Medicine and Health Sciences Commons^™

Metabolism Reprogramming In Hexavalent Chromium-Induced Human Lung Carcinogenesis, James Tate Fortin Wise

Theses and Dissertations--Pharmacology and Nutritional Sciences

Hexavalent chromium, Cr(VI), is an established human carcinogen that is a worldwide environmental health concern. It is well understood that reactive oxygen species, genomic instability, and DNA damage repair deficiency are important contributors to Cr(VI)-induced carcinogenesis. After decades of research some cancer hallmarks remain understudied for the mechanism of Cr(VI) carcinogenesis. Dysregulated cellular energetics have been established as a hallmark of cancer. Energy pathways that become dysregulated in cancer include mitochondrial respiration, lipogenesis, pentose phosphate pathway, one carbon metabolism, and increased anaerobic glycolysis in the presence of oxygen or ‘Warburg effect’.

To investigate metabolism changes in Cr(VI) carcinogenesis, we exposed …

Neurochemical Factors Associated With The Initial Pathophysiological Reaction To Large Vessel Occlusion Stroke, Sarah R. Martha

Theses and Dissertations--Nursing

Ischemic stroke is the leading cause of disability world-wide and affects over 800,000 people per year in the United States. The majority of these strokes are ischemic due to a blockage of blood flow to the brain. Damage to the brain occurs at the onset of stroke, neuronal cell death is irreversible and therefore, quick treatment to remove blockage is critical factor in the recovery from stroke. Mechanical thrombectomy as a treatment for ischemic stroke provides an ideal opportunity to collect blood distal and proximal to the cerebral thrombus to examine neurochemical changes occurring during stroke.

The purpose of this …

Mechanisms Of Trinucleotide Repeat Instability During Dna Synthesis, Kara Y. Chan

Theses and Dissertations--Toxicology and Cancer Biology

Genomic instability, in the form of gene mutations, insertions/deletions, and gene amplifications, is one of the hallmarks in many types of cancers and other inheritable genetic disorders. Trinucleotide repeat (TNR) disorders, such as Huntington’s disease (HD) and Myotonic dystrophy (DM) can be inherited and repeats may be extended through subsequent generations. However, it is not clear how the CAG repeats expand through generations in HD. Two possible repeat expansion mechanisms include: 1) polymerase mediated repeat extension; 2) persistent TNR hairpin structure formation persisting in the genome resulting in expansion after subsequent cell division. Recent in vitro studies suggested that a …

Targeting Maladaptive Plasticity After Spinal Cord Injury To Prevent The Development Of Autonomic Dysreflexia, Khalid C. Eldahan

Theses and Dissertations--Physiology

Vital autonomic and cardiovascular functions are susceptible to dysfunction after spinal cord injury (SCI), with cardiovascular dysregulation contributing to morbidity and mortality in the SCI population. Autonomic dysreflexia (AD) is a condition that develops after injury to the sixth thoracic spinal segment or higher and is characterized by potentially dangerous and volatile surges in arterial pressure often accompanied with irregular heart rate, headache, sweating, flushing of the skin, and nasal congestion. These symptoms occur in response to abnormal outflow of sympathetic activity from the decentralized spinal cord typically triggered by noxious, yet unperceived nociceptive stimulation beneath the level of lesion. …

Protocolized Volume De-Resuscitation In Critically Ill Patients, Brittany Dawn Bissell

Theses and Dissertations--Clinical and Translational Science

While early fluid resuscitation may be a necessary component to decrease mortality in the majority of critically ill patients admitted to the intensive care unit, the benefit of continued administration after the first 24 hours is less clear. Paradoxically, a positive fluid balance secondary to intravenous fluid receipt has been associated with diverse and persistent perpetuating detriment on a multitude of organ systems. Continued clinical harm has been demonstrated on pulmonary and renal function as well as patient outcomes such as rates of mortality and length of stay. Despite the growing body of evidence supporting the potential adverse aspects of …

The Stimulation Of Dendritic Cells By Cationic Lipids, John Peyton Bush

Theses and Dissertations--Medical Sciences

The discovery that cationic lipids can independently stimulate the immune system has generated interest in their potential as vaccine adjuvants. Here, we show that the cationic lipid R-DOTAP can independently stimulate type 1 interferon production in dendritic cells in both primary culture and immortalized cell culture. Levels of type 1 interferon production are cell line-dependent and limited in vitro by lipid-induced cell death. We show that cationic lipids can independently activate TLR-7 and TLR-9, suggesting a mechanism for type 1 interferon induction. This TLR-stimulatory activity is not restricted to R-DOTAP and can be extended to other similar cationic lipids in …

Toward An Enzyme-Coupled, Bioorthogonal Platform For Methyltransferases: Probing The Specificity Of Methionine Adenosyltransferases, Tyler D. Huber

Theses and Dissertations--Pharmacy

Methyl group transfer from S-adenosyl-l-methionine (AdoMet) to various substrates including DNA, proteins, and natural products (NPs), is accomplished by methyltransferases (MTs). Analogs of AdoMet, bearing an alternative S-alkyl group can be exploited, in the context of an array of wild-type MT-catalyzed reactions, to differentially alkylate DNA, proteins, and NPs. This technology provides a means to elucidate MT targets by the MT-mediated installation of chemoselective handles from AdoMet analogs to biologically relevant molecules and affords researchers a fresh route to diversify NP scaffolds by permitting the differential alkylation of chemical sites vulnerable to NP MTs that are unreactive to …

Preclinical Targeting Of Trem2 For The Treatment Of Alzheimer's Disease-Type Pathology In A Transgenic Mouse Model, Brittani Rae Price

Theses and Dissertations--Physiology

Alzheimer's disease (AD) is defined as a progressive neurodegenerative disorder and is characterized by a devastating mental decline. There are three pathological hallmarks of the disease necessary for its diagnosis, these are extracellular amyloid plaques comprised of the beta-amyloid (Aβ) protein, intracellular neurofibrillary tangles comprised of hyperphosphorylated tau protein, and marked neuronal loss. Active immunization against Aβ_1-42 or passive immunization with monoclonal anti-Aβ antibodies has been shown to reduce amyloid deposition and improve cognition in transgenic mouse models of AD, aged beagles, and nonhuman primates. Unfortunately, due to cerebrovascular adverse events, both active and passive immunization strategies targeting Aβ …

The Role Of Cd8 T Cell Immunodominance And Regulatory T Cells In Neonatal Immunity To Influenza Virus, Luke Heil

Theses and Dissertations--Microbiology, Immunology, and Molecular Genetics

Neonates are more susceptible to influenza virus infection than adults, resulting in increased morbidity and mortality as well as delayed clearance of the virus. Efforts to improve influenza infection outcomes in neonates typically center on prevention, although current vaccines fall short of complete protection and can only be administered in humans after 6 months of life. We propose that as the neonatal immune system responds differently than the adult immune system, interventions that are efficacious or tolerable in adults cannot be guaranteed to perform the same in neonates. T cell vaccines that target conserved influenza virus epitopes have been proposed …

Studies Of Oxidative Damage, Brain Proteome, And Neurochemical Metabolites In Cognitive And Neurodegenerative Disorders: (1) Chemotherapy-Induced Cognitive Impairment; (2) Parkinson Disease Rat Model, Xiaojia Ren

Theses and Dissertations--Chemistry

The rate of cancer patients is increasing as the development of science and technology. Twenty million cancer survivors are estimated living in the United States by 2025. However, many cancer survivors show cognitive dysfunction, negatively affecting the quality of life. These cognitive impairments are recognized as chemotherapy-induced cognitive impairment (CICI), also called "chemo brain" by cancer survivors, including the diminished ability of memory and learning, hard to concentrate and focus, as well as diminution of executive function and processing speed. The etiologies and pathologies of CICI are complicated, especially in most cases the anti-cancer drug cannot cross the blood-brain barrier …

Autologous Peripheral Nerve Grafts To The Brain For The Treatment Of Parkinson's Disease, Andrew Welleford

Theses and Dissertations--Neuroscience

Parkinson’s disease (PD) is a disorder of the nervous system that causes problems with movement (motor symptoms) as well as other problems such as mood disorders, cognitive changes, sleep disorders, constipation, pain, and other non-motor symptoms. The severity of PD symptoms worsens over time as the disease progresses, and while there are treatments for the motor and some non-motor symptoms there is no known cure for PD. Thus there is a high demand for therapies to slow the progressive neurodegeneration observed in PD. Two clinical trials at the University of Kentucky College of Medicine (NCT02369003, NCT01833364) are currently underway that …

Neuroprotective Strategies Following Experimental Traumatic Brain Injury: Lipid Peroxidation-Derived Aldehyde Scavenging And Inhibition Of Mitochondrial Permeability Transition, Jacqueline Renee Kulbe

Theses and Dissertations--Neuroscience

Traumatic brain injury (TBI) represents a significant health crisis. To date there are no FDA-approved pharmacotherapies available to prevent the neurologic deficits caused by TBI. Following TBI, dysfunctional mitochondria generate reactive oxygen and nitrogen species, initiating lipid peroxidation (LP) and the formation of LP-derived neurotoxic aldehydes, which bind mitochondrial proteins, exacerbating dysfunction and opening of the mitochondrial permeability pore (mPTP), resulting in extrusion of mitochondrial sequestered calcium into the cytosol, and initiating a downstream cascade of calpain activation, spectrin degradation, neurodegeneration and neurologic impairment.

As central mediators of the TBI secondary injury cascade, mitochondria and LP-derived neurotoxic aldehydes make promising …

Pathological Tau As A Cause, And Consequence, Of Cellular Dysfunction, Shelby Meier

Theses and Dissertations--Physiology

Tauopathies are a group of neurodegenerative diseases characterized by the abnormal deposition of the protein tau, a microtubule stabilizing protein. Under normal physiological conditions tau is a highly soluble protein that is not prone to aggregation. In disease states alterations to tau lead to enhanced fibril formation and aggregation, eventually forming neurofibrillary tangles (NFTs). The exact cause for NFT deposition is unknown, but increased post-translational modifications and mutations to the tau gene can increase tangle formation.

Tauopathic brains are stuck in a detrimental cycle, with cellular dysfunction contributing to the development of tau pathology and the development of tau pathology …

When Brain Stimulation Backfires, Sarah Beth Bell

Theses and Dissertations--Psychology

tDCS brain stimulation does not always work in the intended direction. It has been found to sometimes worsen behavior rather than improve it. A preliminary study shows that people high on sensation-seeking and lack of premeditation were prone to reverse effects of tDCS on performance on a Stop Signal Task. Both of these constructs are related to dopamine levels. Study 2 seeks to intentionally cause a reverse effect of tDCS by increasing participants’ dopamine levels via caffeine. There was not a significant interaction between tDCS and caffeine on errors on the Stop Signal Task in this study. However, other factors …

Changes In Muscle Size, Quality And Power Are Related To Physical Function In Patients With Critical Illness, Kirby Mayer

Theses and Dissertations--Rehabilitation Sciences

Patients admitted to intensive care unit (ICU) are known to develop significant impairments in physical function. Patients with critical illness suffer up to 30% reductions in muscle size within the first ten days of admission to the ICU. Muscle strength testing, Medical Research Council-sum score, is current gold-standard to diagnosis ICU-acquired weakness and predicts risk of mortality and long-term physical function. Muscle power different from muscle strength in that it accounts for velocity of movement, is potentially a better independent predictor of function that has not been studied in this population. In addition, we hypothesize that muscle size and quality …

Chronic Low Intensity Continuous And Interval Training Prevent Heart Failure-Related Coronary Artery Stiffness, An Ouyang

Theses and Dissertations--Kinesiology and Health Promotion

Heart failure (HF) induced by aortic pressure over-load is associated with increased coronary artery stiffness. Perivascular adipose tissue (PVAT) and advanced glycation end products (AGE) both promote arterial stiffness. However, the mechanisms by which coronary PVAT promotes arterial stiffness and the efficacy of exercise to prevent coronary stiffness are unknown. The present study hypothesized both chronic continuous and interval exercise training would prevent coronary artery stiffness associated with inhibition of PVAT secreted AGE. Yucatan mininature swine were divided into four groups: control-sedentary (CON), aortic-banded sedentary heart failure (HF), aortic-banded HF continuous exercise trained (HF+CONT), and aortic-banded HF interval exercise trained …