Medicine and Health Sciences Commons^™

Hypoxia Regulates Vessel-Modifying Macrophages And Vice Versa In Tumors, Kayla Jo Steinberger

Graduate Theses, Dissertations, and Problem Reports

Hypoxia, or low oxygen, is a common feature of solid tumors correlating with poor survival in cancer patients. Growing tumors need a blood supply to deliver oxygen. Tumors attempt to re-acquire oxygen by forming new blood vessels from nearby, pre-existing vessels, a process known as angiogenesis. Past treatments aimed at preventing this process yielded not only disappointing results in the clinic but sometimes worsened the patient’s prognosis making the tumor more hypoxic, emphasizing the urgent need for novel targets. In tumors, angiogenesis is notoriously dysfunctional resulting in leaky, under-perfused blood vessels which cannot adequately deliver oxygen and exacerbates hypoxia. Emerging …

Development And Characterization Of Monoclonal Antibodies Against Pseudomonas Aeruginosa, Jason Kang

Graduate Theses, Dissertations, and Problem Reports

Antimicrobial resistance (AMR) has emerged as a global crisis, posing significant challenges to the treatment and management of infectious diseases. The escalating prevalence of antibiotic-resistant bacteria has made many antimicrobial therapies ineffective, necessitating the development of alternative strategies to combat microbial infections. The rise of multidrug-resistant pathogens, such as Pseudomonas aeruginosa and Serratia marcescens, further exacerbates this problem, as these pathogens exhibit high levels of resistance to multiple antibiotics and cause severe infections in vulnerable populations. In response to the need for alternative therapeutic approaches, monoclonal antibodies (mAbs) have emerged as promising candidates for combating AMR. In this work, we …

Il-27 Negatively Impacts Immunity Developed Following Bcg Administration, Shelby D. Bradford

Graduate Theses, Dissertations, and Problem Reports

Mycobacterium tuberculosis (Mtb) is the causative agent of tuberculosis (TB), a predominantly respiratory pathogen responsible for over ten million infections and one million deaths last year. Despite it being a primary objective of the World Health Organization (WHO) for several decades to irradicate TB, progress toward this objective has fallen short of the 2020 target to end TB by 2035. Meeting this goal will require advancements in diagnostic tools, education, healthcare access, and treatments and preventatives. Regarding prevention, the primary tool for this strategy is through vaccination. Currently, the only licensed vaccine for protection against TB is the century old …

Longitudinal Oxygen Imaging In 3d (Bio)Printed Models, Ryan Curtis O'Connell

Graduate Theses, Dissertations, and Problem Reports

Electron paramagnetic resonance (EPR), and its molecular imaging modality, is a powerful tool to noninvasively map various biological and chemical markers within objects of interest. Reliable data acquisition is a major impeding factor for longitudinal hands-off measurements. Measurements are especially challenging in biomedical applications, as live objects are not static. Frequent changes occur that require constant fine recalibration of the EPR detection system, called the resonator. To enable longitudinal imaging, a technology permitting automatic digital control of resonator coupling, tuning, and EPR data acquisition was developed. Automation was achieved through the utilization of a microcontroller and digital peripheral components such …

Advancing Medical Technology For Motor Impairment Rehabilitation: Tools, Protocols, And Devices, Matthew Yough

Graduate Theses, Dissertations, and Problem Reports

Excellent motor control skills are necessary to live a high-quality life. Activities such as walking, getting dressed, and feeding yourself may seem mundane, but injuries to the neuromuscular system can render these tasks difficult or even impossible to accomplish without assistance. Statistics indicate that well over 100 million people are affected by diseases or injuries, such as stroke, Parkinson’s Disease, Multiple Sclerosis, Cerebral Palsy, peripheral nerve injury, spinal cord injury, and amputation, that negatively impact their motor abilities. This wide array of injuries presents a challenge to the medical field as optimal treatment paradigms are often difficult to implement due …

Influence Of Maternal Nano-Titanium Dioxide Inhalation Exposure On Cyclooxygenase Metabolites: Maternal Microvascular And Sexually Dimorphic Feto-Placental Outcomes., Julie Anne Griffith

Graduate Theses, Dissertations, and Problem Reports

Nano-titanium dioxide (nano-TiO₂) is an engineered nanomaterial (ENM), which is widely utilized in diverse products like surface coatings, cosmetics, medical devices, and filters. Inhaled nano-TiO₂ has been demonstrated to induce pulmonary inflammation, impair microvascular function, and hinder generational reproductive endpoints. These outcomes indicate why it is important to explore gestation, as it requires timely vascular adaptations to support maternal and fetal health and development. Therefore, the central hypothesis of my dissertation is: maternal nano-TiO₂ inhalation exposure will impact maternal microvascular function and fetoplacental hemodynamics and function in a sexually dimorphic manner.

The first purpose of …

Monitoring The Systemic Immune System To Understand And Improve The Efficacy Of Immunotherapy For Metastatic Osteosarcoma, Justin Edward Markel

Graduate Theses, Dissertations, and Problem Reports

Osteosarcoma (OS) is a complex tumor with no effective targeted therapies due to its genomic heterogeneity and pleomorphism. The immune response it creates, particularly against metastatic lesions, is considerable; however, various suppressive mechanisms induced by the tumor prohibit its effectiveness. The presence of infiltrating lymphocytes suggests that therapeutic disinhibition through checkpoint blockade could increase antitumor immunity, though none have been successful in clinical trials. The complexities of the immune response to OS tumors have yet to be unraveled; however, there is evidence to suggest that cell-mediated immunity (CMI, specifically T cells, Natural Killer [NK] cells, and myeloid-lineage cells [MLCs]) plays …

Autonomous And Non-Autonomous Requirements For The C-Jun N-Terminal Kinase Signaling Pathway In Early Forebrain Development, Jessica G. Cunningham

Graduate Theses, Dissertations, and Problem Reports

The cerebral cortex is responsible for a wide variety of high-level functions including cognition, sensory perception, fine motor control, and the orchestration of body movements. The cortex is comprised of cortical excitatory neurons and inhibitory interneurons, which are arranged in a highly organized fashion into different layers and regions. These two types of cells operate in a delicate balance between excitation and inhibition, which is critical for proper cortical circuitry. In order for the cortex to execute its numerous functions, it must both send and receive input to other brain regions through axonal connections. The organization within the cortex and …

Influences Of Disrupted Circadian Rhythms On Stroke Outcome, Jennifer A. Liu

Graduate Theses, Dissertations, and Problem Reports

The circadian system is composed of a subset of temporal oscillators that function through a transcriptional and post-translational molecular and functional negative feedback loop cycling approximately every 24 hours. The central clock located in the suprachiasmatic nucleus is responsible for entrainment using light as the key timekeeper (zeitgeber); it is responsible for synchronizing and optimizing physiological behavior and function to the environment. Exogenous information, such as day length and light-dark cycles, provide critical temporal cues for adjusting to environmental conditions. Proper alignment to natural light dark cycles and circadian rhythms is optimal for vital health, fitness, and survival in organisms. …

Examining The Pulmonary Response To Repeated Vishniacozyma Victoriae Exposure And Its Association With Allergic Airway Disease, Rachael Erin Rush

Graduate Theses, Dissertations, and Problem Reports

Allergic airway diseases such as asthma continue to increase in incidence in industrialized nations like the United States. These diseases are complex inflammatory processes involving numerous cells and mediators and are strongly influenced by fungal exposures. Recent developments in fungal detection methods have highlighted the contribution of Basidiomycota yeast species in indoor environments such as Vishniacozyma (syn. Cryptococcus) victoriae. However, despite the high levels of this yeast detected in indoor environments, very little is known about it or its role in respiratory morbidity. V. victoriae is phylogenetically similar to pathogenic Cryptococcus neoformans but lacks a capsule and is …

Investigating The Mitochondrial Protein Mitoneet In C. Elegans Models Of Aging And Alzheimer's Disease, Jacob Ryan Boos

Graduate Theses, Dissertations, and Problem Reports

Oxidative stress is an imbalance between reactive oxygen species production and elimination, favoring the former. Reactive oxygen species serve as important signaling molecules for physiological homeostasis. However, when produced in excess, these once important signaling molecules become detrimental, disrupting cellular functions, and ultimately leading to cell death. In aging, reactive oxygen species production is increased, accompanied with reductions in oxidative stress resistance, increasing the risk for developing age-related diseases including cardiovascular disease, cancer, stroke, and neurodegenerative diseases. The outer mitochondrial membrane iron-sulfur cluster containing protein mitoNEET (CISD1; gene CISD1) has shown to be a mediator of mitochondrial function and …

Mitochondrial Aspects Of Neuronal Pathology In Triple-Transgenic Alzheimer’S Disease Mice, John Zachary Cavendish

Graduate Theses, Dissertations, and Problem Reports

Alzheimer’s disease (AD) is a fatal, progressive neurodegenerative disease afflicting millions of people in the United States alone and is the only one of the top leading causes of morbidity and mortality with no effective disease-modifying therapies. It is the most common form of dementia, affecting one in three people over the age of 85. While the hallmarks of the disease include accumulation of beta-amyloid-based extracellular plaques and hyperphosphorylated tau-based intracellular neurofibrillary tangles, treatment strategies centered on removing or mitigating these components of AD have all failed in humans. Mitochondrial dysfunction has been increasingly recognized as an early and consistent …

Bypassing The Blood-Brain Barrier: A Physical And Pharmacological Approach For The Treatment Of Metastatic Brain Tumors, Samuel A. Sprowls

Graduate Theses, Dissertations, and Problem Reports

This dissertation (a) provided an in depth literature review of methods to disrupt the BBB/BTB and improve therapeutic distribution to brain tumors, (b) evaluated the use of azacitidine as a single agent therapy for the treatment of brain metastasis of breast cancer and a potential molecular mechanism by which brain tropic cells are sensitized to hypomethylating agents, (c) determined the impact cannabidiol has on P-glycoprotein mediated efflux at the blood-brain barrier and its potential for use as a single agent treatment for metastatic brain tumors, (d) developed a preclinical radiation therapy protocol for use in small animals and in vitro …

Utilizing The Coughing Rat Model Of Pertussis To Improve Vaccine Efficacy, Jesse M. Hall

Graduate Theses, Dissertations, and Problem Reports

Pertussis, also known as whooping cough, is a respiratory disease caused by the highly contagious, Gram-negative pathogen Bordetella pertussis (Bp). Infection occurs through inhalation of aerosolized droplets containing Bp, which then colonizes ciliated epithelial cells of the respiratory tract. Here, Bp expresses toxins and virulence factors that lead to leukocyte recruitment, paroxysmal cough, and impairment of host innate responses. Currently, in developed countries, acellular pertussis vaccines (aP; DTaP; Tdap) are used to prevent Bp infection and whooping cough disease. However, we currently realize that the aP vaccine efficacy quickly wanes resulting in a reemergence of pertussis. Recent …

Novel Mechanisms Of Neuronal And Hormonal Regulation Of Large Intestinal Electrolyte Transport, Andrew John Nickerson

Graduate Theses, Dissertations, and Problem Reports

The mammalian colon plays a vital role in maintaining overall electrolyte and fluid homeostasis in the body, and it possesses the ability to either secrete or absorb water depending upon the needs of the organism. Secretion or absorption of electrolyte ions, such as Na⁺, Cl^- and K⁺, drives the movement of water across the colonic epithelium – the inner gut lining where all transport takes place. Aberrant absorptive and/or secretory activity within the colonic epithelium is central to the pathogenesis of many gastrointestinal diseases, such as irritable bowel syndrome (IBS), inflammatory bowel disease (IBD), constipation …

A Role For Endothelial Tissue-Nonspecific Alkaline Phosphatase In Blood-Tissue Barrier Health And Disease, Allison L. Brichacek

Graduate Theses, Dissertations, and Problem Reports

Sepsis is a disorder that targets the microcirculation with significant effects at blood-tissue barriers such as the blood-brain barrier (BBB) and gut-vascular barrier (GVB). Intestinal barrier dysfunction is thought to be one of the most important contributors to multi-organ dysfunction in sepsis. As a common site of infection, the impaired gut allows the dissemination of bacteria, which exacerbates the disease pathophysiology, and can lead to long-term morbidity and mortality. The mechanisms that influence altered barrier permeability in the GVB in sepsis and other inflammatory disorders are not well understood. Tissue-nonspecific alkaline phosphatase (TNAP) enzyme activity, which has been shown to …

Janus Kinase 1 Drives Endoplasmic Reticulum Stress-Induced Transcriptional Reprogramming In Astrocytes, Savannah Graham Sims

Graduate Theses, Dissertations, and Problem Reports

Neurological and neurodegenerative diseases are heterogenous and devastating diseases with limited therapeutic options and no cures. The broad, long-term goal of this project was to elucidate therapeutic targets for neurodegenerative conditions that attenuate damaging inflammation while leaving the beneficial immune response intact and avoiding broad immunosuppression. Inflammation and the accumulation of misfolded proteins are associated with a wide variety of neurological diseases. Here, we have examined how the accumulation of misfolded proteins shapes inflammatory signaling in the glial cell population astrocytes. Astrocytes are the most populous cell in the central nervous system (CNS) and provide physical and trophic support to …

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. …

Pseudomonas Aeruginosa Vaccine Development Using Dual-Species Whole Cell And Subunit Vaccines, Catherine Bell Blackwood

Graduate Theses, Dissertations, and Problem Reports

Pseudomonas aeruginosa is a Gram-negative opportunistic pathogen which can cause severe, recurrent, and chronic infections. The pathogen is highly adaptable, and pneumonia caused by it is associated with high morbidity and mortality, especially in individuals with the genetic disorder cystic fibrosis. Antibiotic resistance amongst clinical isolates of P. aeruginosa is steadily increasing, and multi-drug resistant strains are prevalent. There is currently no vaccine available for commercial use against P. aeruginosa. For these reasons, we sought to understand the immunity to P. aeruginosa induced by whole cell vaccination and identify antigens for development of future subunit vaccines. In this dissertation, …

Clincial Translational Science Research Of The Functional Role Of Large Conductance Potassium Channels In Selective Destruction Of Triple Negative Breast Cancer Cells, Gina Sizemore

Graduate Theses, Dissertations, and Problem Reports

ABSTRACT

The preliminary background that puts this research into context is threefold; it is the aggressive nature of triple negative breast cancer (TNBC), the complexity surrounding its pathology, and the significant lack of targeted treatment for this disease. To clarify the focus of my research, I have concentrated on identifying a targeted treatment for TNBC. In the process, I have identified cycles of reciprocity between treatment, clinical diagnosis, staging, and pathology that will be addressed in smaller papers. However, the weight of this work is in the discovery of a novel target for triple negative breast cancer. The value of …

Pulmonary Immune Responses To Respirable Elongate Mineral Particles Of Asbestiform And Non-Asbestiform Morphologies, Timur Khaliullin

Graduate Theses, Dissertations, and Problem Reports

Inhalation exposure to asbestiform elongate mineral particles (EMPs) may cause pulmonary fibrosis, lung and pleural cancer. At the same time, epidemiological evidence for non-asbestiform EMP pathogenicity is scarce, with little if any risk of cancer, but consistent findings of pneumoconiosis and increased mortality. Globally, conditions caused by asbestos exposures contribute most to the occupational cancer burden and are responsible for the increasing mortality for occupational respiratory diseases. Immunological components of the fiber-induced lesions are extremely understudied, partly due to the lack of comparable test articles. In this study I utilized respirable preparations of asbestiform and non-asbestiform riebeckite and tremolite to …

Obese Zucker Rats As A Reverse Translational Model Of Human Left Ventricular Hypertrophy, Mackenzie Shelby Newman

Graduate Theses, Dissertations, and Problem Reports

Heart failure is a lifelong disability that for over half of those affected leads to mortality within five years after initial diagnosis. Left ventricular hypertrophy (LVH) is one of the most reliable independent predictors of heart failure. Pathological LVH is irreversible, but early diagnosis is often missed due to its asymptomatic nature. Obese Zucker rats (OZR), which develop obesity due to dysfunctional leptin signaling, naturally exhibit a LVH that mimics the obese human condition. Animal models are necessary because human donor tissue is scarce. The central hypothesis is that genes and proteins that are differentially expressed during development of LVH, …

Understanding The Host Immune Response Against Pseudomonas Aeruginosa To Develop Novel Therapeutics And Vaccines, Emel Sen Kilic

Graduate Theses, Dissertations, and Problem Reports

Pseudomonas aeruginosa is a Gram-negative opportunistic bacterium that causes a broad range of acute and chronic infections. The high adaptability and emergence of multidrug-resistant strains of this bacterium pose a significant threat to human health. Particularly, pneumonia caused by this pathogen is associated with high morbidity and mortality in immunocompromised patients. To prevent these infections, we aimed to develop novel vaccine strategies by characterizing the host immune response against P. aeruginosa. During respiratory infections, P. aeruginosa first contacts with epithelial cells along the respiratory tract. Using RNA-sequencing, we were able to characterize transcriptional changes of the epithelial cells in …

Will Pitch Velocity Remain Consistent Throughout A Competitive Baseball Season Following Blood Flow Restriction: An Observational Study, Mackenzie Marie Evans

Graduate Theses, Dissertations, and Problem Reports

Context: Blood flow restriction (BFR) has previously been used in a rehabilitation setting to decrease the external load applied to post-surgical patients and those with chronic debilitating conditions. BFR in a performance context has been explored minimally, particularly as it applies to baseball pitching over time. Objective: The purpose of this study was to retrospectively investigate the trend in throwing velocity of fastballs with BFR implementation over one competitive season. Design: This study was a retrospective longitudinal design on pitching velocity of fastballs throughout a competitive season. Setting: The data collection and analysis was completed at …

Environmental Regulation Of The Heart: The Role Of Non-Coding Rna And Epigenetics In Influencing Mitochondrial And Cellular Health, Quincy Alexander Hathaway

Graduate Theses, Dissertations, and Problem Reports

The mitochondrion, a small but ubiquitously distributed organelle in the cell, continues to be the focus of many disease pathogeneses, tissue and organ dysfunctions, and other morbidities that occur throughout the body. The purpose of this work was to understand how cardiac mitochondrion are altered in disease and pathological states, specifically in their adaptation to environmentally stimulated regulatory networks, such as epigenetic modifications and promotion/inhibition of non-coding RNAs. Acute stress to mitochondrial regulation (inhalation toxicology) as well as chronic (type 2 diabetes mellitus) was examined. Using a FVB transgenic microRNA-378a mouse knockout model, the cardiovascular impact derived from altering the …

Development Of Improved Acellular Pertussis Vaccines Through Inclusion Of The Rtx Antigen Or Induction Of Mucosal Immunity, Dylan Tyler Boehm

Graduate Theses, Dissertations, and Problem Reports

Pertussis is a human respiratory disease, primarily caused by the Gram-negative pathogen Bordetella pertussis. The infection is most severe and can be life-threatening in young children and infants where it manifests as a series of paroxysmal coughs. The disease is more commonly known as whooping cough, due to the whoop omitted during a massive inspiratory effort to bring air back into the lungs. Pertussis is a toxin-mediated disease that persists due to an early release of toxins that allow that bacteria to evade the cells of the innate immune response. The inhibition of the host response continues as toxin activity …

Role Of Sox9 In Cancer Stem Cell Regulation In Lung Cancer Chemoresistance And Particle-Induced Carcinogenesis, Maria Voronkova

Graduate Theses, Dissertations, and Problem Reports

Lung cancer is a leading cause of cancer-related death worldwide. Every year it claims more lives than other common malignancies, breast, prostate, and colorectal cancers, combined. And despite recent improvements in disease diagnostics and treatment, drug resistance and tumor relapse remain major contributors to low patient survival. Both issues have been largely attributed to the existence of cancer stem-like cells (CSCs) or tumor initiating cells (TICs). CSCs are a small cell population within heterogeneous tumors that is inherently resistant to apoptosis, chemo- and radiation therapy. Thus, it is critical to elucidate CSC-specific signaling pathways and identify early biomarkers for therapeutic …

Investigation Of Bovine Conceptus Galectins And The Effect Of Bovine Conceptus Secretory Proteins On The Endometrial Epithelial Transcriptome, Heather Lynn Baldwin

Graduate Theses, Dissertations, and Problem Reports

Pregnancy loss in cattle is greatest in the first 30 days of gestation. Near d15 of gestation, bovine conceptuses elongate and express LGALS1, an immunosuppressive glycan-binding protein believed to be essential for implantation. However, other members of the bovine galectin family, including LGALS3, LGALS4, LGALS7, LGALS8, LGALS9 and a galectin-13-like gene (LGALS13L), also may be expressed by the elongating conceptus. Therefore, galectin expression in elongating, d16 bovine conceptuses and intercaruncular endometrium as well as elongating, d14 ovine conceptuses and intercaruncular endometrium was assessed by RT-qPCR. Angus heifer and Texel ewes underwent estrous cycle synchronization and either inseminated or not bred. …

Alternative Splicing In Vertebrate Photoreceptors And Mechanisms Underlying Retinitis Pigmentosa, Jesse C. Sundar

Graduate Theses, Dissertations, and Problem Reports

RNA binding proteins (RBPs) have emerged as important regulators of gene expression. RBPs typically contain RNA binding domains that recognize a specific sequence and/or structural motifs within the RNA. This allows them to modulate metabolism of RNAs in several possible ways including regulation of alternative splicing and processing, polyadenylation, translocation, localization, modification, stability, or translation. Previous studies have shown the Musashi (MSI) RBP family to be highly expressed in the retina, and more specifically, photoreceptors, but the importance of this expression remains largely unknown. We identified the MSI proteins as potential regulators of alternative exon splicing in murine photoreceptors. We …

A Biomimetic Approach To Controlling Restorative Robotics, Matthew T. Boots

Graduate Theses, Dissertations, and Problem Reports

Movement is the only way a person can interact with the world around them. When trauma to the neuromuscular systems disrupts the control of movement, quality of life suffers. To restore limb functionality, active robotic interventions and/or rehabilitation are required. Unfortunately, the primary obstacle in a person’s recovery is the limited robustness of the human-machine interfaces. Current systems rely on control approaches that rely on the person to learn how the system works instead of the system being more intuitive and working with the person naturally. My research goal is to design intuitive control mechanisms based on biological processes termed …