biosynthesis pathway (HBP) for O-linked N-acetylglucosaminylation (O-GlcNAcylation). O-GlcNAcylation is an evolutionarily-conserved, post-translational process that modifies serine and threonine residues on a variety of proteins. O-GlcNAcylation is also considered a nutrient sensor that can regulate cellular processes such as metabolism, signal transduction, and proliferation. In this respect, O-GlcNAcylation may be similar to, and possibly mediate, AMP-activated protein kinase (AMPK) signaling and its nutrient-sensing actions. However, the occurrence of O-GlcNAcylation and its relative importance to …

The Relationship Between Sarcopenia And Diabetes Among Different Ethnic Groups, Rachel K. Williams

Honors Undergraduate Theses

Sarcopenia and diabetes are two conditions that reflect ongoing changes in global health trends: aging and obesity. Sarcopenia affects approximately 10-40% of the global population and type II diabetes affects around 415 million individuals (6.28% globally), with obesity contributing to a majority of the cases. Currently, approximately 9.3% of the population (727 million individuals) is aged 65 years or older; this number is predicted to reach 16% of the global population (around 1.5 billion individuals) in 2050. Many developed countries are undergoing demographic population pyramid rearrangements whereby an increasingly aging population must be supported by a shrinking youth cohort. Sarcopenia …

Regulation Of Skeletal Muscle Plasticity By The Gut Microbiome, Taylor R. Valentino

Theses and Dissertations--Physiology

Recent evidence suggests that the gut microbiome could play a role in skeletal muscle plasticity, providing novel treatments for muscle wasting diseases and/or performance enhancements. I first sought to determine if the gut microbiome is necessary for skeletal muscle adaptation to exercise. Forty-two, four-month old, female C57Bl/6J underwent nine weeks of weighted wheel running or remained in cage with a locked wheel, without or without the administration of antibiotics (treated). In response to wheel running, I found that antibiotic depletion of the microbiome led to a blunted hypertrophic response in the soleus muscle as measured by normalized muscle wet weight …

Varied Levels Of Fructose Consumption Induce Physiological, Cognitive, And Mitochondrial Alterations In Aged Female Rats, Emilie L. Bjerring

Theses and Dissertations

Since the 1970s, fructose consumption has dramatically increased within the United States, as well as the world. While adolescents tend to be the largest consumer of fructose, mostly seen in the form of sugary beverages, the consequences of a high fructose diet started in adulthood can also have severe implications on physiological parameters as well as cognition. Several studies have linked fructose consumption to metabolic syndrome, a clustering of symptoms related to overall health, with particular emphasis placed on obesity, type II diabetes, and the relationship with Alzheimer’s Disease. These findings largely stem from the outcomes of studies on cognition, …

Nicotine And Cotinine: Microbial Modulators Of The Immune Response, Jourdan Lakes

Theses and Dissertations--Chemistry

The consumption of tobacco products is a known contributor to a variety of health conditions and disease pathologies including cardiovascular and lung diseases. In addition to these well-known pathological effects of tobacco use, it has been established recently that tobacco consumption as well as nicotine consumption alone results in distinct, dysbiotic perturbations to the enteric microflora of the gastrointestinal tract. Previous research into the intestinal microbiome has demonstrated that these microbes are active contributors to the maintenance of a homeostatic and tolerogenic environment within the host. In fact, the presence of our enteric microflora is necessary for the proper development …

Understanding The Protumorigenic Functions Of St6gal1 In Glioblastoma Stemness And Metabolism, Sajina Gc

All ETDs from UAB

Glioblastoma (GBM) is a rare but deadly cancer with median survival of just 15 months despite of aggressive treatment. Advancement in novel treatment modalities is hindered by its heterogeneous nature, which includes subsets of neural stem cell-like brain tumor initiating cells (BTICs) that are highly tumorigenic and therapy-resistant. bgalactoside a-2,6-sialyltransferase 1 (ST6Gal1) is elevated in most tumors including in normal and neoplastic stem cells. ST6Gal1 imparts oncogenic phenotypes such as invasion, apoptosis evasion, therapy resistance, TIC maintenance among others via sialylation of critical receptors like, Fas, TNFR1, EGFR and more. Yet ST6Gal1 led regulation of BTIC specific cell surface proteins …

The Role Of Dock3 In Normal Skeletal Muscle Function And Metabolism, Adrienne Samani

All ETDs from UAB

DOCK (dedicator of cytokinesis) are proteins of an 11-member family of typical guanine exchange factors (GEFs) expressed almost exclusively in the brain and spinal cord. Human pathogenic DOCK3 variants have been identified to cause debilitating neuromuscular phenotypes such as muscle hypotonia, ataxia, and intellectual disability. Our lab identified DOCK3 as being strongly upregulated in Duchene muscular dystrophy (DMD), specifically in the skeletal muscles of DMD patient and mouse skeletal muscles. Global Dock3 KO mice on the dystrophin-deficient background exacerbated skeletal muscle and cardiac phenotypes. Similarly, DOCK3 KO mice appeared to have poor muscle architecture, locomotive activity, reduced myogenic fusion, impaired …

Deletion Of Period Genes Exacerbates Diet-Induced Obesity In Female, But Not Male, Mice, Elizabeth Kantra

Theses and Dissertations--Biology

Sex differences in obesity in mice are mediated by differential responses of circadian rhythms to high-fat feeding in males and females. Other studies also showed circadian Period genes regulate diet-induced obesity in mice. In this study, we investigated the role of the Period genes in regulating sex differences in obesity. Male and female C57BL/6J wild type, Per1/2 KO, and Per1/2/3 KO mice were housed in 12L:12D and fed high-fat diet for 12 weeks. We found a striking sex difference in obesity such that disabling the Period genes exacerbated adiposity in female, but not male, mice. Increased adiposity in female Period …

Lxr Acts As A Differentiator In The Regulation Of Fas And G6pdh Gene Expression Under Insulin Resistant Conditions, Jaafar Hachem

Dissertations

Diabetes is a chronic disease that effects 10 percent of the world’s population and causes more than 1.5 million deaths a year and billions of dollars in associated health care cost. It can lead to very serious complications such as renal failure, liver cirrhosis, heart attack, and vision loss. The most common type of diabetes is type 2 diabetes. Type 2 diabetes arises when blood glucose levels remain chronically high due to insulin resistance. The reason for this elevation is due to the failure of insulin to allow tissues to uptake glucose causing problems in subsequent metabolic pathways. Over the …

Trim24 Promotes Mammary Tumor Development By Upregulating Metabolic Reducing Power, Shucheng Miao

Dissertations & Theses (Open Access)

Metabolic reprograming is an emerging hallmark of cancer cells. Changes in cellular metabolism can contribute to cancer cell survival and tumor progression. Tripartite motif-containing protein 24 (TRIM24) is an E3 ligase for p53, a nuclear receptor co-regulator, and a histone reader. Over expression of TRIM24 correlates with poor overall survival of breast cancer patients. Previously, our lab created a mouse model that conditionally over-expresses (COE) TRIM24 protein in mammary epithelia (Trim24^COE) and develops carcinosarcoma or metaplastic mammary tumors (70% of all Trim24^COE tumors), a rare and aggressive triple-negative subtype called metaplastic TNBC in humans (MpBC). RNA-sequencing …

Metabolic-Epigenetic Regulation Of Macrophage Polarization., Jordan T. Noe

Electronic Theses and Dissertations

Tumor-associated macrophages polarized to an M2 phenotype (M2-TAMs) promote neo-angiogenesis, tumor-stromal matrix remodeling, and immuno-evasion, which, collectively, contribute to immunotherapeutic resistance and reduced cancer patient survival. Highly glycolytic “Warburg” cancer cells produce lactate that independently drives naïve M0→immunosuppressive M2 (M0→M2) macrophage polarization, but the mechanisms have not been fully elucidated. The atypical cytokine macrophage migration inhibitory factor (MIF) is a fundamental underlying requirement for immunosuppressive M2 macrophage polarization. Still, it is unknown whether a molecular link exists between lactate-supported and MIF-dependent M2 macrophage polarization. Using a combination of gene expression assays, chromatin immunoprecipitation, and metabolomic analyses, we identified that M2 …

Mri Of Structural & Functional Changes Associated With Western Diet Consumption, Lauren M. Smith

Electronic Thesis and Dissertation Repository

The Western diet (WD) is a high-fat, high-sugar diet increasingly common in the Western world and is associated with adverse effects in many organs, though the mechanisms behind these changes are unclear. Magnetic resonance imaging (MRI) techniques that provide structural and functional information non-invasively were used to investigate the effect of the WD on the liver and placenta in a guinea pig model.

The WD leads to a manifestation of the metabolic syndrome in the liver known as non-alcoholic fatty liver disease (NAFLD). Fat-fraction MRI was used to confirm the onset of NAFLD in a guinea pig model fed a …

Homeostatic T Cell Receptor Interactions With Self-Peptide Tune Cd4+ T Cell Function, Juliet Marie Bartleson

Arts & Sciences Electronic Theses and Dissertations

Homeostatic T Cell Receptor Interactions with Self-Peptide Tune CD4+ T Cell Function

by

Juliet Marie Bartleson

Doctor of Philosophy in Biology and Biomedical Sciences

Immunology

Washington University in St. Louis, 2021

Professor Paul M. Allen, Chair

Mature CD4+ T cells circulate throughout peripheral secondary lymphoid organs using their T cell receptor (TCR) to surveil peptide presented on major histocompatibility complex class II molecules (pMHC) in search of cognate, antigenic peptide. In the absence of an immune challenge, however, the TCR is continuously interacting with self-pMHC, which induces a relatively weak TCR signal known as tonic signaling. These homeostatic TCR:self-pMHC interactions …

Mechanisms And Therapeutic Interventions For Breast Cancer-Induced Fatigue And Mitochondrial Dysfunction, David Andrew Stanton

Graduate Theses, Dissertations, and Problem Reports

According to the latest statistics from the National Cancer Institute (NCI), about 1 in 8 U.S. women (~13%) will develop invasive breast cancer over the course of their lifetime. This translates to an estimated 268,600 new cases of breast cancer for the year 2019, and these diagnoses will collectively make up 15% of all new cancer cases across all cancer types. The majority of these women will experience the often-debilitating symptom of breast cancer-induced fatigue. these patients often have difficulty performing normal activities of daily living, have decreased tolerance to traditional tumor-directed therapies, and have higher rates of cancer recurrence. …

Transcriptional Regulation And Islet Transplantation Advantages Of Brown Adipose Tissue, Jessica D. Kepple

All ETDs from UAB

Metabolic disease encompasses various disorders, including obesity and diabetes, that negatively impact glucose and lipid homeostasis and increase the risk of co-morbidities. Adipose tissue, which regulates whole-body energy balance and acts as a specialized endocrine tissue, is negatively affected by obesity and diabetes. Brown adipose tissue (BAT) functions to dissipate excess energy as heat and therefore is an attractive target against metabolic disease. To develop more effective therapeutic strategies, BAT physiology and genetic regulatory mechanisms need to be better understood. This dissertation highlights studies seeking to illuminate novel transcriptional regulation and islet transplantation applications of BAT. We investigated the requirement …