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Articles 1 - 30 of 60
Full-Text Articles in Medicine and Health Sciences
Protumorigenic Role Of Cathelicidin-Related Antimicrobial Peptide In Chemotaxis And Differentiation Of Myeloid Lineage During Prostate Cancer Progression, Ha-Ram Cha
All ETDs from UAB
A growing body of evidence indicates a positive correlation between the expression of human antimicrobial peptide leucine leucine 37 (LL-37) and the progression of epithelial cancers, including carcinomas of the breast, lung, ovary, and prostate. Although the molecular mechanisms for this correlation have not yet been clearly elucidated, the primary function of LL-37 as a chemotactic molecule for innate immune effector cells suggests its possible association in coordinating protumorigenic mechanisms mediated by tumor-infiltrating immune cells. Using a mouse model of epithelial prostate cancer (PCa), the present study identified a unique role for cathelicidin-related antimicrobial peptide (CRAMP), a murine orthologue of …
A New Form Of Rod Photoreceptor Light Adaptation, Alex S. Mckeown
A New Form Of Rod Photoreceptor Light Adaptation, Alex S. Mckeown
All ETDs from UAB
In the first step in light perception, rod and cone photoreceptors convert photon absorption into an electrical impulse that is transmitted through the visual pathway. While the biochemistry and the signaling physiology have largely been defined in dark-adapted, isolated mammalian rods, there are still unanswered questions regarding photoreceptor light adaptation processes that involve extracellular components. In particular, the proteins of the interphotoreceptor matrix have not been considered in the studies of rod signaling and adaptation. This thesis details a new form of light adaptation, now known as adaptive potentiation (AP), in which extracellular components act on rods to transiently increase …
Innate Immunity Mechanisms In Parkinson Disease, Mark Moehle
Innate Immunity Mechanisms In Parkinson Disease, Mark Moehle
All ETDs from UAB
Parkinson disease (PD) is a late onset, progressive neurodegenerative movement disorder with cardinal symptoms of tremor at rest, bradykinesia, postural instability, and rigidity. These motor symptoms of PD are caused by the progressive loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). However, despite PDs first modern observation in 1817, little is understood about the causes and molecular mechanisms behind dopaminergic neuron loss. The relatively weak understanding of pathological mechanisms has hindered the development of treatments to slow or halt the progression of PD. However, recently, mounting evidence from post-mortem, imaging, and retrospective studies suggest an important role …
Structural Implications Of P22 Bacteriophage Coat Protein A-Domain Modifications, David Samuel Morris
Structural Implications Of P22 Bacteriophage Coat Protein A-Domain Modifications, David Samuel Morris
All ETDs from UAB
Modification of virus capsids as target-specific delivery devices has become highly popularized in recent years and P22 bacteriophage has been proposed as a potential candidate for development of a targeting drug delivery system. As a proof of concept for our system, we hypothesized that the A-domain of P22 coat protein could be utilized to alter the binding affinity of virus-like procapsids for biological targets. Addition of acidic residues to the A-domain revealed that this could be accomplished through the quarternary localization of charged residues in three-dimensional space without interrogating procapsid assembly. Further manipulations implemented in vivo were performed to examine …
Gaba(A) Receptor Trafficking And Localization In Schizophrenia, Toni Marie Mueller
Gaba(A) Receptor Trafficking And Localization In Schizophrenia, Toni Marie Mueller
All ETDs from UAB
Mechanisms underlying the complex etiology of schizophrenia have long been a subject of scientific inquiry. Early investigations focused on identifying functional deficits in dopaminergic and glutamatergic neurotransmission, but evidence for disrupted GABAergic signaling has also emerged. Recent studies from our lab have identified disrupted N-glycosylation of glutamate receptor and transporter subunits and abnormal subcellular distribution of glutamate receptor subunits, suggesting a potential functional consequence of perturbed N-glycosylation in schizophrenia. N-glycosylation is the posttranslational enzymatic attachment of an oligosaccharide precursor to a protein. This modification plays a significant role in protein processing in the ER and Golgi, and is known to …
Nadph Oxidase-Derived Superoxide: A Potentiator Of Autoimmune Responses In Type 1 Diabetes, Lindsey E. Padgett
Nadph Oxidase-Derived Superoxide: A Potentiator Of Autoimmune Responses In Type 1 Diabetes, Lindsey E. Padgett
All ETDs from UAB
Type 1 Diabetes (T1D) is an autoimmune disease culminating in pancreatic β-cell destruction, inducing reactive oxygen species (ROS), pro-inflammatory cytokines, and islet-infiltrating leukocutes. Macrophages, one of the first islet-infiltrating cells in T1D, secrete ROS and pro-inflammatory cytokines, which lyse pancreatic β-cells and activate diabetogenic T cells to further propagate β-cell destruction, while autoreactive CD4 T cells recruit islet-infiltrating, pro-inflammatory, M1 macrophages, and enhance CD8 T cell cytotoxicity. We previously demonstrated the importance of NADPH oxidase (NOX)-derived ROS synthesis in T1D, as Non-obese diabetic (NOD) mice lacking NOX-derived superoxide (NOD.Ncf1m1J) exhibited a delay in spontaneous and adoptive transfer of T1D. In …
The Role Of C-Reactive Protein In Acute Kidney Injury, Melissa A. Pegues
The Role Of C-Reactive Protein In Acute Kidney Injury, Melissa A. Pegues
All ETDs from UAB
Acute kidney injury (AKI), which manifests as an abrupt decline in renal function, occurs in ~1% of all hospitalization. Ischemia reperfusion injury (IRI), a common cause of AKI, can occur in any situation where blood flow to the kidney is significantly reduced such as hypertensive crisis, cardiovascular surgery, and inevitably during renal transplantation. Mortality from AKI is up to 80% due to incomplete knowledge of the pathogenesis of IRI and the lack of an effective therapy. It is thought that cellular damage as a result of hypoxia signals the release of proinflammatory cytokines that lead to a systemic inflammatory response. …
Role Of Macrophages In The Cardiomyopathy Associated With Obesity And Type 2 Diabetes, Mehak Goel
Role Of Macrophages In The Cardiomyopathy Associated With Obesity And Type 2 Diabetes, Mehak Goel
All ETDs from UAB
Obesity is a state of chronic low-grade systemic inflammation that, along with type 2 diabetes (T2D), increases the risk of developing cardiovascular disease (CVD). Despite the wealth of information on the link between macrophages and cytokines in adipose tissue and peripheral insulin resistance, their role in the pathogenesis of diabetic cardiomyopathy and cardiac diastolic dysfunction is unclear. We hypothesized that activated immune cell mediators, in particular monocytes and macrophages, are fundamental drivers of diet-induced obesity and diabetic cardiomyopathy. Herein, firstly, a diet-induced model of diabetic cardiomyopathy was developed in C57BL/6 mice by feeding a high fat diet (HFD, 45% kcal …
G Protein-Coupled Inwardly-Rectifying Potassium (Girk) Chanels Mediate Entrainment Of Circadian Rhythms, Lauren Marie Hablitz
G Protein-Coupled Inwardly-Rectifying Potassium (Girk) Chanels Mediate Entrainment Of Circadian Rhythms, Lauren Marie Hablitz
All ETDs from UAB
Circadian rhythms are 24-hour cycles in biological and behavioral processes. These cycles enable an organism to predict changes in its environment, like changes in food availability and seasonality. Although endogenously driven, these rhythms can entrain or synchronize to daily changes in the environment, allowing the animal to adapt. One way entrainment occurs is shifts in circadian phase following the presentation of nonphotic, or non-light, stimuli, such as exercise, arousal, or stress at certain times of day. The molecular mechanisms underlying nonphotic entrainment are poorly understood - specifically, how nonphotic cues alter excitability within the suprachiasmatic nucleus (SCN) of the hypothalamus, …
Metabolic And Oxidative Regulation Of Neuronal Autophagy And Survival, Matthew Dodson
Metabolic And Oxidative Regulation Of Neuronal Autophagy And Survival, Matthew Dodson
All ETDs from UAB
Neurodegenerative diseases, such as Parkinson's disease, Alzheimer's disease and Huntington's disease are all characterized by metabolic dysfunction, increased oxidative damage to proteins and organelles, formation of proteinaceous inclusions, decreased autophagic and proteasomal function, and eventual neuronal and glial cell death. While our understanding of the mechanisms that underlie many of these pathologies is constantly growing, their exact cause, onset, interplay and progression still remain unclear. The gap between the description of disease pathologies and understanding the fundamental mechanisms of disease pathogenesis, progression and potential therapeutics to mitigate disease progression is still large. Based on the observation that altered glucose utilization, …
Defining The Role Of Trps1 In Phosphate Mediated Mineralization, Maria Kuzynski
Defining The Role Of Trps1 In Phosphate Mediated Mineralization, Maria Kuzynski
All ETDs from UAB
Mineralization is a tightly controlled bi-phasic process that occurs when crystals of calcium and phosphate (Pi) are laid down within the extracellular matrix. However, the molecular networks regulating the initiation and progression of this process have not been well characterized. Pi, as one of the components of mineral crystals and a signaling molecule that regulates expression of mineralization-related genes, is essential to the mineralization process. In our studies, we discovered a novel function for Pi in this process: Pi is sufficient to induce secretion of matrix vesicles, which support the initiation of mineralization. Furthermore, we determined that this induction is …
An Nphp-4 Enhancer Mutagenesis Screen For Modifiers Of Cilia Phenotypes Reveals Novel Mks Alleles, Uncovers, A Specific Genetic Interaction Between Osm-3 And Nphp-4, And A Novel Ciliary Calcium Channel., Dawn Landis
All ETDs from UAB
Nephronophthisis (NPHP) is a ciliopathy with diverse clinical features likely caused by genetic modifiers. To identify NPHP modifiers, a screen was conducted on nphp-4(tm925) mutant C. elegans to reveal mutations that exacerbate the NPHP ciliary defects. Ten loci were generated, five of which have now been identified. Three are mutations in ciliopathy genes mks-1, mks-2, and mks-5. The fourth allele (yhw66) is a missense mutation (S316F) in OSM-3, a kinesin required for cilia distal segment assembly. As in osm-3 null mutants, nphp-4(tm925);osm-3(yhw66) mutants lack distal segments, are dye-filing defective (Dyf), and have osmotic avoidance defects (OSM). The osm-3(yhw66) mutant alone …
The Regulation Of Vitamin A Metabolism, Mark Adams
The Regulation Of Vitamin A Metabolism, Mark Adams
All ETDs from UAB
Bioactive vitamin A takes form as several molecules, among them all-trans-retinoic acid (RA) is the major form and influences a wide range of biological processes. RA must be synthesized through a two-step mechanism, where all-trans-retinol is first oxidized to all-trans-retinaldehyde by retinol dehydrogenases (RDHs) and retinaldehyde is further oxidized to RA by retinaldehyde dehydrogenases (RALDHs). The first step, retinol to retinaldehyde conversion is the rate limiting step and therefore a likely target of mechanisms that modulate RA synthesis. Despite this, many of the enzymes that are involved in retinol and retinaldehyde interconversion have yet to be identified and thus many …
Competition From New Neurons Drives Circuit Refinement In The Adult Dentate Gyrus, Elena W. Adlaf
Competition From New Neurons Drives Circuit Refinement In The Adult Dentate Gyrus, Elena W. Adlaf
All ETDs from UAB
The hippocampus encodes sensory information into memories. The dentate gyrus (DG) region is viewed as the entry point into the hippocampus, receiving sensory and spatial signals from perforant path axons of the entorhinal cortex (EC). Ever since researchers discovered a neurogenic niche in the subgranular zone (SGZ) of the DG in adult animals and humans, many studies have been aimed at discovering how these continually proliferating granule cells (GCs) contribute to the network. Immature GCs have dendrites that project densely into the molecular layer alongside mature GCs and there is morphological evidence that immature excitatory spines preferentially synapse onto existing …
Pathophysiology And Metabolic Dysfunction Following Polytrauma, Robert Mackay Akscyn
Pathophysiology And Metabolic Dysfunction Following Polytrauma, Robert Mackay Akscyn
All ETDs from UAB
Polytrauma, a combination of injuries to more than one body part or organ system, is common in modern warfare and in automobile and industrial accidents. The combination of injuries can include burn, fracture, hemorrhage, trauma to the extremities, and trauma to specific organ systems. These injuries are highly survivable when occurring singly. However, when they occur in combination the prognosis is worsened. To investigate the effects of combined injuries, we have developed a new and highly reproducible model of polytrauma. This model combines burn injury with soft tissue and gastrointestinal (GI) tract trauma. Male Sprague Dawley rats were subjected to …
Regulation Of The Regulatory T Cell-Immunoglobulin A Pathway, Katie Lynn Alexander
Regulation Of The Regulatory T Cell-Immunoglobulin A Pathway, Katie Lynn Alexander
All ETDs from UAB
A dysregulated immune response to the microbiota is a defined characteristic of Crohn's Disease (CD), a type of Inflammatory Bowel Disease (IBD). Understanding how homeo-stasis is maintained in the intestine despite the immense concentration of bacteria present is an active area of research. Regulatory T cells (Tregs) play an important role in mucosal tolerance by controlling inflammation and modulating immune responses initiated by T effector cells (Teffs). Tregs also provide vital survival factors to IgA+ B cells in the intes-tine in order to support Immunoglobulin A (IgA) responses as part of a protective Treg-IgA pathway, which functions to maintain mutualism …
The I507-Atc→Att Silent Codon Change Contributes To The Misfolding Of ∆F508 Cftr, Vedrana Bali
The I507-Atc→Att Silent Codon Change Contributes To The Misfolding Of ∆F508 Cftr, Vedrana Bali
All ETDs from UAB
Synonymous codon changes (SCCs) do not alter the amino acid sequence of proteins, but may significantly change the phenotype. The frequency of synonymous codons is species- and gene-specific, described as codon usage bias (CUB). Over the past 50 years, research has shown that SCCs affect protein biogenesis, development of human disorders and the function of recombinant proteins developed for therapeutic applications. However, the molecular mechanisms by which SCCs alter the function of gene products are not completely understood. In Chapter 2 we summarize present knowledge in this field. The most common cause of cystic fibrosis (CF) is the deletion of …
Transient-State Kinetic Analysis Of The Rna Polymerase I Nucleotide Incorporation Mechanism, Francis Dean Appling
Transient-State Kinetic Analysis Of The Rna Polymerase I Nucleotide Incorporation Mechanism, Francis Dean Appling
All ETDs from UAB
The diversity of enzymes and the reactions which they catalyze is enormous. Careful study of enzymatic reaction mechanisms has taught us a great deal about chemical reactivity and has given us insight into the chemical and physical basis of life. One particularly ubiquitous class of enzymes, the RNA polymerases, are expressed in all forms of life. RNA polymerases are central components of nucleic acid metabolism and display a variety of distinctive enzymatic features; two points which solicit their thorough study. The central theme of this dissertation is the use of kinetic techniques to describe enzymatic reaction mechanisms. Although the main …
Tau-Sh3 Interactions: Implications For Alzheimer's Disease, Jesse Nicholas Cochran
Tau-Sh3 Interactions: Implications For Alzheimer's Disease, Jesse Nicholas Cochran
All ETDs from UAB
Alzheimer’s disease (AD) is the most common neurodegenerative disease and with Americans’ increasing longevity it is becoming an epidemic. There are currently no effective treatments for this disorder. Abnormalities of tau track more closely with cognitive decline than the most studied therapeutic target in AD, amyloid-beta, but the optimal strategy for targeting tau has not yet been identified. Based on considerable preclinical data from AD models, we hypothesize that interactions between tau and SH3 domain–containing proteins are pathogenic in AD. Genetically reducing either tau or tau interactants has beneficial effects relevant to AD. Here, we describe a drug screen for …
A Novel Role For Usp14 In Regulating Non-Proteolytic Ubiquitin Signaling, Jada Hallengren Vaden
A Novel Role For Usp14 In Regulating Non-Proteolytic Ubiquitin Signaling, Jada Hallengren Vaden
All ETDs from UAB
Loss of the deubiquitinating enzyme (DUB) USP14 in the ataxia (axJ) mice leads to altered neuromuscular junction (NMJ) structure, reduced synaptic transmission at the NMJ, and decreased mobility. However, the types of processes that USP14 regulates in the nervous system remain unclear. Because association with the proteasome stimulates USP14's ubiquitin hydrolase activity, it is thought to act primarily on proteasomal substrates. Therefore, one way for USP14 to support nervous system function is by modulating protein turnover. While a number of studies done in yeast and immortalized cell lines demonstrate that loss or inhibition of USP14 alters proteasome function, there is …
The Effects Of The Initially Transcribed Sequence On Reiterative Transcription In Escherichia Coli, Jeffery Michael Vahrenkamp
The Effects Of The Initially Transcribed Sequence On Reiterative Transcription In Escherichia Coli, Jeffery Michael Vahrenkamp
All ETDs from UAB
Transcription, the synthesis of a ribonucleic acid transcript using a nucleic acid template, is the first step in gene expression for all life. In most organisms, high fidelity transcription is achieved through the formation of an RNA:DNA hybrid which allows the RNA polymerase to maintain the correct register. Slippage, which would lead to improper base pairing, is prevented by the heterogeneous sequence of the DNA template. However, when homogenous tracts of bases are present in the template, slippage can occur, allowing a single base in the template to encode multiple bases in the transcript in a process called reiterative transcription. …
C-Reactive Protein, Autoimmunity, And Inflammation In The Central Nervous System, Tyler T. Wright
C-Reactive Protein, Autoimmunity, And Inflammation In The Central Nervous System, Tyler T. Wright
All ETDs from UAB
C-reactive protein (CRP) is an acute phase reactant whose blood concentration rises in response all types of inflammation. And while CRP is widely used as a clinical marker of inflammation, it has several biological functions, e.g. activation of the classical complement cascade and binding Fcγ receptors in order to mediate multiple immune processes. The full extent of CRP’s physiological activities has not yet been fully elucidated, but there is significant evidence to establish that CRP plays an important role in the onset and progression of autoimmune disease. Seminal work from our lab showed that human CRP, hepatically expressed in transgenic …
Intestinal Microbiota And Its Role In Mucosal And Systemic Immune Responses, Qing Zhao
Intestinal Microbiota And Its Role In Mucosal And Systemic Immune Responses, Qing Zhao
All ETDs from UAB
Host-microbiota mutualism is established with long-term co-evolution. The abundant and diverse microbes colonizing on the surface of the host’s body, especially those in the gastrointestinal (GI) tract, play an essential role in the development and maturation of the host’s immune system. Failure of intestinal microbial control may lead to the development of an array of autoimmune diseases, including inflammatory bowel disease (IBD). As a well-recognized inflammation mediator, Th17 cells are actually among the most abundant effector CD4+ T cells in the normal adult gut. What the role of intestinal Th17 cells is under steady state conditions and how the intestinal …
Glutamate And The Biology Of Malignant Glioma, Stephanie Marie Robert
Glutamate And The Biology Of Malignant Glioma, Stephanie Marie Robert
All ETDs from UAB
Malignant gliomas are the most prevalent primary brain tumor. They are highly aggressive and lack effective treatment options. Standard therapy includes a combination of radiation, chemotherapy, and tumor resection; however, even with aggressive treatment, median patient survival remains a dismal 12 – 14 months after diagnosis. Research has focused on understanding the unique biological mechanisms involved in glioma growth and survival in an effort to design novel therapies to treat this devastating disease. In the unique environment of the brain, gliomas have developed the ability to grow and survive at the cost of the normal surrounding brain tissue. Glutamate, the …
The Mechanism Of Small Molecule Viral Fusion Inhibitors, Michael Joseph Rowse
The Mechanism Of Small Molecule Viral Fusion Inhibitors, Michael Joseph Rowse
All ETDs from UAB
All negative stranded RNA viruses (NSRV) have genomes encapsidated by oligomerized nucleoprotein (N). The N-RNA complex acts as the template for both transcription and replication. The crystal structure of the N protein from the model NSRV vesicular stomatitis virus (VSV) established the structural basis for the oligomerization of N-protein and the encapsidation of RNA. To determine how the structure of N protein changes in response to specific sequences of RNA, we developed a strategy to digest the random RNA encapsidated in the recombinant N-protein and reencapsidated specific RNA sequences. Poly-rA, poly-rC, poly-rU, and poly-rG sequences were encapsidated and co-crystallized with …
The Sialyltransferase St6gal-I Promotes A Cancer Stem Cell Phenotype, Matthew Jonathan Schultz
The Sialyltransferase St6gal-I Promotes A Cancer Stem Cell Phenotype, Matthew Jonathan Schultz
All ETDs from UAB
Alterations in tumor cell glycosylation have been observed for decades, but the functional consequences of specific glycosyltransferase activity are not well understood. This dissertation focuses on the role of the sialyltransferase ST6Gal-I in driving ovarian and pancreatic cancer development. ST6Gal-I adds a negatively-charged sialic acid sugar in an alpha 2-6 linkage to select receptors, which can alter their function. We show that ST6Gal-I protein is upregulated in ovarian and pancreatic cancers but not expressed in normal epithelial tissue from these organs. ST6Gal-I expression in ovarian cancer correlates with decreased progression-free and overall survival, and we present evidence that ST6Gal-I expression …
Role Of Vapb/Als8 Signaling Through Lar Receptor, Jessica Lindsey Winek Schultz
Role Of Vapb/Als8 Signaling Through Lar Receptor, Jessica Lindsey Winek Schultz
All ETDs from UAB
In humans, a P56S point mutation in the VAPB/ALS8 MSP domain is associated with amyotrophic lateral sclerosis (ALS) and late-onset spinal muscular atrophy (SMA). The N-terminal MSP domain is cleaved from the C-terminus, and secreted through an unknown, nonconventional manner. The P56S mutation inhibits secretion of the MSP domain. We use Caenorhabditis elegans to study live secretion of VPR-1, as well as to understand vMSP receptor signaling in muscle and gonad. To study the secretion mechanism of VPR-1 we created a transgenic line of C. elegans with a fluorescently tagged VPR-1. Using this model, we were able to visualize live …
The Multifactorial Roles Of The Cytokines Il-21 And Il-22 In Mediating Host Defense Against Enteropathogenic Infection, Daniel James Silberger
The Multifactorial Roles Of The Cytokines Il-21 And Il-22 In Mediating Host Defense Against Enteropathogenic Infection, Daniel James Silberger
All ETDs from UAB
Enteropathogenic strains of Escherichia coli are a major public health concern, causing diarrhea and mortality particularly among infants and children in developing countries. Citrobacter rodentium is a murine intestinal pathogen that models pathogenic E. coli infection. Both innate and adaptive immune cells contribute to the clearance of C. rodentium. In particular, B cells and CD4+ T cells but not CD8+ T cells are required for protection during a primary infection with C. rodentium. In addition, T cell-dependent antibody responses are required for clearance. Th17 cells are a major CD4+ T cell population that accumulates in the large intestine during C. …
Exploiting The Glioblastoma Tumor Microenvironment For Enhanced Oncolytic Herpes Simplex Virus Therapy, Tyrel Talbert Smith
Exploiting The Glioblastoma Tumor Microenvironment For Enhanced Oncolytic Herpes Simplex Virus Therapy, Tyrel Talbert Smith
All ETDs from UAB
Gliomas are the most common and fatal malignancy of the adult central nervous system. The need for new therapeutic options is clear, as standard of care therapies only extend median survival 12-14 months beyond diagnosis. Conditionally replication-competent oncolytic herpes simplex type-1 viruses (oHSV) have emerged as promising therapeutics for treating malignant gliomas. However, two factors that contribute to the dismal prognosis of malignant gliomas, immunosuppression and invasive growth, are also thought to limit virotherapeutic efficacy. We examined these factors in tumor microenvironments to explore novel strategies to treat malignant gliomas with oHSV for improved therapeutic response. In a Phase 1b …
The Role Of Ribosome Biogenesis In Exercise-Induced Skeletal Muscle Anabolism In Aging, Michael Stec
The Role Of Ribosome Biogenesis In Exercise-Induced Skeletal Muscle Anabolism In Aging, Michael Stec
All ETDs from UAB
Numerous chronic medical conditions, as well as normal aging result in a significant loss of skeletal muscle mass. This has profound effects on quality of life and can increase the risk of all-cause mortality. Currently, the most potent treatment for reversing the loss of muscle mass is resistance exercise training (RT); however, the human muscle fiber growth (hypertrophy) response to this treatment is quite variable, and older adults do not respond as favorably to this treatment as younger adults. The focus of this dissertation is to elucidate the role that ribosome biogenesis plays in regulating the RT-induced hypertrophic response. We …