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The Impact Of Blimp1 On Etreg Stability And The Tumor Microenvironment, Michael Dixon Jan 2021

The Impact Of Blimp1 On Etreg Stability And The Tumor Microenvironment, Michael Dixon

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CD4+ Foxp3+ regulatory T (Treg) cells are responsible for maintaining immunological homeostasis and self-tolerance through the regulation of immune responses against foreign and self-antigens, and they comprise both central Treg and effector Treg (eTreg) subsets. Because of their ability to suppress potent immune responses, eTreg cells expressing the transcription factor Blimp1 are frequently recruited to the tumor microenvironment (TME) to suppress anti-tumor responses by tumor infiltrating effector cells. Here, we demonstrate in murine transplantable tumor models that Blimp1 is required for intratumoral eTreg stability and that loss of Blimp1 by intratumoral eTreg cells results in their reduced suppressive activity and …

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How Inflammation, High-Density Lipoproteins, And Genes Affect The Relationship Between Apol1 And Kidney Outcomes, Ninad S. Chaudhary Jan 2021

How Inflammation, High-Density Lipoproteins, And Genes Affect The Relationship Between Apol1 And Kidney Outcomes, Ninad S. Chaudhary

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Over the past decade, the discovery of novel genetic loci on chromosome 22q, apolipoprotein-L1 (APOL1), has given insights into the racial differences in kidney outcomes at the population level. APOL1 risk alleles are unique to African ancestry and confer increased susceptibility to end-stage kidney disease (ESKD) especially among individuals without diabetes. However, the diseases do not occur in all who inherit these alleles. Current efforts are driven towards identifying the factors that can interact with APOL1 in the development of kidney diseases. This dissertation investigated whether the association between APOL1 and kidney outcomes is affected by inflammatory markers (AIM1), high-density …

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Dopamine-Dependent Transcriptional Dynamics In Striatal Physiology And Cocaine Reward, Morgan Elizabeth Zipperly Jan 2020

Dopamine-Dependent Transcriptional Dynamics In Striatal Physiology And Cocaine Reward, Morgan Elizabeth Zipperly

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Exposure to drugs of abuse alters transcriptional programs and neuronal activity, leading to long-lasting cellular and behavioral adaptations that may contribute to addiction. The nucleus accumbens (NAc), part of the mesocorticolimbic dopamine pathway, plays a central role in motivation, reward, and reward-related learning, and this brain region is highly implicated in the development and maintenance of addiction. However, the specific contributions of defined cell populations in the NAc to drug reward processes is still poorly understood. Here, we used electrophysiological, optogenetic, and single-nucleus RNA-sequencing (snRNA-seq) approaches in a rodent model system to define the acute physiological and transcriptional responses of …

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The Hunter And The Hunted: Kipling's Challenge To Human Exceptionalism In "The White Seal" And "Quiquern", Jessica Marie Robbins Jan 2020

The Hunter And The Hunted: Kipling's Challenge To Human Exceptionalism In "The White Seal" And "Quiquern", Jessica Marie Robbins

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Rudyard Kipling’s The Jungle Books are some of the most well-known stories about nonhuman animals from the Victorian period, but rarely have scholars discussed this text without privileging the Mowgli stories or Kipling’s well-known colonialist alignments. In this thesis, I have challenged this scholarly tendency, showing how Kipling has paid careful attention to his nonhuman characters and given them characteristics that model the most current scientific information available at the time. My thesis argues that two of Kipling’s stories in particular, “The White Seal” and “Quiquern,” challenge the notion of human exceptionalism and force readers to confront the unsettling parallels …

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Neurobiological Signatures Of Treatment Response – A Multi-Modal Study In Schizophrenia, Eric A. Nelson Jan 2020

Neurobiological Signatures Of Treatment Response – A Multi-Modal Study In Schizophrenia, Eric A. Nelson

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Schizophrenia is a heterogeneous mental illness and even though it has been studied for over a century, the neuropathology of the disease is still not fully under-stood. Only 1/3 of patients respond well to antipsychotic drug (APD) treatment while another 1/3 show only a partial response and yet another 1/3 of patients are non-responsive, exhibiting little to no change in positive symptoms and a general reduction in quality of life. In order to develop treatments that better serve non-responding and partial re-sponse patients, a greater understanding of APD neuromechanisms is needed. In order to provide a more comprehensive assessment of …

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Genetic And Immunologic Predictors Of Genital Chlamydia Reinfection In African American Women Using Bayesian Hierarchical Models, Kristin Olson Jan 2020

Genetic And Immunologic Predictors Of Genital Chlamydia Reinfection In African American Women Using Bayesian Hierarchical Models, Kristin Olson

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Chlamydia trachomatis (CT) infection is the most common sexually transmitted infec-tion. The burden is greatest in young, African American women. CT reinfections are common and increase risk for reproductive morbidity. Why some women are more sus-ceptible to reinfection is not well understood. Emerging evidence suggests immunologic and genetic variants may predict reinfection susceptibility. The primary goal of this dissertation is to evaluate immunologic and genetic vari-ants as predictors of CT reinfection in young, African American women using different modeling approaches, which has never been reported previously. To evaluate a much larger number of potential predictors than our sample size (a …

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The Effects Of Oscillatory Forces On Epithelial Ovarian Cancer, Molly Buckley Jan 2020

The Effects Of Oscillatory Forces On Epithelial Ovarian Cancer, Molly Buckley

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Oscillatory forces such as blood pressure pulse, interstitial fluid flow, and body movement are present throughout ovarian tumors. These forces have been shown to strongly regulate mechanotransduction signaling, leading to tumor progression, metastasis, and invasion. Mechanotransduction studies are rarely conducted in ovarian cancer. This study is the first of its kind to understand how oscillatory forces impact ovarian tumor progression and the efficacy of a cancer therapeutic under these unique conditions. Herein, a novel oscillating flow bioreactor was developed housing an ovarian cancer tumor model using OVCAR-8 and IHFOT-208 cell lines and compared to the same bioreactor under constant flow. …

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Circadian Clock And Lipid Metabolism Disruption In Fatty Liver Disease, Jennifer Valcin Jan 2020

Circadian Clock And Lipid Metabolism Disruption In Fatty Liver Disease, Jennifer Valcin

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Hepatic Steatosis, characterized by the accumulation of triglyceride (TG) in the liver is the first stage of Alcoholic Liver Disease (ALD) and Nonalcoholic Fatty Liver Disease (NAFLD). Many metabolic pathways, including lipid metabolism, are regulated by the molecular circadian clock. Importantly, alcohol consumption and obesity induce circadian clock disruption, a risk factor for many diseases, including liver disease. In our first study, we investigated the combined effect of clock disruption and alcohol feeding on liver pathology, and diurnal rhythms in the liver molecular clock and lipid metabolism. Male liver-specific Bmal1 knockout (LKO) mice and control littermates were fed a control …

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Dna Methylation: A Mechanism For Sustained Alteration Of Kir4.1 Expression Following Central Nervous System Insult, Jessica Boni Jan 2020

Dna Methylation: A Mechanism For Sustained Alteration Of Kir4.1 Expression Following Central Nervous System Insult, Jessica Boni

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Astrocytes are the most numerous cells in the brain and play a critical role in maintaining homeostatic extracellular potassium ([K+]e). Maintaining low [K+]e is essential for many cellular functions including maintenance of intensely negative resting membrane potentials in the central nervous system. This process is mediated, in part, by a glial-specific, inwardly rectifying potassium channel, Kir4.1. Underscoring the role of Kir4.1 in CNS functioning, genetic mutations in Kcnj10, the gene which encodes Kir4.1, causes seizures, ataxia and developmental disability in humans. Notably, loss of Kir4.1 protein and mRNA are consistently observed after CNS injury, and in a number of neurological …

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Development Of Mitochondrial-Targeted Genetic Tools To Investigate How Changes In Mitochondrial Function Affect The Heart, Patrick James Ernst Jan 2020

Development Of Mitochondrial-Targeted Genetic Tools To Investigate How Changes In Mitochondrial Function Affect The Heart, Patrick James Ernst

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Mitochondria are an important organelle found in all human cells, they fulfill several crucial roles necessary for cellular function such as energy production, calcium handling, metabolic regulation, and inducing pre-programmed cell death. Mitochondrial dysfunction is associated with many different diseases such as heart failure, aging, and cancer, as well as multiple neurodegenerative diseases. While there are currently different tools and approaches for studying different aspects of both mitochondrial function and dysfunction, they tend to have major drawbacks that limit their practicality and conclusions that can be drawn using them. We hypothesized that by finding the correct genetic mitochondrial targeting sequence, …

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Counter Narratives Of Black Female Educators In Exurban Schools, Monisha Douglas Moore Jan 2020

Counter Narratives Of Black Female Educators In Exurban Schools, Monisha Douglas Moore

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This study explored how three Black female educators characterized their personal narratives regarding their teaching experiences. Guided by a social justice framework, this study attempted to show how Black women’s identities have been co-created, how their perceptions of success have been formulated, and how perceptions of academic success have helped them frame their pedagogy for diverse students. Because limited research has examined how Black female educators in exurban areas situated their perceptions and pedagogy to facilitate the needs of diverse students, this study added to the limited knowledge. Purposeful sampling was conducted at the site and participant level. The research …

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Contribution Of Adaptive Immune Responses In Chronic Lung Diseases, Thi Kim Tran-Nguyen Jan 2020

Contribution Of Adaptive Immune Responses In Chronic Lung Diseases, Thi Kim Tran-Nguyen

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Immune dysregulation is a hallmark of various chronic lung diseases such as Chronic Obstructive Pulmonary Diseases (COPD) and Idiopathic Pulmonary Fibrosis (IPF). Previous studies in our lab have shown evidences of autoimmunity such as increases in autoantibodies, abnormal T cell profile, immune complex deposition and the presence of ectopic lymphoid structures in the lung of these patients. This thesis consolidates two separate projects about various aberrant immune responses in these diseases. The first project identified Glucose-Regulated-Protein 78 (GRP78) as the common autoantigen in COPD and characterized how GRP78 autoantibodies may increase COPD mortality via its atherogenic effects. I demonstrated that …

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Assessment Of Emergency Department High Utilizer Program In Public Health System Setting, Michael Malaise Jan 2020

Assessment Of Emergency Department High Utilizer Program In Public Health System Setting, Michael Malaise

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is study examined whether a case management model designed to reduce emergency department utilization among patients described as super-utilizers in a public health system could also reduce the per patient cost of those super-utilizers. The setting for this study was a large public health system in a major metropolitan area. The study focused on a low-income, urban population. Given the program’s stated desire to improve the self-efficacy of patients over time so that they could take more ownership of their own health status, this study reviewed the program within the framework of self-efficacy theory. This research predicted that the case …

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The Viper Pit, Brett Hurst Jan 2020

The Viper Pit, Brett Hurst

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he Viper Pit was born out of a writing prompt from Jim Braziel’s fiction writing class. We had to write a short story based on a photo from The American Photobooth. On page 174 of that book, a photo on the far right corner sparked my interest last year. It was the type of picture you see and automatically do a double-take. The man in the photo held the snake so close to his face like a newborn baby. The connection between the man and the snake ignited something in my imagination. On that day, I gave that man a …

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The Relationship Between Government Grants And Nonprofit Revenue Diversification, Samantha Jeanne Arceneaux Jan 2020

The Relationship Between Government Grants And Nonprofit Revenue Diversification, Samantha Jeanne Arceneaux

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The financial health of nonprofits has been of interest to researchers for decades and continues to be of concern as the size United States nonprofit sector continues to grow both in the number of registered nonprofits and in finances, and third-party government increasingly uses partnerships with nonprofits to deliver services to the public. Empirical studies of revenue diversification and concentration indicate that they can both contribute to nonprofit financial health by assisting in developing a strategy of financial sustainability or financial capacity. However, empirical studies on the relationship between government funding and the nonprofit sector have been limited. This analysis …

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Locus Coeruleus Degeneration In Alzheimer’S Disease And Its Effect On Beta-Adrenergic Signaling In The Hippocampus, Bethany Langner Jan 2020

Locus Coeruleus Degeneration In Alzheimer’S Disease And Its Effect On Beta-Adrenergic Signaling In The Hippocampus, Bethany Langner

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Locus coeruleus (LC) degeneration in Alzheimer’s Disease (AD) and loss of noradrenergic (NA) innervation in hippocampus contributes to learning and memory deficits. Recently, a novel rat model (TgF344-AD) has been created that allows for a more thorough investigation into these mechanisms due to its similarity to human AD pathology. The McMahon lab has recently demonstrated heightened long-term potentiation (LTP) and a ‘supersensitivity’ of -adrenergic receptors (-ARs) at excitatory synapses in the dentate gyrus (DG) in TgF344-AD rats. These mechanisms could be responsible for maintaining learning and memory during buildup of AD pathology. The first goal of this Master’s thesis was …

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Impact Of Different Human Coronaviruses (Hcovs) On Pediatric Patients At A Tertiary Pediatric Hospital – Retrospective Study, Abdulsalam Alsulami Jan 2020

Impact Of Different Human Coronaviruses (Hcovs) On Pediatric Patients At A Tertiary Pediatric Hospital – Retrospective Study, Abdulsalam Alsulami

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Background: Human Coronaviruses (HCoV) are important pathogens associated with respiratory disease in humans and animals. The majority of HCoVs are emerging human pathogens with 7 known types causing human disease and 5 being identified in the last 2 decades. Methods: We performed a retrospective review of all encounters with known HCoV at a tertiary pediatric hospital from January 2015 until January 2018. Electronic medical records (EMRs) were reviewed for demographic data, HCoV type, viral copathogens, time to testing, admission, need for increased intensity of care (HLC), requirement for supplemental oxygen, radiographic findings suggestive lower respiratory tract disease (LRT) when available …

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The Role Of Neutrophils In Chronic Heart Failure, Sergey Antipenko Jan 2020

The Role Of Neutrophils In Chronic Heart Failure, Sergey Antipenko

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Acute myocardial infarction (MI) produces massive, sudden cardiomyocyte death, triggering an inflammatory and healing response that initially leads to scar formation and ultimately may induce progressive ischemic cardiomyopathy and heart failure (HF). Scar formation and left ventricular (LV) hypertrophy occur in response to MI to stabilize injury compensating for lost myocardial function. Over time, heart function can become decompensated due to neuroendocrine dysfunction and adverse LV remodeling, ultimately leading to HF. Adverse remodeling is characterized by continued dysregulated collagen deposition, cardiomyocyte hypertrophy, and increased inflammation. Studies have documented a resurgence in inflammatory cytokines and infiltrating leukocytes after resolution of the …

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Molecular Regulation Of Glioblastoma Spatial Heterogeneity And Therapeutic Resistance, Soniya Bastola Jan 2020

Molecular Regulation Of Glioblastoma Spatial Heterogeneity And Therapeutic Resistance, Soniya Bastola

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Glioblastoma multiforme (GBM) is a highly invasive, highly vascularized, and heterogeneous malignant tumor of the brain. Due to the highly infiltrative phenotype of GBM, surgery often leaves behind residual tumor cells. In many cases, recurrence occurs close to the surgical margin suggesting the role of these remaining cells in promoting tumor aggressiveness. Rapidly growing tumor creates subsequent hypoxic, and hypovascular core due to limited nutrients, whereas tumor cells in the leading edge have access to nutrients from vasculature enriched microenvironment. Studies have identified the cellular and molecular heterogeneity between the tumors in core and edge. Still, their mechanisms of intercellular …

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Tau-Dependent Regulation Of Network Hyperexcitability By Alzheimer’S Disease Risk Gene Bin1, Yuliya Voskobiynyk Jan 2020

Tau-Dependent Regulation Of Network Hyperexcitability By Alzheimer’S Disease Risk Gene Bin1, Yuliya Voskobiynyk

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Alzheimer’s disease (AD) is the leading neurodegenerative disorder that affects an astonishing 5.8 million Americans, a number projected to reach 14 million by the year 2050. While only about 1% of all AD cases are caused by mutations in APP, PSEN1, and PSEN2, the cause of sporadic AD remains unknown. Variations in several risk genes have been proposed to contribute to the development of sporadic AD cases. Since, currently, there are no disease-modifying therapies for families affected by AD and multiple anti-amyloid-beta therapies failed in clinical trials, determining how these risk genes contribute to the development of AD is crucial …

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Gene–Environment Interaction In Parkinson Disease: The Gut Microbiome, Zachary D. Wallen Jan 2020

Gene–Environment Interaction In Parkinson Disease: The Gut Microbiome, Zachary D. Wallen

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GENE–ENVIRONMENT INTERACTION IN PARKINSON DISEASE: THE GUT MICROBIOME ZACHARY D. WALLEN GENETICS, GENOMICS, AND BIOINFORMATICS ABSTRACTParkinson disease (PD) is a progressive neurodegenerative disease with no cure. Majority of cases are idiopathic, and the cause is unknown. Studies have been conducted in human and animals to identify PD risk factors, resulting in a list of genetic and environmental factors that modestly increases risk of PD. Still, no individual risk factor fully explains the cause of PD, and neither has the combination of these factors. Additional avenues of research are being investigated to find potential triggers of PD, and factors that might …

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The Role Of The Viral Envelope Protein Gpul132 In Assembly Compartment Formation And Virion Production: Intracellular Lipids And/Or Cholesterol, Hui Wu Jan 2020

The Role Of The Viral Envelope Protein Gpul132 In Assembly Compartment Formation And Virion Production: Intracellular Lipids And/Or Cholesterol, Hui Wu

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Human cytomegalovirus (HCMV) is a ubiquitous pathogen that infects over 50% of the world’s population. HCMV infection is asymptomatic in healthy individuals, however can cause severe morbidity and mortality in individuals with compromised innate or adaptive immunity. As a complex virus that has been known for about 70 years, we are still in search of vaccines or effective treatments against it. HCMV genome encodes over 175 open reading frames with the function of majority proteins remains to be defined. A unique feature of HCMV among herpesvirus is the reorganization of cellular secretory pathway and membranes to form assembly compartment (AC). …

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Circadian Control Of Blood Pressure And Renal Electrolyte Excretion, Dingguo Zhang Jan 2020

Circadian Control Of Blood Pressure And Renal Electrolyte Excretion, Dingguo Zhang

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Many physiological processes, including blood pressure (BP) regulation, follow specific rhythms tied to a 24-h cycle. This is largely because circadian genes operate in virtually every cell type in the body. In healthy individuals, BP during nighttime is 10-20% lower compared to daytime, a phenomenon known as “nocturnal dipping”. It is acknowledged that the dipping of BP is essential in maintaining normal cardiovascular and renal function. However, it remains unclear as to what factors contribute to nocturnal dipping. The purpose of this dissertation is to elucidate mechanisms underlying the circadian rhythm of BP. Bmal1 is one of the core circadian …

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Toward The Mechanism Underlying Latanoprost- And Benzalkonium Chloride-Induced Meibomian Gland Dysfunction In Patients Treated For Glaucoma, Jillian Ziemanski Jan 2020

Toward The Mechanism Underlying Latanoprost- And Benzalkonium Chloride-Induced Meibomian Gland Dysfunction In Patients Treated For Glaucoma, Jillian Ziemanski

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Once thought to be no more than a vexing eye condition, ocular surface disease (OSD) is now being viewed as a differentiating factor between sight and no sight. In the setting of glaucoma, OSD can interfere with treatment success, potentially allowing the visually devastating pathology of glaucoma to plow onward with little restraint. Compounding the clinical challenge is the growing awareness that glaucoma-associated OSD appears to be iatrogenically induced by topical ophthalmic medications. Daily, topical instillation of preserved prostaglandin analogs (PGAs), the most common first-line treatment for glaucoma, has been linked to a variety of OSD subtypes, including meibomian gland …

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A Modified Standard American Diet (Msad) Induces Physiological Parameters Associated The With Metabolic Syndrome In C57bl/6j Mice, Sophie Bru Chehade Jan 2020

A Modified Standard American Diet (Msad) Induces Physiological Parameters Associated The With Metabolic Syndrome In C57bl/6j Mice, Sophie Bru Chehade

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Obesity manifests physiologically in multiple organ systems of the body, typically increasing the risk of developing cardiometabolic disorders. Researchers have questioned the causative role that western dietary patterns have on disease pathogenesis and have speculated that quality and quantity of dietary fats and/or carbohydrates have a predictive role in the development of these disorders. Standard reference diets such as the AIN-93 rodent diet have historically been used to promote optimal animal model health and reduce variation of results across experiments. These diets have been invaluable to murine research; however, their translational value in studying human nutrition-related pathologies is limited. Early …

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Lim Transcriptional Complexes That Impact Endocrine Pancreas Development And Function, Maigen Bethea Jan 2020

Lim Transcriptional Complexes That Impact Endocrine Pancreas Development And Function, Maigen Bethea

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The Ldb1:Isl1 LIM transcriptional complex is critical for endocrine pancreas development as well as b-cell terminal differentiation. These complexes have been shown to interact with various proteins to elicit transcriptional regulation in other tissues, yet few interactors have been identified in b-cells. Therefore, the objective of this dissertation was to identify interactors of Ldb1 and Isl1 and assess their contributions to endocrine pancreas development and function. Using a reversible crosslink immunoprecipitation (ReCLIP) and mass spectrometry (MS) strategy to isolate endogenous Ldb1 and/or Isl1 interacting protiens, SSBP3, Rnf20, and Rnf40 (E3 ubiquitin ligases) coregulators were identified. SSBP3 was found to interact …

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Transcriptional, Translational, And Enzymatic Metabolic Regulation By L-2 Hyroxyglutarate, Garrett Brinkley Jan 2020

Transcriptional, Translational, And Enzymatic Metabolic Regulation By L-2 Hyroxyglutarate, Garrett Brinkley

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Recent studies have identified elevated levels of a small metabolite, L-2 Hydroxyglutare (L-2HG), which curiously has no known metabolic roles. Renal tumors, hypoxia as well as larval development, specifically in Drosophila, all have been identified to have high levels of L-2HG. These broad categories suggest L-2HG has a physiological role. This work uncovers the impact of elevated levels of L-2HG in altering normal kidney and renal tumors. With structural similarity to α-Ketoglutarate (αKG), L-2HG acts as a competitive inhibitor to enzymes that utilize αKG as substrates or co-factors. L-2HG is known to be metabolized by L-2HG dehydrogenase (L2HGDH). Loss of …

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Restless Legs Syndrome And Multiple Sclerosis: The Possible Role Of Physical Activity For Managing Symptoms, Katie Cederberg Jan 2020

Restless Legs Syndrome And Multiple Sclerosis: The Possible Role Of Physical Activity For Managing Symptoms, Katie Cederberg

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Restless legs syndrome (RLS) is an idiopathic neurological disorder characterized by unpleasant sensations in the legs that affects 26% of persons with multiple sclerosis (MS). The current pharmacological treatments for RLS are associated with a number of side effects, including the worsening of symptoms (i.e., augmentation). Physical activity represents a promising, behavioral approach for managing symptoms of RLS in MS. To date, physical activity has demonstrated tremendous benefits for managing many consequences of MS, but there is no evidence on its efficacy for managing RLS in MS. This dissertation described the current literature regarding physical activity and RLS in adults …

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Distinct Tissue Specific Functions Of Bone Marrow Regulatory T Cells, And Their Therapeudic Applications In Myeloid Neoplasms, Virginia Camacho Jan 2020

Distinct Tissue Specific Functions Of Bone Marrow Regulatory T Cells, And Their Therapeudic Applications In Myeloid Neoplasms, Virginia Camacho

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In the bone marrow, Regulatory T cells (Tregs) constitute nearly 30% of CD4+ T cells, a significantly higher ratio than other tissues. Although a few of the mechanisms by which Tregs regulate normal hematopoiesis have been elucidated, our understanding of this process during leukemogenesis is ex-tremely limited. In this work, we define how Tregs maintain and support the bone marrow microenvironment. We propose that the role of Tregs extends be-yond their canonical immuno-suppressive function and that these cells are re-quired to maintain healthy hematopoiesis. We have defined tissue-specific roles for Tregs in the bone marrow including the maintenance of hematopoietic …

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Abnormalities In The Akt-Mtor Signaling Pathway In The Dorsolateral Prefrontal Cortex In Schizophrenia, Radhika Chadha Jan 2020

Abnormalities In The Akt-Mtor Signaling Pathway In The Dorsolateral Prefrontal Cortex In Schizophrenia, Radhika Chadha

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Schizophrenia (SZ) is a complex and heterogeneous mental illness in which myriad changes across multiple neurotransmitter systems (dopamine, serotonin, GABA, glutamate, and others) have been reported. Numerous regulatory mechanisms have been explored in SZ research and rather than being a disorder of one specific neurotransmitter pathway, SZ may instead be a disturbance of intracellular signaling processes that underlie the regulation of these systems. The AKT-mTOR signaling cascade plays an important role in core cellular processes of cell growth, metabolism and survival and is one such potential candidate. Abnormalities in AKT expression and activity have been consistently implicated in SZ pathophysiology …

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