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Full-Text Articles in Medicine and Health Sciences
Hur Regulation In Central Nervous System Disorders, Crystal G. Wheeler
Hur Regulation In Central Nervous System Disorders, Crystal G. Wheeler
All ETDs from UAB
In inflammatory diseases of the central nervous system (CNS), astrocytes play a major role in the systemic response to disease by either enhancing or limiting the inflammatory response through secretion of growth factors or cytokines. HuR RNA binding protein regulates many genes involved in inflammation. Inflammatory diseases such as brain tumors, Amylotrophic Lateral Sclerosis (ALS), and Multiple Sclerosis (MS), have been linked to HuR, by our laboratory and others. To determine whether astrocytic overexpression of HuR would regulate inflammation in diseases of the CNS, we designed a transgenic mouse in which the HuR gene is overexpressed. In the first study, …
Genetic And Biochemical Characterizations Of The Capsular Glycosyltransferases In Streptococcus Pneumoniae Serotype 2, David Boyd Anthony James
Genetic And Biochemical Characterizations Of The Capsular Glycosyltransferases In Streptococcus Pneumoniae Serotype 2, David Boyd Anthony James
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The principle objective of this dissertation is to develop a thorough understanding of the genetics and biochemistry of capsule synthesis. Specifically, it involves the identification and characterization of the capsular glycosyltransferases in Streptococcus pneumoniae serotype 2, with investigations into their regulation. S. pneumoniae (the pneumococcus) is a significant human pathogen that has the ability to persist as a commensal and then transition to a virulent state, the latter of which is a major contributor to global morbidity and mortality. The capsular polysaccharide (CPS) of S. pneumoniae is a protective surface structure that plays an integral role in this disease process. …
Regulation Of Stim1 By O-Glcnacylation In Cardiomyocytes, Xiaoyuan Zhu-Mauldin
Regulation Of Stim1 By O-Glcnacylation In Cardiomyocytes, Xiaoyuan Zhu-Mauldin
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In non-excitable cells, STIM1 and Orai1 are the primary mediators of store-operated Ca2+ entry (SOCE); however little is known about their roles in cardiomyocyte Ca2+ handling. We have previously shown that acute increases in the levels of O-GlcNAcylation (the attachment of O-linked N- acetylglucosamine (O-GlcNAc) to target proteins) are cardioprotective through attenuating Ca2+-mediated injury and increased O-GlcNAcylation blunts SOCE in cardiomyocytes. Therefore, the goals here were to determine the regulation of STIM1 and STIM1-mediated SOCE by O-GlcNAcylation in cardiomyocytes. Immunohistochemical analysis demonstrated the co-localization of STIM1 with SERCA and RyR in adult cardiomyocytes. NRVMs were transfected with the eYFP-tagged STIM1 …
Gabaergic Dysfunction In Huntington Disease, Sarah Elizabeth Dougherty
Gabaergic Dysfunction In Huntington Disease, Sarah Elizabeth Dougherty
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GABAergic neurons are responsible for regulation of neuronal signaling through inhibition. Alterations in the delicate balance of excitation and inhibition have been observed in many neurological disorders, including neurodegenerative diseases. Huntington disease (HD) is an autosomal dominant neurodegenerative disorder that is characterized by motor, psychiatric, and cognitive disturbances. As the hallmark movement pathology of HD is hyperkinesis it is intriguing to postulate that alterations in inhibition, and by extension within GABAergic cell networks, could be part of the pathogenesis of this disorder. In order to elucidate the role of GABAergic cell populations in HD we have used behavioral paradigms, molecular …
Cyclic Gmp Phosphodiesterase As A Novel Target For Colorectal Cancer Chemoprevention, Nan Li
Cyclic Gmp Phosphodiesterase As A Novel Target For Colorectal Cancer Chemoprevention, Nan Li
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Nonsteroidal anti-inflammatory drugs (NSAIDs) display promising antineoplastic activity for colorectal and other cancers, but toxicity from cyclooxygenase (COX) inhibition limits their long-term use for chemoprevention. However, many investigators have concluded that COX-independent mechanisms are responsible for their antineoplastic activity. We previously reported that cyclic guanosine monophosphate phosphodiesterase (cGMP PDE) is a non-COX target of sulindac sulfide (SS). However, the specific isozyme families involved have not been well studied. Here we demonstrate that SS inhibits the growth of colon tumor cells through a novel mechanism involving inhibition of two cGMP degrading isozymes, PDE5 and PDE10, to activate cGMP-dependent protein kinase (PKG). …
Therapeutic Potential Of Genetically-Engineered Mesenchymal Stem Cells In Multiple Myeloma, Jerome T. Higgs
Therapeutic Potential Of Genetically-Engineered Mesenchymal Stem Cells In Multiple Myeloma, Jerome T. Higgs
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ABSTRACT Multiple Myeloma (MM) remains the second most common hematologic malig-nancy occurring in adults, which primarily affects the skeletal system causing severe bone destruction, spinal cord compression and hypercalcemia. Current therapies, which include chemotherapy, radiotherapy, autologouos stem cell transplantation and in some cases surgery, have extended the median survival between 3 and 10 years. However, MM is still incurable and therefore improving current therapies or developing newer ones to reduce the burden of osteolytic damage and extend survival rate will be highly beneficial for patient management. The long-term goal of this study is to develop a novel therapeutic approach to …
The Role Of Complement In Experimental Cerebral Malaria, Theresa N. Ramos
The Role Of Complement In Experimental Cerebral Malaria, Theresa N. Ramos
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Cerebral malaria (CM) is one of the most severe clinical complications of P. falciparum malaria with a fatality rate of 15-30%, and 10% of CM survivors have permanent neurological sequelae. Since inflammation is a central pathophysiological tenet of CM, we began examining the role of the complement system in pathogenesis of experimental cerebral malaria (ECM) using Plasmodium berghei ANKA (PbA) model. Previous studies using this model indicated that mice naturally deficient in complement component C5 were protected from cerebral complications, and wild type mice treated with anti-C5aR antibody were also protected. To determine the protective mechanism of naturally-C5 deficient mice, …
The Role Of Pneumococcal Choline-Binding Protein A (Pcpa) In The Mechanism Of Virulence And Protective Immunity, Melissa Marie Walker
The Role Of Pneumococcal Choline-Binding Protein A (Pcpa) In The Mechanism Of Virulence And Protective Immunity, Melissa Marie Walker
All ETDs from UAB
pcpA is under control of the Mn 2-dependent repressor PsaR. In the high manganese environment of mucosal sites pcpA gene expression is repressed and at the low manganese environment of the lung and blood derepression of pcpA gene expressionis observed. Previous data has shown that immunization of mice with rPcpA elicits protection against pneumonia and sepsis but had no effect on nasal colonization. We and others have shown that pcpA expression significantly enhances adherence of pneumococci to lung epithelial cell lines and although it is a virulence factor for pneumonia in mice there is no biologically relevant role for PcpA …
Role Of Endothelial Mannose Residues In Monocyte Adhesion Under Flow, David Wayne Scott
Role Of Endothelial Mannose Residues In Monocyte Adhesion Under Flow, David Wayne Scott
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Atherosclerosis is a chronic inflammatory disease of the vessel wall and underlying cause of most cardiovascular disease. Much is understood about the nature of atherosclerosis development, including contributions from leukocytes that drive the disease process forward. The general process by which leukocytes are trafficked to sites of atherosclerosis development, and sites of inflammation in general, is understood and relies upon endothelial expressed protein adhesion molecules which serve as ligands for cognate leukocyte receptors. While these adhesion molecules share the post-translation modification of N-glycosylation, relatively little is known as to what functional role these modification plays in: i) interactions of leukocytes …
Determinant Of G-Chain Mediated Fc Receptor Signaling, Spandan Shah
Determinant Of G-Chain Mediated Fc Receptor Signaling, Spandan Shah
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Fc receptors provide an interface between humoral immunity and cellular immunity by binding to the Fc portion of immunoglobulin and mediating effector functions. Cells expressing Fc receptors play a major role in immune complex clearance via phagocytosis, leading to a context dependent pro- or anti-inflammatory environment. Signaling by multi-chain Fc receptor complexes, including FcgRI, FcgRIII, FceRI and FcaRI is mediated by the ITAM-containing common FceRIg (g-chain) subunit. However, despite the use of a common g-chain, different Fc receptor complexes elicit specific cellular programs, suggesting additional layers of regulation of tyrosine based signaling by g-chain. We hypothesized that the unique g-chain …
The Role Of O-Glcnacylation In Synaptic Function, Erica Wynette Taylor
The Role Of O-Glcnacylation In Synaptic Function, Erica Wynette Taylor
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O-GlcNAcylation is a dynamic protein posttranslational modification that adds the monosaccharide ß-N-acetylglucosamine (GlcNAc) to specific serine and threonine residues on nucleocytoplasmic proteins. The hippocampus is a part of brain that has been shown to play a crucial role in learning and memory. Hippocampal neurons have high expression of O-GlcNAc transferase and O-GlcNAcase, which catalyze the addition and removal of GlcNAc from proteins respectively. Moreover, synaptic plasticity which is the strengthening or weakening of synaptic function on short- and long-term time scales is believed to be a cellular correlate of learning and memory. Several forms of synaptic plasticity have been characterized …
Role Of Gsk3 In The Immunopathogenesis Of Eae, Amber Rowse
Role Of Gsk3 In The Immunopathogenesis Of Eae, Amber Rowse
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Lithium, a glycogen synthase kinase 3 (GSK3) inhibitor, ameliorates experimental autoimmune encephalomyelitis (EAE), the murine model of multiple sclerosis (MS) in different mouse models. However, the mechanism of lithium's attenuation of EAE and the role of GSK3 in these processes are currently unknown. IFN-g producing Th1 cells and IL-17-producing Th17 cells are both effector cells in MS and in EAE models. However, relapsing remitting MS patients segregate into Th1 or Th17 serum cytokine signatures and each is differentially responsive to IFN-ß therapy, a first line therapy for MS. Studies in this dissertation revealed a differential effect of lithium on Th1 …
Clinical Consequences Of Micrornas In Colorectal Cancer, Liselle C. Bovell
Clinical Consequences Of Micrornas In Colorectal Cancer, Liselle C. Bovell
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Colorectal cancer (CRC) is a heterogeneous disease, and factors such as tumor location, the environment, genetics, and ethnic differences, can influence its development and progression. Over the last few decades, overall CRC mortality rates have declined; however, racial disparities in mortality rates have increased. The discovery of biomarkers that focus on identifying individual differences based on confounders such as tumor stage and patient race/ethnicity is needed, for such biomarkers can lead to development of personalized therapeutic approaches to target these molecules. MicroRNAs (miRNAs) are a class of small molecules that regulate genes at the post-transcriptional level. Altered miRNA expression levels …
Intrinsic Properties Of Rna Polymerase I And Trans-Acting Factors Control Transcription Elongation Efficiency, Olga V. Viktorovskaya
Intrinsic Properties Of Rna Polymerase I And Trans-Acting Factors Control Transcription Elongation Efficiency, Olga V. Viktorovskaya
All ETDs from UAB
Transcription of ribosomal (r) DNA by RNA polymerase I (Pol I) is the initial step of ribosome synthesis. Pol I transcription is unique in its high rate of initiation, specific organization within the nucleolus and tight connection to cell growth and proliferation. Moreover, transcription elongation by Pol I is functionally coupled with rRNA processing and assembly of the ribosomes. Regulatory insights into transcription elongation by Pol I and its interface with rRNA processing are limited, despite decades of research. To fulfill that gap, we asked several important questions: Do the obvious functional divergences between Pol I and other eukaryotic polymerases …
Surveying The Serum Proteome For Biomarkers Of Early-Stage Pancreatic Cancer, Michael Robert Ludwig
Surveying The Serum Proteome For Biomarkers Of Early-Stage Pancreatic Cancer, Michael Robert Ludwig
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SURVEYING THE SERUM PROTEOME FOR BIOMARKERS OF EARLY STAGE PANCREATIC CANCER MICHAEL ROBERT LUDWIG MICROBIOLOGY ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is a uniformly fatal disease due to its refractory nature to conventional therapies at the time of initial diagnosis. In order to in-crease the curative potential of surgical resection, early detection of organ-confined neoplasia is needed. Currently, no effective diagnostic tools are available to detect early-stage pancreatic ductal lesions termed pancreatic intraepithelial neoplasia (PanIN) or lo-cally invasive, organ-confined disease. One way to identify biomarkers that may be use-ful for the early detection of PDAC is through the study of the …
Commensal Microbiota And Its Impact On Health And Autoimmune Diabetets, Kyle James Wolf
Commensal Microbiota And Its Impact On Health And Autoimmune Diabetets, Kyle James Wolf
All ETDs from UAB
Environmental exposures such as diet, use of antibiotics, and lifestyle have significant impact on the health of an individual. One mechanism that acts as a major pathway in these environmental exposures is the role intestinal commensal microbiota play in both metabolic and immunological responses. Metabolic pathways are altered through changes in metabolites provided by commensal microbiota; alterations in microbial make-up can have drastic impacts on metabolic function. Similarly, the development and maturation of the immune system is dependent on the intestinal microbes to induce tolerance and act as both an immune modulator as well as a barrier against pathogens. We …
Adapter Based Strategies For Adenovirus Vector Retargeting To T Lymphocytes, Matthew S. Beatty
Adapter Based Strategies For Adenovirus Vector Retargeting To T Lymphocytes, Matthew S. Beatty
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Adenoviruses are the most commonly used gene therapy vector for cancer therapy clinical trials. While adenovirus has shown a great track record in a variety of cancer therapeutics it has not progressed as a vector system for the modification of T lymphocytes. One of the major roadblocks towards utilizing adenovirus for T cell therapy is the lack of coxsackie virus and adenovirus receptor on the cell surface of T cell lineages. Exploitation of alternative receptors has allowed adenovirus vectors to be utilized in a variety of cell types that native adenovirus type 5 cannot infect. Thus, retargeting adenovirus to an …
Experience-Dependent Synaptic Integration Of Adult-Generated Dentate Granule Cells, Jessica Hotard Chancey
Experience-Dependent Synaptic Integration Of Adult-Generated Dentate Granule Cells, Jessica Hotard Chancey
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The dentate gyrus (DG) contains neural stem cells that continually generate new neurons throughout life. The contribution of adult neurogenesis to hippocampal function is not well understood, but ablation or silencing of adult-generated neurons in the DG disrupts learning and memory, and neurogenesis is altered in many pathologies associated with impaired cognition including Alzheimer's Disease, epilepsy, and schizophrenia. Neurogenesis in the DG is a stepwise process in which neural stem cells leave the cell cycle and undergo an approximately two month long maturation process to form fully functional dentate granule cells (GCs) that are indistinguishable from those formed during development. …
Identification Of Claudin-1 As An Entry Factor In Dengue Infection And Development Of A High Throughput Screening Assay For Antivirals Against Dengue Virus, Pulin Che
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Dengue virus (DENV) has become a huge public health concern around the world with no vaccine or antivirals available. More than one-third of the world's population is living in areas at risk of infection. To conquer the dengue disease, a better understanding of virus-host interactions and development of the appropriate therapeutic treatments are required. In this dissertation, we first broadly reviewed the factors involved in dengue viral entry and the role of tight junctions as a pathogen target. Second, we developed, optimized and validated a high throughput screening (HTS) assay for anti-dengue virus drug screening. Taking advantage of using live …
Structure-Function Analysis Of Tyrosyl-Dna Phosphodiesterase I, Evan Comeaux
Structure-Function Analysis Of Tyrosyl-Dna Phosphodiesterase I, Evan Comeaux
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Tyrosyl-DNA phosphodiesterase I (Tdp1) functions to remove 3'phospho-DNA adducts, such as eukaryotic DNA Topoisomerase I (Top1) covalently bound to the DNA by a 3'phospho-tyrosyl bond. As member of the Phospholipase D superfamily Tdp1 contains two HxK(n)N motifs, each of which provide a catalytic histidine: one functioning as a nucleophile to bind the 3'phosphate and the other as a general acid/base to hydrolyze Tdp1's 3'phospho-histidyl bond. Mutation of the general acid/base catalytic histidine (Hisgab) to arginine has been implicated in the autosomal recessive neurodegenerative disease SCAN1. Further study of the yeast enzyme revealed that substitution of Hisgab in yeast Tdp1 to …
Tgf-Ss And Erg In Intervertebral Disc Development, Megan Karen Cox
Tgf-Ss And Erg In Intervertebral Disc Development, Megan Karen Cox
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The intervertebral disc (IVD) is a fibrocartilaginous tissue that acts as a shock absorber between adjacent vertebrae in the spinal column. It is comprised of two parts, the inner jelly-like nucleus pulposus (NP) and the outer more fibrous annulus fibrosus (AF). Most IVD research has focused on the development of the NP, which is derived from condensations of the notochord involving sonic hedgehog (Shh) signaling. In contrast, very little is known about the molecular mechanisms underlying the specific development of the AF of the IVD. The AF is derived from the sclerotome, which is formed by the ventral half of …
Characterization Of The Mumps Virus Replicase, Robert Marsden Cox
Characterization Of The Mumps Virus Replicase, Robert Marsden Cox
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Negative strand RNA viruses (NSV) are unique because their nucleocapsids are used directly as the template for both transcription and replication. The viral genomic RNA is coated by the nucleoprotein (N) for the entirety of the NSV replication cycle. The viral polymerase, which is composed of the L and P proteins, can only recognize encapsidated RNA as the template for RNA synthesis. Our previous studies have solved the EM structure of the MuV N-RNA complex at 25Å . This structure revealed how the nucleocapsid is assembled and provides an initial model for examining how the viral polymerase may recognize the …
Selection And Evolution Of Pneumococci In Response To Conjugate Vaccines, Christina M. Croney
Selection And Evolution Of Pneumococci In Response To Conjugate Vaccines, Christina M. Croney
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Pneumococcal conjugate vaccines (PCVs) containing subsets of the >90 capsular polysaccharide antigens have been successful as a means of decreasing invasive and non-invasive pneumococcal disease worldwide. However, this success is limited to the specif-ic capsular serotypes against which PCVs are formulated and studies have reported the increase of nonvaccine serotypes. The 13-valent pneumococcal conjugate vaccine (PCV13) was introduced in the United States in 2010 for the prevention of invasive pneumococcal disease (IPD) and otitis media and was released without efficacy data. In this study we set out to 1) determine potential efficacy for invasive and noninvasive pneumococcal disease and 2) …
The Role Of Il-21 And Il-17 In Regulating Follicular T Helper Cells In Germinal Center Response Of Autoimmunity, Yanna Ding
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Overreactivity of the germinal center (GC) is a central feature of autoantibody-mediated autoimmune diseases. Follicular T helper (Tfh) cells are the primary T helper subset that migrates to the incipient GC and forms close contacts with GC-B cells to promote GC formation and help GC-B cell differentiation, resulting in high-affinity antibody production. Increased levels of interleukin (IL)-21 and aberrant accumulation or function of Tfh cells have been associated with autoimmune disease severity in humans and lupus-prone mice. Follicular regulatory T (Tfr) cells are the regulatory T cell subset that also localizes in the GC and inhibits GC B cell differentiation. …
Modulation Of Intrinsic Activity In Sensory Cortex Facilitates Task Performance, Aburahman Elkhetali
Modulation Of Intrinsic Activity In Sensory Cortex Facilitates Task Performance, Aburahman Elkhetali
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Due to the changing demands of the environment and our behavioral intentions the brain has to adapt in order to produce task appropriate responses. Part of the challenge is the large amount of sensory information received by the brain. Depending on individu-al goals, the brain must select and react to task appropriate stimuli while ignoring other irrelevant sensory input. Since behavioral intentions are dynamic, this requires the re-sponses within the brain to also be dynamic. Cognitive control, exerted by higher centers on sensory cortex allow for selection of task relevant stimuli. In this study we find that intrinsic, non-stimulus driven …
Adap1 And Arf6 Mediate Regulated Secretory Trafficing In Neurosecretory Cells And Neurons, Sharday Ewell
Adap1 And Arf6 Mediate Regulated Secretory Trafficing In Neurosecretory Cells And Neurons, Sharday Ewell
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ADP ribosylation factor 6 (Arf6) is a member of the Arf family of small GTPases known to function in vesicular membrane trafficking and cytoskeletal organization. Arf6 cycles between its GTP and GDP bound states, facilitated by GTP exchange factors (GEFs) and GTPase activating proteins (GAPs), respectively. In my dissertation studies I have investigated the neuronal functions of Arf6 and ADAP1, an Arf6 GAP and candidate PI 3-kinase target required for dendritic differentiation in developing neurons. I demonstrated that in neurosecretory PC12 cells and neurons, ADAP1 and Arf6 colocalize with regulated secretory granules (SGs) that traffic chromogranin B and brain-derived neurotrophic …
Neuropathological Alterations In Alzheimer's Disease: An Up Close Look At Sympathetic Sprouting, Amy Renee Nelson
Neuropathological Alterations In Alzheimer's Disease: An Up Close Look At Sympathetic Sprouting, Amy Renee Nelson
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Pathological hallmarks of AD include neurofibrillary tau tangles, amyloid beta (Abeta) accumulation and cholinergic degeneration. Cholinergic degeneration can be mimicked in rats by lesioning cholinergic neurons in medial septum. Hippocampal cholinergic denervation disrupts retrograde transport of nerve growth factor (NGF), leading to its accumulation, which subsequently triggers sprouting of noradrenergic sympathetic fibers from the superior cervical ganglia into hippocampus. Dr. McMahon's lab previously reported that coincident with this sprouting, there is an increase in cholinergic innervation that correlates with a recovery of M1 muscarinic receptor dependent plasticity at CA3-CA1 synapses and visual cortex. These findings suggest that noradrenergic sympathetic sprouting …
Epigenetic Regulation Of Kir4.1 In Normal And Pathological States: A Focus On Spinal Cord Injury, Sinifunanya Elvee Nwaobi
Epigenetic Regulation Of Kir4.1 In Normal And Pathological States: A Focus On Spinal Cord Injury, Sinifunanya Elvee Nwaobi
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Astrocytes are the most numerous cells in the brain and play a critical role in maintaining homeostatic extracellular potassium ([K+]e). This process is mediated, in part, by a glial-specific, inwardly rectifying potassium channel, Kir4.1. Pharmacological inhibition, knock down, or complete knock out of this channel results in astrocytes with increased membrane resistance, depolarized resting membrane potential, and altered extracellular potassium dynamics. Subsequent to the dysregulation of [K+]e, Kir4.1 knockout (KO) animals suffer from ataxia, seizures, and early postnatal death. Interestingly, Kir4.1 has long been characterized as a seizure susceptibility gene. The importance of Kir4.1 is further underscored by recent studies …
New Mouse Models To Aid Studies Of The Role Of Primary Cilia In Limb Patterning And Bone Development, Amber Kathleen O'Connor
New Mouse Models To Aid Studies Of The Role Of Primary Cilia In Limb Patterning And Bone Development, Amber Kathleen O'Connor
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Hedgehog (Hh) signaling is required for many developmental processes, and causes several diseases and cancers. Described in chapter one below, vertebrate Hh sig-naling is dependent on the primary cilium (PC), a small organelle that extends from the surface of most mammalian cell types. A better understanding of how the PC modulates Hh signaling is important, as defects in the structure or function of PC result in severe human disorders termed the ciliopathies. For example, patients with Meckel-Gruber Syndrome have extra digits and neural tube defects, which are Hh both related pheno-types. In chapter two we sought to further understand the …
Microevolution Of Capsule Synthesis Genes Contributes To Pneumococcal Capsule Diversity, Melissa Beth Oliver
Microevolution Of Capsule Synthesis Genes Contributes To Pneumococcal Capsule Diversity, Melissa Beth Oliver
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Streptococcus pneumoniae (pneumococcus) is an important human pathogen that expresses a capsular polysaccharide (PS) to shield underlying antigenic structures from complement-mediated opsonophagocytosis. Thus, capsular PS is the major virulence factor, the target of primary immune responses to pneumococcal infections, and the antigenic component of pneumococcal vaccines. Pneumococci have diverse capsular PS synthesis (cps) loci and express over 90 different capsule types. Such diversity helps pneumococci escape immune detection and adapt to changing environments. Recombination of cps genes has been recognized as the main driver of capsule diversity. However, we show point mutations in cps genes encoding glycosyltransferases can broaden enzymes' …