Pharmacology, Toxicology and Environmental Health Commons^™

Heat Shock Factor 1 Signaling: A Novel Pathway Implicated In Rett Syndrome Pathophysiology, Sonia Gonzalez

Dissertations

Rett syndrome (RTT) is a severe neurodevelopmental disorder that is associated with loss-of-function mutations in the methyl-CPG binding protein 2 (MECP2) gene. There are limited therapeutic options to address the wide range of social, cognitive, motor, and respiratory symptoms that patients experience throughout their lifetime. To identify novel therapeutic targets, we leveraged a rare form of RTT known as MeCP2-mutation-negative or atypical RTT. Traditionally, RTT is first diagnosed clinically and then confirmed through the identification of mutations in the MECP2 gene. However, ~5% of RTT patients are found to be MeCP2-mutation-negative (atypical), despite sharing overlapping symptomology with typical RTT. We …

Muscarinic Acetylcholine Receptor 1: Implications For Precision Medicine And Rett Syndrome Therapeutics, Mackenzie Smith

Dissertations

Rett syndrome (RTT) is a rare neurodevelopmental disorder caused by mutations in the gene coding for methyl-CpG binding protein 2 (MeCP2). Currently, there is no cure for RTT and few effective treatment options to address the social, cognitive, motor, and respiratory symptoms that patients face. With the goal of identifying novel targets, our lab performed RNA-sequencing experiments in human autopsy samples and found decreased levels of the M1 muscarinic acetylcholine receptor. We have established that potentiation of this receptor in a Mecp2+/- mouse model of RTT rescues social, cognitive, and respiratory phenotypes, providing support for using drugs that act on …

Investigating Whether Txnrd2 Is A Therapeutic Target Against Triple Negative Breast Cancer Using African American-Derived Models, Keacha Chang

Dissertations

Despite similar breast cancer incidence rates, African American (AA) women experience a 40% higher mortality rate compared to Caucasian American (CA) women. This disparity is multifactorial and particularly pronounced in the Chicago area. AA women are twice as likely to be diagnosed with triple-negative breast cancer (TNBC), often at a younger age and with more aggressive disease. TNBC is a heterogeneous subtype lacking targeted therapies and is associated with the poorest prognosis among breast cancer types. Therefore, there is an urgent need for novel therapeutic strategies for TNBC, especially those tailored to AA patients. The thioredoxin pathway is essential for …

Bridging The Gap: Psychopharmacologic Education And Side Effect Screening For Non-Prescribing Mental Health Professionals, Elaine Fitzgerald

Dissertations

Abstract

Problem: The United States is experiencing a growing demand for pediatric mental health support. Surges in mental health diagnoses and psychotropic medication prescriptions have occurred, compounded by a shortage of psychiatric providers. Non-prescribing mental health professionals are well-positioned to recognize psychotropic medication side effects. However, psychologists and counselors lack formal pharmacology education.

Methods: The quality improvement (QI) initiative was guided by the Plan-Do-Study-Act (PDSA) model. The evidence-based psychopharmacologic education for non-prescribers utilized a quasi-experimental pre- and post- test design. Data collected from clinicians included knowledge, confidence, and skill concerning psychotropic medications. The Psychotropic Medication Monitoring Checklist (PMMC) screen clients …

The Role Of Extracellular Vesicles And Their Cargo In Intercellular Communication, Chongyu Zhang

Dissertations

Extracellular vesicles (EVs) are membranous vesicles secreted by most cells. They contain lipids, proteins, and nucleic acids, including microRNAs (miRNA), and function in intercellular communication by endocytosis into other cells. EVs in diseased states carry miRNAs and proteins reflective of the changed state of cells and can be endocytosed into other cells to exert regulatory effects. Thus, EVs represent a form of paracrine genetic regulation in health and disease. Myocardial infarction (MI) and pulmonary embolism (PE) are leading causes of cardiovascular deaths worldwide. It is important to develop new diagnostic and therapeutic approaches that could lead to medical advances. Circulating …

Nursing Education In Complementary Alternative Modalities: A Case Study, Deborah Bird

Dissertations

Purpose: The purpose of this embedded case study was to describe the preparation for and utilization of complimentary alternative modality (CAM) interventions by an experienced Doctor of Nursing Practice (DNP) prepared nurse practitioner (NP) working in an outpatient setting.

Background: Given the widespread use of CAM by the American public and the potential complications involved in combining CAM and standard medical care, a lack of educational preparation in CAM interventions by NPs delivering primary care in outpatient health care settings represents both a potential risk and a missed opportunity to provide holistic patient care. Such a lack of knowledge also …

Exploring Fused Deposition Modeling (Fdm) Three-Dimensional Printing Tablet Design Options For Pharmaceutical Dosage Forms, Guluzar Gorkem Buyukgoz

Dissertations

This dissertation examines the use of Fused Deposition Modeling (FDM) based three-dimensional (3D) printing approach for developing patient-specific dosage forms and addressing related technical challenges in such drug delivery systems. The first main objective is to explore pharmaceutical tablet design options using novel FDM 3D printing technology as the drug delivery platform such that drug form and tablet properties are tailored by considering patient age-specific formulations and dissolution control. Of the five different design options, two proposed options meet the main objective of providing similar drug release, whereas the popular option of fixed drug concentration but differing tablet size could …

Comparative Studies On Biochemical And Pharmacological Profiles Of Unfractionated Heparins & Their Depolymerized Derivatives From Bovine, Ovine And Porcine Origins, Ahmed Kouta

Dissertations

Heparin and heparin related drugs have remained the anticoagulant of choice for medical and surgical indications. These drugs are comprised of poly-component sulfated chains of varying length and biophysical structure with direct and indirect pharmacological effects. Heparins produce their therapeutic effects by multiple mechanisms involving both the cellular and humoral targets. These drugs represent natural products which are isolated from mammalian tissue rich in mast cells. Currently used heparin and LMWHs are obtained from porcine mucosal tissue. Other animal sources including bovine and ovine tissues also provide additional sources for the manufacturing of heparins. While there may be microchemical and …

Cardioprotective Extracellular Vesicles Derived-Micrornas: Sorting Mechanisms And Functions, Anh P. Phan

Dissertations

Extracellular vesicles (EVs) are nano-size membrane bound vesicles that are derived from the fusion of multivesicular endosomes with the plasma membranes. EVs have important roles in intercellular communication through the transfer of their unique cargoes including RNA, DNA and protein molecules to recipient cells. Mesenchymal stem cell (MSC)-derived EVs have been shown to reduce infarct size and reduce the progress of heart failure after cardiac ischemia/reperfusion (I/R) injury in animal models. Small non-coding RNAs such as microRNA (miRNA) have been indicated as one of the active components that mediate the beneficial effects of MSC-derived EVs. However, the selective packaging mechanisms …

The Assessment Of Co2 Exposures, Workload Demands, And Musculoskeletal Disorder Risk On Heart Rate For Select Craft Brewery Job Tasks, David L. Huizen

Dissertations

Americans have embraced craft beer, and the ensuing demand has resulted in an ever-increasing number of craft breweries opening over the past 20 years. Craft brewers are generally small employers and, as such, lack the resources necessary to address the safety and health of their employees adequately. Brewers face many safety and health hazards in their work environment. These hazards include exposures to carbon dioxide (CO₂), workload demand, and MSD risk. It is essential to evaluate these hazards in craft breweries as they handle carbon dioxide (CO₂) differently than large breweries by having the CO_{2 …}

Nanocarbon Modification Of Membranes For Enhanced Water Desalination And Water Treatment, Worawit Intrchom

Dissertations

Water scarcity is foreseen to be one of the great global issues in the coming decades. The challenges are not only in providing water supply to cope with the growing public demand, but recovering clean water to natural resources. Clean water supply, from brackish and seawater is attractive. Membrane distillation (MD) is an emerging thermal membrane-based process that has been used for desalination and other pollutant separations from water. MD can be operated at low temperature, so low-grade energy sources are a good alternative heat source for MD. High salt rejection and low membrane fouling also make MD interesting for …

Molecular Responses To Deepwater Horizon Oil Spill Contaminants In Estuarine Fish, Elizabeth Jones

Dissertations

The 2010 Deepwater Horizon (DWH) oil spill resulted in the oiling of approximately 2100 km of shoreline. During that time, resident organisms had to contend with the effects of multiple contaminants and suboptimal environmental conditions. This research examines the molecular effects of DWH oil spill contaminants in estuarine fish (CyprinodonvariegatusandFundulusgrandis) across multiple life stages, contaminant concentrations, and in conjunction with environmental stressors.

Our results indicate that:

1. Oil elicits substantial transcriptional effects across life stages in C. variegatus. In adults, exposure to low concentrations of oil and dispersant results in transcriptional effects related …

Fouling And Aging In Membrane Filtration : Hybrid Afm-Based Characterization, Modelling And Reactive Membrane Design, Wanyi Fu

Dissertations

Membrane filtration has been extensively used in water and wastewater treatment, desalination, dairy making, and biomass/water separation. However, membrane fouling, aging and insufficient removal efficiency for dissolved organic matters remain major challenges for wider industrial applications. In order to tackle these challenges, this doctoral dissertation investigates mechanisms of membrane fouling and development of antifouling membrane filtration technologies. Specifically, four major research areas are explored: (i) nanoscale physicochemical characterization of the chemically modified polymeric membranes; (ii) quantitative modelling between membrane properties and membrane fouling and defouling kinetics; (iii) development of quantitative structure-activity relationships for membranes that undergo thermal and chemical aging …

Elucidation Of The Molecular Mechanisms Of Electrically-Induced Cardioprotection, Anne Elizabeth Roessler

Dissertations

Cardiovascular disease is the leading cause of death worldwide. A myocardial infarction (MI), commonly known as a heart attack, is a major event in cardiovascular disease characterized by reduced blood flow to the heart. The ischemia and reperfusion (I/R) injury associated with an MI results in a region of dead tissue in the heart called an infarct, the size of which influences patient prognosis. In the 1980s, it was discovered that short, non-lethal episodes of I/R, termed ischemic preconditioning (IPC), can protect the heart against a subsequent MI. Ischemic preconditioning demonstrated the phenomenon of endogenous cardioprotection. Cardioprotection has great potential …

Functionalized Carbon Nanotubes In Hydrophobic Drug Delivery, Kun Chen

Dissertations

The direct incorporation of carboxylated carbon nanotubes (f-CNTs) into hydrophobic drug particles during their formation via anti-solvent precipitation is presented. The approach is tested using two drugs namely antifungal agent Griseofulvin (GF) and antibiotic Sulfamethoxazole (SMZ) that have very different aqueous solubility. It is observed that the f-CNTs dispersed in the water serve as nucleating sites for crystallization and are readily incorporated into the drug particles without altering crystal structure or other properties. The results show that the hydrophilic f-CNTs dramatically enhance dissolution rate for both drugs. The increased degree of functionalization leads to higher hydrophilicity and therefore faster dissolution …

Studying The Antagonistic Relationship Between Nkg2d And Tgf-Β Signaling In Cd8+ T Cells, Kushal Prajapati

Dissertations

Despite the remarkable success of cancer immunotherapies in treating patients with hematological cancers, the clinical response rates of immunotherapies in the case of solid tumors have been dismal. One major reason for the lower response rates is tumor-induced immune-suppression mediated by TGF-?, which directly suppresses the functionality of CD8+ T cells by inhibiting their activation, proliferation, and acquisition of inflammatory cytokines, granzyme B and perforin. On the other hand, NKG2D, a potent co-stimulatory receptor, has effects on CD8+ T cells opposite to that of TGF-?. In T cells from 22 healthy human donors, we found that the suppression by TGF-? …

Examining The Regulation Of Kv7 K+ Channels In Airway Smooth Muscle Cells And Their Potential As Novel Therapeutic Targets For The Treatment Of Asthma, Jennifer Haick

Dissertations

Asthma is a disease characterized by nonspecific and exaggerated airway narrowing, termed airway hyperresponsiveness (AHR), which involves the excessive contraction of airway smooth muscle. Despite the fact that airway smooth muscle is widely studied and understood to play a role in AHR, little is known about the specifics of that role. Our laboratory recently found that Kv7 potassium (K+) channels are expressed in airway smooth muscle cells (ASMCs). Kv7 channels are voltage sensitive K+ channels whose outward flux of K+ ions promotes a negative resting membrane voltage in excitable cells, thereby opposing electrical excitability. Inhibition of K+ channels is known …

Characterization Of The Effect Of Aeration On A Commercially Available Fibrin Sealant For Use In Wound Therapy, Adam Robert Marek

Dissertations

Wound care affects millions of people worldwide each year, and the need for an effective wound therapy still exists. The aim of this study was to characterize a novel, aerated biopolymer, fibrin foam, which is generated through a patented mixing process using a commercially-available fibrin sealant. This research developed a distinct preparation of fibrin foam that creates a porous environment with improved wound healing properties. With this fibrin foam, characterization assessments were performed, including evaluation of mixing parameters, biocompatibility, and biomechanical strengths.

Fibrin foam is created by performing six passes through a mixing device, which generates a foam matrix with …

A Microbiomic Approach To The Characterization Of The Impacts And Influences Of Viral, Bacterial, And Harmful Algal Bloom Toxins On The Bottlenose Dolphin, Corey David Russo

Dissertations

As apex predators that display high site fidelity Tursiops truncatus (bottlenose dolphin) are indicators of marine ecosystem health. Bottlenose dolphins, additionally, display pathogenesis and immune response similar to that of humans. Humans and coastal bottlenose dolphins, in particular, are constantly exposed to the same industrial, agricultural and domestic toxins and pathogens, contaminants and pollutants. Thus, studies on the bottlenose dolphin are also valuable in bridging the gap between ocean and human health. Bottlenose dolphins are susceptible to viral bacterial and toxin infection. Infection in the bottlenose dolphin manifests itself in the form of mass stranding events, unusual mortality events, chronic …

Macrobenthic Communities In The Northern Gulf Of Mexico Hypoxic Zone: Testing The Pearson-Rosenberg Model, Shivakumar Shivarudrappa

Dissertations

The Pearson and Rosenberg (P-R) conceptual model of macrobenthic succession was used to assess the impact of hypoxia (dissolved oxygen [DO] ≤ 2 mg/L) on the macrobenthic community on the continental shelf of northern Gulf of Mexico for the first time. The model uses a stress-response relationship between environmental parameters and the macrobenthic community to determine the ecological condition of the benthic habitat. The ecological significance of dissolved oxygen in a benthic habitat is well understood. In addition, the annual recurrence of bottom-water hypoxia on the Louisiana/Texas shelf during summer months is well documented.

The P-R model illustrates the decreasing …

Aminoglycoside-Induced Otoneurotoxicity: Analysis Of Inner Hair Cell Synaptic Plasticity Following Drug Exposure, Matthew M. Abernathy

Dissertations

Aminoglycoside antibiotics are powerful drugs for combating bacterial infections, but are limited in use due to their ototoxicity. This class of drug targets the auditory hair cells of the cochlea, causing cell death, which leads to a decline in auditory function. In spite of much research aimed at revealing a mechanism of damage, there are no co-therapies available to diminish the ototoxic liability of aminoglycosides. Existing research does show that there may be a neurodegenerative process that contributes to the observed toxicity. In an effort towards clarifying present understanding of issue, this dissertation project was conducted to characterize the neurodegenerative …

Compositional Determinants Of The Pharmacological Actions Of Heparins, Angel Lee Gray-Shah

Dissertations

This dissertation primarily focuses on how differences in molecular weight (MW) and structural composition affect the pharmacological activity of heparin and its derivatives. Heparins are a mixture of glycosaminoglycans chains which are used to prevent thrombosis in a number of clinical indications. Heparins promote the inhibition of blood coagulation via their plasmatic cofactors antithrombin (AT) and heparin cofactor II (HCII).

In these studies, various heparins with molecular weights ranging from 2.6 to 16.5 kDa were investigated. Not only the molecular weight but also the oligosaccharide composition greatly varied in these agents. One of the major objectives of this research was …

Gabab Regulation Of Methamphetamine-Induced Associative Learning, Robin Michelle Voigt

Dissertations

Addiction is a chronic, relapsing disorder for which strikingly few effective therapies exist, and there are no FDA-approved pharmacotherapies for methamphetamine (Meth) addition. There is an immense need to identify the neurobiological underpinnings of psychostimulant addiction and develop efficacious drug therapies to compliment the current mainstay treatment of behavioral/cognitive therapy.

Re-exposure to cues associated with psychostimulants (e.g., drug paraphernalia) increase neuronal activity and can elicit drug-craving and -seeking; an effect which is profound and long-lasting. A mechanism to disrupt those brain processes which are necessary to maintain the association may reduce the incidence of cue-elicited relapse.

Conditioned place preference (CPP) …

Use Of Monoclonal ∆-9-Tetrahydrocannabinol Antibodies Chemically Bound To A Polystyrene Surface Using Glutaraldehyde For The Purpose Of Extracting ∆-9-Tetrahydrocannabinol And ∆-9-Tetrahydrocannabinol Carboxylic Acid From Postmortem Whole Blood Samples For Analysis By Gas Chromatography Mass Spectrometry, Thomas Sidney Pittman

Dissertations

Quantitations of drugs and their respective metabolites in postmortem blood samples using gas chromatographic instrumentation is a primary analytical practice used to determine if drugs played a role in or were the cause of a victim's death. Postmortem blood samples often prove difficult to work with due to interfering substances formed during the putrefaction process. Attempts to eliminate interfering substances with present day extraction methods can be time-consuming, costly and often ineffective when dealing with drugs that exhibit toxicity or impairment at very low concentrations. This study was conducted using monoclonal antibodies chemically bound to a polystyrene surface to extract …

Cellular Proliferation, Death And Histology In Gambusia Affinis Livers After Exposure To 2-Aminofluorene And Benzidine, Susan J. Lentz

Dissertations

A fundamental need exists for aquatic animals in the biomonitoring of aquatic ecosystems for environmental carcinogens. G. affinis, a small fish species, is selected for this study due to its hardiness, non-migratory nature, geographic diversity and ability to develop tumors. Molecular tools for cellular proliferation and death are examined for use with G. affinis. Additionally, these tools are used to investigate the early carcinogenic effects of 2-aminofluorene and benzidine, both individually and combined, on G. affinis livers.

Antibodies to proliferating cell nuclear antigen (PCNA), p53, cleaved caspase-3 and cleaved poly(ADP-ribose) polymerase (PARP) were examined for use in G. …

Amyloid-β Deposition In Rat Brain: Histopathological And Functional Sequelae, Einar M. Sigurdsson

Dissertations

No abstract provided.

Characterization Of Adaptive Changes In 5-Htia Receptor Systems Induced By Repeated Injections Of 5-Ht Uptake Inhibitors, Qian Li

Dissertations

No abstract provided.

Corticosteroid Modulation Of Hippocampal Neural Activity, Dayne Y. Okuhara

Dissertations

No abstract provided.

Effect Of Af64a On Rat Brain Septo-Hippocampal And Striatal Cholinergic Systems: A Neurochemical And Molecular Analysis, Qing Ivy Fan

Dissertations

No abstract provided.

Androgen Receptors In The Hippocampus: Localization, Autoregulation, And Modulation Of Gene Expression In The Adult Male Rat, Janice E. Kerr

Dissertations

No abstract provided.