Medicine and Health Sciences Commons^™

Influence Of Metabolic Capacity On The Consequences Of Spreading Depolarization, Katelyn M. Reinhart

Biomedical Sciences ETDs

In the United States, stroke is the fifth leading cause of death and stroke survivors often face long-term disability. After ischemic stroke, the ischemic territory can expand and recruit previously viable tissues into the lesioned area. During this critical period, there is an unsettling lack of interventions that prevent or treat secondary neuronal loss and cognitive decline. Clinical subdural recordings have revealed a close link between infarct progression and waves of spreading depolarizations (SD) in the acutely injured brain. SD is a slowly progressing wave of near-complete neuroglia depolarization that is extremely energetically demanding and this additional metabolic ‘hit’ …

Mechanisms And Consequences Of Myb Gene Activation In Salivary Gland Tumors, Candace Frerich

Biomedical Sciences ETDs

Salivary gland adenoid cystic carcinoma (ACC) is an aggressive tumor with a tendency to infiltrate surrounding nerves and metastasize to distant sites. The standard treatment often fails to control local tumor recurrence and distant metastases and no approved targeted therapeutic options exist for these tumors. The goal of our studies was to reveal the molecular mechanisms driving ACC tumor development and novel drug targets to improve patient morbidity and mortality.

We first analyzed clinical and RNA-sequencing (RNA-seq) data for 68 formalin-fixed paraffin-embedded (FFPE) ACC tumor samples and described previously unappreciated molecular heterogeneity that predicts patient outcome. The poor outcome subgroup …

Neuron Specific Gene 2 (Nsg2): A Novel Regulator Of Excitatory Neurotransmission Via Ampa Receptor Trafficking At A Subset Of Glutamatergic Synapses, Praveen Chander

Biomedical Sciences ETDs

Members of the Neuron-Specific Gene family (NSG1-3) play critical roles in excitatory synaptic transmission via regulation of AMPA receptor surface expression within the post-synaptic density (PSD). While NSG1 and NSG3 regulate AMPAR recycling and endocytosis, respectively, the function of NSG2 has remained elusive. Here we undertook a series of studies to assess the role of NSG2 in excitatory synaptic transmission. We found that a portion of NSG2 punctae localized with HOMER1 and surface AMPARs at excitatory synapses and that NSG2 AMPAR subunits in mouse brain. Knockout of NSG2 selectively impaired the frequency of AMPA mEPSCs, while overexpression caused a significant …

Assessment Of Particulate Matter Toxicity And Physicochemistry At The Claim 28 Uranium Mine Site In Blue Gap, Az, Jessica G. Begay

Biomedical Sciences ETDs

Particulate matter (PM) inhalation is known to have adverse effects on the respiratory and cardiovascular systems. Community concerns in the southwestern US have been expressed in regions of extensive open-pit hard-rock (especially uranium) mining that windblown dusts may pose an excess health risk. To address these concerns, we have undertaken a campaign to detail: (1) the amount and composition of the PM_2.5 in the region, (2) meteorological characteristics, such as wind speed and direction, and (3) and immunological and physiological responses of mice after PM_2.5 exposures.

For toxicity studies, C57BL/6 and apolipoprotein E-null (ApoE^-/-, a vascular …

Chronic Environmental Exposure To Metal Mixtures In Tribal Populations And Potential Immune System Effects, Jennifer Ong

Biomedical Sciences ETDs

Hardrock mining in the United States (US) has left a legacy of mixed metal mine waste sites. Wastes may contain multiple metals of health concern, including arsenic, cadmium, lead, mercury, and uranium, among others. Mining waste sites are disproportionately located on or contiguous to the watersheds of tribal lands. Due to proximity, and because of reliance on natural resources to maintain traditional diets and customs, Native American communities’ contact with multiple metals is often increased. Two impacted communities are the Cheyenne River Sioux Tribe (CRST) and Navajo Nation. Both tribes have expressed concerns that metals in mine waste adversely affect …

The Role Of Omega-3 Polyunsaturated Fatty Acids In Blood Pressure Regulation And Secondhand Smoke-Induced Vascular Dysfunction, Emily Anna Wheeler

Biomedical Sciences ETDs

Omega-3 polyunsaturated fatty acids (n-3 PUFAs) may lower cardiovascular disease risk by reducing blood pressure (BP). We hypothesized that fat-1 transgenic mice, which convert n-6 PUFAs to n-3 PUFAs, would have improved vascular function in BP regulation and following secondhand smoke (SHS) exposure, compared to wild type (WT) mice.

BP was recorded in mice fed an n-6 PUFA, or standard chow diet. On the n-6 PUFA diet fat-1 mice had a lower mean arterial pressure and a greater decrease in diastolic BP when treated with an ACE inhibitor, compared to WT mice. No differences were observed on the chow diet. …

The Role Of Adaptive Immunity In Chronic Hypoxia-Induced Pulmonary Hypertension, Levi David Maston

Biomedical Sciences ETDs

Inflammation is a prominent pathologic feature in pulmonary arterial hypertension as demonstrated by pulmonary vascular infiltration of inflammatory cells, including T and B lymphocytes. However, the contribution of the adaptive immune system is not well characterized in pulmonary hypertension (PH) caused by chronic hypoxia (CH). Inflammatory cells, through various mechanisms, have the capability to increase pulmonary vascular resistance in various disease states. CD4⁺T cells have the potential to play a significant role in the disease process initiated by hypoxia. CD4⁺T cells are largely responsible for orchestrating downstream immune processes and are critical in focusing and amplifying …

Cyclic Amp Efflux Inhibition As A Potential Therapeutic Target For Acute Leukemia: Small Molecule Discovery And Validation, Dominique R. Perez

Biomedical Sciences ETDs

Evasion of apoptosis and resistance to chemotherapy are major therapeutic challenges for acute leukemias. Presumably as a means to promote cell survival, multiple elements of the cyclic AMP (cAMP) pathway are aberrantly regulated in acute leukemias. Furthermore, increased intracellular cAMP (icAMP) is known to induce apoptosis. Therefore, modulation of icAMP has long been a target in leukemias. The central hypothesis of this dissertation is that malignant cells produce and remove excess intracellular cAMP to evade apoptosis and promote survival. Consequently, inhibition of cAMP efflux could selectively trigger leukemia cell death. We designed a novel assay to assess icAMP efflux from …

Improving Proton Pump Inhibitor Prescription Practices As A Means To Decreasing Nosocomial Infections, Jens Langsjoen

Biomedical Sciences ETDs

Proton pump inhibitors (PPIs) are commonly prescribed to treat stomach acid related illnesses, but increase the risk of hospital acquired infections. Measuring hospital PPI overuse trends and provider willingness to adopt PPI reduction interventions can inform the feasibility of reducing PPI overuse. We: (1) interviewed physicians, pharmacists and IT leaders to determine options for hospital PPI reduction, (2) analyzed electronic health record data to determine patterns of PPI overuse, and (3) surveyed providers regarding their willingness to adopt PPI reduction interventions. PPI use was inappropriate in 32% of inpatient encounters locally and 38% nationally. ICU exposure increased the odds of …

Intratypic Genetic Variability Of Human Adenovirus Type 4: Implication For Viral Pathogenesis, Camden Roy Bair

Biomedical Sciences ETDs

Human adenovirus type 4 (HAdV-E4) is a causative agent of acute respiratory disease and conjunctivitis worldwide. Two major lineages of HAdV-E4 genomic variants have been identified by their distinct BamHI restriction profiles: prototype-like (p-like) strains and the a-like genomic variants. Recent molecular epidemiology studies have shown a predominance of a-like genomic variants detected in association with disease which suggests a-like strains have a fitness advantage or they may be more pathogenic. The impact of HAdV-E4 intratypic genetic variability on in vitro and in vivo phenotypes relevant to pathogenesis is a major gap in knowledge. I hypothesize that HAdV-E4 comprises two …

Tauopathies, Novel Optogenetic Tools, And The Future Of Artificial Intellience In Medicine., Jessica L. Binder

Biomedical Sciences ETDs

To this day, there is no cure for Alzheimer’s disease (AD) and related dementias (ADRD). With the daunting rise at an exponential rate of ADRD burden and related deaths, the necessity to find a new line of attack is vital. Pathological accumulation of microtubule associated protein tau in neurons is a major neuropathological hallmark of Alzheimer’s disease (AD) and related tauopathies. Attempts have been made to promote clearance of pathological tau (p-Tau) from neurons via autophagy. Transcription factor EB (TFEB) has shown to clear p-Tau from neurons via autophagy. However, sustained TFEB activation and autophagy can create burden on cellular …

Identification Of A Novel Class Of Er-Selective Ligands Lacking Cross-Reactivity To Gper, Richard A. Pepermans

Biomedical Sciences ETDs

Estrogen plays multiple roles in health and disease, exerting its effects through the classical estrogen receptors (ERα and ERβ) and the G protein‑coupled estrogen receptor (GPER). Current ER‑targeting ligands, including the therapeutic ERα antagonist tamoxifen, have been shown to cross‑activate GPER. This cross‑activation is hypothesized to contribute to clinically observed endocrine resistance in breast cancer, highlighting the potential benefit of truly ER‑selective antagonists. We report the identification of a novel class of ER‑selective ligands that lack cross‑reactivity towards GPER, identifying a truly ER‑selective agonist (AB‑1) and antagonist (AB‑82P). Importantly, AB‑82P degrades a clinically relevant ERα mutant and exhibits inhibitory effects …

Determining The Pathological Effects Of Prenatal Alcohol Exposure On Peripheral Neuropathy Via Spinal And Peripheral Immune Mechanisms, Joshua J. Sanchez

Biomedical Sciences ETDs

Previous studies have suggested that children with Fetal Alcohol Spectrum Disorder (FASD) display hypersensitivity to light touch. In support of this notion, we have demonstrated that applying a chronic constriction injury (CCI) to the sciatic nerve of rats that have prenatal alcohol exposure (PAE) results in heightened sensitivity to light touch, clinically termed allodynia. These observations coincided with heightened glial activation and enhanced peripheral immune reactivity. Considering allodynia is known to be mediated by both peripheral immune responses and spinal glial activation, it is reasonable to speculate that allodynia following PAE may be mediated through an alteration of immune reactivity. …

Utilizing Quantitative Fluorescence Microscopy To Study Oncogenesis, Ellen W. Hatch

Biomedical Sciences ETDs

Quantitative fluorescence microscopy is a highly technical, swiftly evolving field of methodologies that are uniquely able to probe the nano-scale biological environment. With these optimized, advanced technologies available, scientists and medical providers are equipped to illuminate a plethora of puzzles in science and medicine through the multiplexing and high spatiotemporal resolution offered. Here I first exploit these capabilities to study a rare cancer with multiplex immunohistofluorescence (IHF) to confirm cell type and undocumented protein expression that may have implications for our understanding of the biology of mast cells and the potential efficacy of treatment and symptom management in mast cell …

Determining Mediators Of Naive T Cell Motility And Dc Association In The Lymph Node, Janie R. Byrum

Biomedical Sciences ETDs

To become activated and perform effector functions, naive T cells move within lymph nodes to scan dendritic cells presenting antigen. Previous work has shown naive T cell activation is promoted by interleukin 7 in vivo, and it does so by regulating the T cell:dendritic cell interaction. Our work identifies a novel role for IL-7 in mediating naive T cell motility in the lymph node and promoting T cell association with DCs. Additionally, we have developed a method for analyzing microscopy images, regionalized normalized mutual information, to assess intercellular associations between T cells and other cells within the lymph node. Dendritic …

Mechanisms Of Arsenic-Induced Suppression Of Early Red Blood Cell Development, Sebastian Medina

Biomedical Sciences ETDs

Anemia adversely impacts the health of more than a billion people worldwide. A strong association between anemia and arsenic exposure has been reported in epidemiological studies from multiple countries. However, the mechanistic bases for the association between arsenic exposure and anemia is not fully understood. In this study, we found an inverse association between drinking water arsenic exposures and clinical indicators of anemia (i.e., red blood cell counts and hematocrit/packet cell volumes) in a cohort of men from rural Bangladesh enrolled in the Health Effects of Arsenic Longitudinal Study.

Follow-up studies in mice, revealed that 60-day exposure to trivalent inorganic …