Digital Commons Network^™

Epigenetic Dysregulation In Levodopa-Induced Dyskinesia, David Anthony Figge

All ETDs from UAB

Levodopa-induced dyskinesia (LID) is a persistent behavioral sensitization that develops after repeated levodopa (L-DOPA) exposure in Parkinson disease (PD) patients. LID is characterized by a “priming effect”, whereby initial administrations of L-DOPA trigger a sensitized biochemical and transcriptional response upon subsequent administrations of L-DOPA. In neurons, transcriptional regulation through dynamic changes to epigenetic modifications, including DNA methylation and histone acetylation, have been shown pivotal to many long-term behavioral modifications; however, their role in LID has been minimally explored. Using a rodent model, we show LID development leads to the aberrant expression of DNA demethylating enzymes and locus-specific changes to DNA …

The Function Of Prmt1 In Normal And Abnormal Megakaryopoiesis, Hairui Su

All ETDs from UAB

Protein arginine methylation is a common type of post-translational modifications. Protein arginine methyltransferase 1 (PRMT1) is the predominant PRMT that is involved in diverse physiological and pathological processes in mammalian cells. Dysregulation of PRMT1 is often positively correlated with cancer development, yet many aspects of PRMT1’s role in cancer, especially in acute megakaryoblastic leukemia (AMKL) remain unclear. We identified two PRMT1-methylated substrates and how they impact normal and abnormal megakaryopoiesis. In this dissertation, we demonstrate that dual-specificity protein phosphatase 4 (DUSP4) and RNA binding motif protein 15 (RBM15), two crucial factors for megakaryocytic (MK) differentiation, are methylated by PRMT1 and …

Microglia Orchestrate The Inflammatory Response To Alpha-Synuclein In Parkinson Disease Models, Aaron Thome

All ETDs from UAB

Parkinson disease (PD) is the most common neurodegenerative movement disorder characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and widespread aggregates of the protein alpha-synuclein (α-syn). Increasing evidence points to inflammation as a chief mediator of PD with many of the inflammatory manifestations of human PD cases recapitulated in animal models of PD. We began by examining the inflammatory potential of α-syn fibrils, a newly characterized α-syn conformation that is neurotoxic and prion-like in its endogenous α-syn recruitment and cellular transmission. Our studies provide evidence that the α-syn fibrils evoke a pro-inflammatory response …

Human Cytosolic Sulfotransferase (Sult) 1b1 Half-Site Reactivity And The Identification And Characterization Of A Novel Variant Sult1b1 Isoform (L145v), Zachary Evan Tibbs

All ETDs from UAB

The human cytosolic sulfotransferases (hSULTs) are a fourteen-member family of phase II drug-metabolizing enzymes that catalyze the transfer of a sulfonate moiety from 3’-phosphoadenosine 5’-phosphosulfate (PAPS) to a recipient substrate. SULT-mediated sulfation serves to deactivate physiological hormones and detoxify xenobiotics. SULT1B1 is primarily resident to the gastrointestinal tract, liver, and possibly peripheral white blood cells (WBCs), whereby it performs its supposed physiological role. The iso-form has the capacity to sulfate thyroid hormones, small phenols, and polyaromatic hy-drocarbons resulting in their inactivation, detoxification, and bioactivation/detoxification, respectively. Immunohistochemistry was used to show hSULT1B1 protein is present in periph-eral lymphocytes and neutrophils. Further, …

Polycomb Repressive Complex 2 And Heterochromatin Protein 1 Beta Regulate Neural And Neural Crest Development, Chih-Liang Tien

All ETDs from UAB

Epigenetic factors control gene expression via modulating chromatin conformation. Current studies on epigenetics mainly focus on biochemical mechanisms or functions of epigenetic factors in cancer or neurobiology. The underlying mechanism for epigenetic regulation in early embryonic development, particularly neural and neural crest development, is not well understood. In this thesis, the model organism, Xenopus laevis, is used to study epigenetic factors – polycomb repressive complex 2 (PRC2) and heterochromatin protein 1 beta (HP1β) in neural and neural crest development. In chapter one, the processes of neural and neural crest development are described, and the concepts of epigenetic mechanisms, such as …

Role Of Autocrine And Paracrine Wnt Signaling In Chronic Myeloid Leukemia Stem Cells, Puneet Agarwal

All ETDs from UAB

Treatment of chronic myeloid leukemia (CML) with BCR-ABL tyrosine kinase inhibitors (TKIs) fails to eradicate the leukemia stem cells (LSCs) from which the disease arises. Previously, we and others have shown that LSC persistence is related to kinase-independent mechanisms and mediated in part by signals from the bone marrow microenvironment (BMM). Specifically, we found that WNT signaling from the BMM may contribute to preservation of CML LSC following TKI treatment. Wnt secretion and activity requires their palmitoylation by the Porcupine acyltransferase (PORCN). WNT974 (formerly LGK974) is a potent PORCN inhibitor that blocks WNT signaling and demonstrates in vivo efficacy against …

Mechanisms Of Innate And Adaptive Immune Function In Parkinson Disease, Heather Elizabeth Allen

All ETDs from UAB

Parkinson disease (PD) is a common neurodegenerative movement disorder characterized pathologically by loss of dopaminergic neurons in the substantia nigra and aggregation of alpha-synuclein (α-syn) into large inclusions. The association of mutations and gene multiplications in SNCA, the gene encoding α-syn, with rare familial forms of PD led to the discovery that α-syn plays a key role in the pathogenesis of PD. The mechanism by which α-syn mediates its toxicity remains uncertain. A leading hypothesis states that the toxic effects of α-syn are mediated by activation of both the innate and adaptive immune systems within the central nervous system. Supporting …

Suppression Of Neutrophil-Mediated Tissue Damage—A Novel Skill Of Mesenchymal Stem Cells, Dongsheng Jiang, Jana Muschhammer, Yu Qi, Andrea Kügler, Juliane C. De Vries, Mona Saffarzadeh, Anca Sindriaru, Seppe V. Beken, Meinhard Wlaschek, Mark A. Kluth, Christoph Ganss, Natasha Y. Frank, Markus H. Frank, Klaus T. Preissner, Karin Scharffetter-Kochanek

Research outputs 2014 to 2021

Mesenchymal stem cells (MSCs) are crucial for tissue homeostasis and regeneration. Though of prime interest, their potentially protective role on neutrophil-induced tissue damage, associated with high morbidity and mortality, has not been explored in sufficient detail. Here we report the therapeutic skill of MSCs to suppress unrestrained neutrophil activation and to attenuate severe tissue damage in a murine immune-complex mediated vasculitis model of unbalanced neutrophil activation. MSC-mediated neutrophil suppression was due to intercellular adhesion molecule 1-dependent engulfment of neutrophils by MSCs, decreasing overall neutrophil numbers. Similar to MSCs in their endogenous niche of murine and human vasculitis, therapeutically injected MSCs …

The Role Of Hydrogen Peroxide In The Modulation Of Capsule Biosynthesis In Streptococcus Pneumoniae Serotype 2, Jocelyn Renee Hauser

All ETDs from UAB

Streptococcus pneumoniae is a gram-positive bacterial pathogen that causes diseases such as pneumonia, meningitis, bacteremia and middle ear infections. The major virulence factor of S. pneumoniae is its polysaccharide capsule. The capsule enables the organism to evade host defenses by providing protection against complement-mediated opsonophagocytosis in systemic sites and by allowing the organism to successfully colonize the nasopharynx. The nasopharynx is the natural reservoir of S. pneumoniae. In the nasopharynx, S. pneumoniae is in a high oxygen (O2) environment, however when it has the opportunity to bypass host defenses and invade systemic sites, it reaches environments with low O2. Capsule …

Novel Biomarkers For Parkinson Disease, Kyle Bradley Fraser

All ETDs from UAB

Parkinson disease (PD) is the most common neurodegenerative movement disorder for which no treatments exist capable of slowing progression of the disease. One obstacle slowing the development of novel therapies is the lack of molecular biomarkers for PD prognosis, tracking of disease progression, and assessing efficacious target engagement of compounds that do reach clinical trials. Missense mutations in LRRK2 account for between 1-5% of late onset PD and lead to increases in LRRK2 kinase activity and LRRK2 autophosphorylation. This thesis characterizes the secretion of LRRK2 into extracellularly secreted microvesicles called exosomes. We find that kinase-active LRRK2 is secreted within exosomes …

Copper Chaperone In Streptococcus Mutans Biofilm Formation And Dispersion Of Biofilms By Small Molecules, Sandra Stephanie Garcia

All ETDs from UAB

program pilot study randomly assigned 100 women, aged 19 to 25 to two groups. One

Neurobiological Consequences Of Perinatal Ssri Exposure, Matthew Edward Glover

All ETDs from UAB

Selective serotonin reuptake inhibitors (SSRIs) have been a mainstay pharmacological treatment for women experiencing depression during pregnancy and postpartum for nearly three decades. Recently, though, growing evidence indicates that early-life SSRI exposure triggers long-lasting behavioral abnormalities. Clinically, children exposed to SSRIs in early life exhibit increased internalizing behavior, reduced social behavior, and increased risk for depression in adolescence. Similarly, in rodents, perinatal SSRI exposure leads to increased traits of anxiety- and depression-like behavior. Interestingly, certain individuals are more susceptible to early-life SSRI exposure than others, suggesting that perinatal SSRI exposure poses greater risks for negative outcome within certain populations; however, …

Genome-Wide Transcription And Dna Methylation Profiling In An App Mouse Model Of Alzheimer’S Disease, Mikael C. Guzman Karlsson

All ETDs from UAB

The ability to encode information for long-term behavioral adaptation relies on experience-dependent alterations in neuronal plasticity. Neuronal plasticity encompasses the cellular and molecular changes that modulate synaptic communication between neurons as well as intrinsic electrophysiological properties within neurons. Epigenetic mechanisms, including DNA cytosine methylation and histone post-translational modifications, are powerful regulators of neuronal gene expression, allowing for dynamic, bidirectional regulation of transcriptional signatures necessary for neuronal plasticity. Emerging evidence using candidate-gene and microarray-based approaches suggest that the deficits in neuronal plasticity and cognitive impairment observed in Alzheimer’s disease (AD) is attributable, in part, to aberrant cytosine methylation and transcription of …

Regulation Of The Mitochondrial Thiol Network With Targeted Electrohpiles, Matthew Ryan Smith

All ETDs from UAB

Cells possess a remarkable plasticity to alter their metabolism and change their function based on stimuli within their resident microenvironment. The mitochondria within these cells utilize a variety of sources such as pyruvate, glutamine, or fatty acids in order to generate metabolites, amino acids, and reducing equivalents needed for cellular proliferation.Many mitochondrial enzymes possess contain a cysteine which possesses a thiol group, a unique redox-signaling moiety that can be activated under specific circumstances by bio-reactive compounds forming a network of mitochondrial proteins which are responsible for mitochondrial respiration. However, it is unknown whether targeting these reactive thiol groups present a …

Synthesis Of Neoglycoproteins/Neoglycopeptides And Their Immunological Evaluation In The Context Of Chagas Disease, Nathaniel Scott Schocker

Open Access Theses & Dissertations

The protozoan parasite, Trypanosoma cruzi, the etiologic agent of Chagas disease (ChD), has a cell surface covered by immunogenic glycoconjugates. A synthetic glycoarray containing non-reducing α-galactopyranosyl moieties related to mucin O-glycans of the parasite T. cruzi was evaluated by a chemiluminescent enzyme-linked immunosorbent assay (CL-ELISA) with sera from patients with chronic ChD, revealing the disaccharide Galα(1,3)Galβ as the immunodominant glycotope (Chapter 2). This disaccharide comprises the two terminal sugars of the known immunodominant glycotope Galα(1,3)Galβ(1,4)GlcNAcα, which is expressed on glycosylphosphatidylinositol-anchored mucins of the infective trypomastigote stage of T. cruzi and triggers high levels of protective anti-α-Gal antibodies (Abs) in infected …

The Effect Of Arsenic On Type 2 Diabetes And Inflammation, Kayla Penta

Theses and Dissertations

Arsenic, a ubiquitous environmental contaminant, has been shown to cause a number of health effects. At high concentrations the inorganic form is a well-known toxin, but at lower concentrations the effects range from various cancers, to cardiovascular disease and type 2 diabetes. At higher concentrations of arsenic (500- 1000μg/L) there have been epidemiological studies conducted demonstrating an increased risk in the development of type 2 diabetes with this exposure. At lower levels of arsenic exposure (<500 μg/L) the epidemiological results are inconclusive. Arsenic is also an immunotoxicant, meaning that it will cause changes in the immune response. The changes in the immune response will vary depending on a number of variables, including amount of arsenic exposure, forms of exposure and route of exposure. We wanted to determine if arsenic could modulate the immune system, and if this change could lead to an increase in susceptibility to type 2 diabetes development. We chose to examine this in C57BL/6 and db/+ mice – two non-susceptible strains. After 8 weeks (4 weeks old to 12 weeks old) of low dose inorganic arsenic exposure (50 μg/kg or 500 μg/kg) we evaluated changes in body composition, glucose tolerance and immune response. We saw that there were differences based on sex, genotype and treatment group present after the 8-week treatment period in body composition, while there were minimal changes in glucose tolerance. Finally, the immune response showed great variability depending on sex, genotype and treatment group. This project has demonstrated that while we are trying to compare differences in in vivo and epidemiological studies to find a link between arsenic and type 2 diabetes, there may be deeper levels of complications based on individual variability to arsenic exposure.

Examining The Effects Of Anti-Nogo A Immunotherapy On Post-Stroke Neurogenesis In The Adult Rat, Daniel Shepherd

Dissertations

Stroke is a leading cause of adult disability with no pharmacological treatments to restore lost function. Our laboratory has shown that treatment with neutralizing antibodies against the neurite growth-inhibitory protein Nogo-A improves sensorimotor and cognitive recovery after stroke in adult and aged rats. This recovery is paralleled by increased dendritic and axonal plasticity in anti-Nogo-A-treated rats. Neurogenesis, an alternate form of plasticity involving the de novo production of new neurons, may contribute to post-stroke neural repair. While previous studies have found roles for Nogo-A in adult neurogenesis, neurogenesis has not been investigated after stroke and anti-Nogo-A treatment. The goal of …

Cellular Consequences Of Lysosomal Rupture Induced By Alpha Synuclein, Zachary Carpenter Green

Master's Theses

Misfolded, toxic forms of amyloid alpha synuclein (α-syn) have been implicated in Parkinson’s disease (PD) pathology and have been shown to spread throughout the brain in a prion-like manner, explaining the progressive loss of neurons in PD. The mechanisms of spread and cell death are unknown, however, evidence from previous studies suggests that neurons may undergo apoptosis due to the uptake of exogenous α-syn aggregate through the endocytic pathway and subsequent lysosomal rupture.

This study aimed to corroborate previous evidence of α-syn induced lysosomal rupture and investigate the cellular repercussions of rupture with respect to cell death and α-syn transfer. …

Estrogen Regulation Of Mir-181a Stability In Neurons, Chun Kim

Master's Theses

Estrogens are an important class of steroid hormones involved in many cellular signaling processes. Levels of estrogens fluctuate across the lifespan suggesting that they target intracellular mediators, such as microRNAs, to fine-tune homeostatic cellular processes. Previous work in our lab demonstrated that 17β-estradiol (E2), the predominant circulating estrogen, stabilized miR-181a in a neuronal cell line derived from rat hypothalamus. These results lead to the hypothesis that E2 regulated miR-181a stability by altering the pool of endogenous RNA and by recruiting PNRC2 away from the miRNA degradation machinery. By utilizing miRNA degradation assays and immunostaining techniques, it was determined that the …

Drug And Vaccine Development For Neisseria Gonorrhoeaea, Devin R. Cash

Theses and Dissertations

Neisseria gonorrhoeae, the causative agent of the STI gonorrhea, is not preventable by vaccination and is rapidly developing resistance to antibiotics. One important strategy for gonococcal survival in the host is iron acquisition in the face of nutritional immunity. To overcome iron limitation, the gonococcus expresses TonB dependent transporters (TdTs), outer membrane proteins that facilitate nutrient acquisition. Of the TdTs, the transferrin (Tf), lactoferrin (Lf), and hemoglobin (Hb) receptors hijack iron directly from host proteins, and studies have already shown that the Tf receptor is essential for the initiation of human infection. Given that the TdTs are virulence factors, …

Post-Tbi Hippocampal Neurogenesis In Different Tbi Models, Kaushal S. Patel

Theses and Dissertations

Traumatic brain injury (TBI) leads to short-term and long-term consequences that can cause many different life-long disorders. Studies of TBI have generally focused on the acute stage; however, it is now becoming important to investigate chronic responses following TBI as clinical reports of dementia and cognitive impairments have been linked to a history of TBI. Recent data have established that cognitive function is associated with hippocampal neurogenesis. Chronic injury induced changes in the brain may affect this endogenous process. Chronic responses following TBI include cell death pathways and inflammatory responses that are persistent in the brain for months to years …

Effects Of Traumatic Brain Injury On Oxycodone Reinstatement And Physical Dependence, Neil B. Varshneya

Theses and Dissertations

Epidemiological data indicate that patients who experience a traumatic brain injury (TBI) have an elevated risk of developing a substance use disorder (SUD), but the underlying neurobiological connections remain unclear. To further understand the relationship between TBI and SUD, we investigated the effects of TBI on the abuse-related effects of oxycodone in preclinical models. Our evaluation utilized a lateral fluid percussion injury of moderate severity in adult male Sprague-Dawley rats. In the first aim, we tested the hypothesis that moderate TBI increases the risk for relapse to an opioid use disorder as measured by reinstatement of lever-pressing behavior following extinction …

Human Neural Progenitor Cells Are Productively Infected By R5-Tropic Hiv-1: Opiate Interactions On Infection And Function Involve Cdk5 Signaling, Joyce Magat Balinang

Theses and Dissertations

Human immunodeficiency virus type 1 (HIV-1) is known to cause a spectrum of neurological, behavioral and motor deficits collectively termed as HIV-1 associated neurocognitive impairments (HAND). Opiates augment HIV-related CNS complications through both direct and indirect mechanisms that disrupt glial and neuronal function. All CNS macroglia and neurons derive from neural progenitor cells (NPCs) during development, and NPCs in the adult brain contribute to repair processes. Since disruptions in NPC function are known to impact CNS populations and brain function in a number of disease/injury conditions, we determined whether HIV ± opiate exposure affected the maturation and fate of human …

Examining The Potential Clinical Value Of Curcumin In The Prevention And Diagnosis Of Alzheimer's Disease, K. G. Goozee, T. M. Shah, Hamid R. Sohrabi, Stephanie Rainey-Smith, B. Brown, Guiseppe Verdile, Ralph Martins

Research outputs 2014 to 2021

Curcumin derived from turmeric is well documented for its anti-carcinogenic, antioxidant and anti-inflammatory properties. Recent studies show that curcumin also possesses neuroprotective and cognitive-enhancing properties that may help delay or prevent neurodegenerative diseases, including Alzheimer’s disease (AD). Currently, clinical diagnosis of AD is onerous, and it is primarily based on the exclusion of other causes of dementia. In addition, phase III clinical trials of potential treatments have mostly failed, leaving disease-modifying interventions elusive. AD can be characterised neuropathologically by the deposition of extracellular β amyloid (Aβ) plaques and intracellular accumulation of tau-containing neurofibrillary tangles. Disruptions in Aβ metabolism/clearance contribute to …

Human Oocytes And Embryos Viewed By Time-Lapse Videography, And The Development Of An Embryo Deselection Model, Yanhe Liu

Theses: Doctorates and Masters

Despite its wide application today, in vitro fertilization (IVF) treatment continues to have relatively low efficacy, largely due to inaccuracy in selecting the best quality embryo(s) from the cohort for transfer. Novel methodologies for improved selection are being developed, and time-lapse observation of human embryos is gaining increasing popularity due to the more detailed morphokinetic information obtained plus uninterrupted culture conditions. The morphokinetic information enables the use of quantitative timings in developmental milestones of embryos and qualitative measures of abnormal biological events, to assist embryo selection/deselection. This project aimed to identify current limitations in the use of such measures and …

Mitochondrial Function Assessed By 31p Mrs And Bold Mri In Non-Obese Type 2 Diabetic Rats, Yuchi Liu, Xunbai Mei, Jielei Li, Nicola Lai, Xin Yu

Electrical & Computer Engineering Faculty Publications

The study aims to characterize age-associated changes in skeletal muscle bioenergetics by evaluating the response to ischemia-reperfusion in the skeletal muscle of the Goto-Kakizaki (GK) rats, a rat model of non-obese type 2 diabetes (T2D). ³¹P magnetic resonance spectroscopy (MRS) and blood oxygen level-dependent (BOLD) MRI was performed on the hindlimb of young (12 weeks) and adult (20 weeks) GK and Wistar (control) rats. ³¹P-MRS and BOLD-MRI data were acquired continuously during an ischemia and reperfusion protocol to quantify changes in phosphate metabolites and muscle oxygenation. The time constant of phosphocreatine recovery, an index of mitochondrial oxidative capacity, …

Potential Treatments For Malformation Associated Epilepsy, Olivia M. Bowles

Theses and Dissertations

Epilepsy has been previously attributed to either increased excitation or decreased inhibition. With this closed frame of mind, modern medicine has been unable to develop a permanent treatment against the mechanisms of epilepsy. In order to treat patients with intractable seizures, especially those caused by developmental malformations, it is essential to understand the entirety of mechanisms that could possibly play a role in the abnormal cortical function. One such developmental malformation is known as polymicrogyria. Epileptogenesis occurs in an area laterally adjacent to this malformation known as the paramicrogyral region (PMR). Past studies have narrowed down the potential cause of …

Role Of Vav2 In Podocyte Inflammasome Activation And Glomerular Injury During Hyperhomocysteinemia, Sabena Conley

Theses and Dissertations

Hyperhomocysteinemia (hHcys) is a widely known pathogenic factor in the progression of end-stage renal disease (ESRD) and it is also associated with an increased risk for injurious cardiovascular pathologies during ESRD. HHcys is linked to the formation and activation of the NOD-like receptor protein 3 (NLRP3) inflammasome, characterized as a critical early mechanism initiating the inflammatory response. NADPH oxidase (NOX)-derived reactive oxygen species (ROS) mediate the activation of the NLRP3 inflammasome in podocytes in response to elevated levels of homocysteine (Hcys) in vitro and in vivo. However, it remains unknown how NLRP3 inflammasome activation is triggered by NOX. The …

Determining The Effect Of Knocking Out Microrna-21 On Subsarcolemmal And Interfibrillar Mitochondria, Madhur Batra

Theses and Dissertations

Type 2 diabetes mellitus is a growing problem across the world and has significant pathological changes associated with it, including diabetic cardiomyopathy, wherein cardiac function is reduced. MicroRNA-21 has been shown to play a role in both the heart and diabetes so it was thought that knocking out miR-21 could have a protective effect on oxidative phosphorylation function in diabetic mice. Subsarcolemmal and interfibrillar mitochondria were isolated from adult male WT, miR-21 KO, db/db, and double knockout mice (db/db and miR-21 KO cross) and evaluated for function. Knocking out miR-21 in diabetic mice showed a restorative effect in Complex I …

Incidence And Factors Associated With Nonalcoholic Fatty Liver Disease Among Patients With Rheumatoid Arthritis, Ani K. John

Walden Dissertations and Doctoral Studies

Nonalcoholic fatty liver disease (NAFLD) has become one of the most common hepatic diseases worldwide, making the diagnosis and management of NAFLD an emerging public health issue. Theories associated with NAFLD surmise that inflammation may be the root cause, along with the complex interplay of other chronic conditions such as obesity, metabolic syndrome, diabetes, dyslipidemia, and cardiovascular disease (CVD). It is unknown if other inflammatory conditions such as rheumatoid arthritis (RA), along with the use of methotrexate (MTX), might confer increased risk for NAFLD. Longitudinal data collected from a retrospective cohort of 17,481 adult RA patients in the United States …