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Articles 1 - 30 of 58
Full-Text Articles in Medicine and Health Sciences
Using Mouse Models To Investigate Ciliopathies, Raymond Carl Pasek
Using Mouse Models To Investigate Ciliopathies, Raymond Carl Pasek
All ETDs from UAB
Cilia and flagella are microtubule based organelles found on nearly every cell type in the mammalian body. Flagella have an essential role in sperm locomotion and reproduction, while motile cilia have a known role in fluid movement in the brain, lungs, and portions of the female reproductive tract. While the role of most primary cilia remained unknown for decades, they are now recognized as being essential to mammalian development, renal homeostasis, and satiety, just to name a few. Because of their widespread presence and importance, dysfunction of cilia and flagella can lead to a variety of human diseases, collectively referred …
Regulatory T Cells In The Fvb.Mdr1a-/- Model Of Colitis, Scott Tanner
Regulatory T Cells In The Fvb.Mdr1a-/- Model Of Colitis, Scott Tanner
All ETDs from UAB
Regulatory T cells (Treg) are necessary for the maintenance of immune homeostasis, and have been implicated in several autoimmune diseases, including inflammatory bowel disease (IBD). Most murine studies focusing on the function of Tregs have been done on the C57BL/6 or BALB/c background, creating a bias towards these two strains. In addition, it has been shown that C57BL/6 and BALB/c Tregs function in different manners. To further investigate potential strain differences in Treg phenotype and function, we chose to analyze FVB/N Tregs. Several differences were observed, including de-creased FVB/N Treg suppression in a non-cell contact dependent manner, decreased FVB/N and …
The Role Of St6gal-I Sialylation In Fas (Cd95) Death Receptor Function And Tumorigenesis, Amanda F. Swindall
The Role Of St6gal-I Sialylation In Fas (Cd95) Death Receptor Function And Tumorigenesis, Amanda F. Swindall
All ETDs from UAB
The golgi glycosyltransferase, ST6Gal-I, adds a negatively-charged sialic acid in an alpha-2-6 linkage to N-linked glycans. ST6Gal-I is upregulated in many cancers, and is associated with increased metastasis and poor patient prognosis. ST6Gal-I expression has been shown to be driven by oncogenic-ras signaling. However, mechanistic details of the role ST6Gal-I plays in tumor initiation and progression are not well defined. Historically, studies have focused on contributions of ST6Gal-I to the malignant cell phenotypes of migration and invasion. Emerging evidence including studies contained in this dissertation have begun to elucidate a role for ST6Gal-I as a regulator of apoptotic signaling by …
A Role Of Angiogenin In Models Of Parkinson's Disease, Trent Steidinger
A Role Of Angiogenin In Models Of Parkinson's Disease, Trent Steidinger
All ETDs from UAB
Parkinson's Disease (PD) is the most common neurodegenerative movement disorder and is characterized by the loss of dopaminergic neurons in the substantia nigra. Gene multiplication of alpha-synuclein causes an autosomal dominant inheritance pattern of PD. A mouse model overexpressing alpha-synuclein demonstrates some of the phenotype seen in PD. In a microarray of these mice, a downregulation of angiogenin was observed prior to symptom onset, demonstrating a potential link of angiogenin to pathology in this model. Angiogenin has also been associated with the onset of Amyotrophic Lateral Sclerosis (ALS), and is neuroprotective in models of ALS through activation of the Akt …
Myosin Ii Regulates Actin Dynamics Critical For Structural Plasticity And Fear Memory Formation, Cristin Gavin
Myosin Ii Regulates Actin Dynamics Critical For Structural Plasticity And Fear Memory Formation, Cristin Gavin
All ETDs from UAB
Dynamic changes to the actin cytoskeleton are required for synaptic plasticity and long-term memory formation. However, the molecular mechanisms that mediate filamentous actin (F-actin) dynamics during both activity-dependent synaptic potentiation and long-term memory encoding are poorly understood. Myosin II motor proteins are highly expressed in actin-rich growth structures in neurons, including dendritic spines. Recent work demonstrates that these molecular machines mobilize F-actin in response to synaptic stimulation and are required for memory encoding in CA1 hippocampus of rodents. The aims of this project were two-fold. First, we sought to establish if myosin II regulates actin filament polymerization necessary for structural …
Scaffold-Mediated Size Determination Of Bacteriophage Capsids By Mobile Genetic Elements, Altaira Davida Dearborn
Scaffold-Mediated Size Determination Of Bacteriophage Capsids By Mobile Genetic Elements, Altaira Davida Dearborn
All ETDs from UAB
Bacteriophage can mediate the transfer of unrelated mobile genetic elements (MGE) from a carrier bacterial cell to the susceptible population around it. This transfer results in the spread of virulence or other accessory genes encoded on the MGE. During viral particle assembly, the MGE can discourage the formation of viable bacteriophage progeny by limiting the size of the particles to those large enough to encapsidate the MGE, but too small to fit the complete bacteriophage genome which is three times larger. Here, I present models for size determination by an external scaffolding protein which is independent of and dominant over …
Structural And Molecular Studies Of Nucleic Acid Chaperones, Lei Ding
Structural And Molecular Studies Of Nucleic Acid Chaperones, Lei Ding
All ETDs from UAB
Nucleic acids are the storage of genetic information that needs to be expressed and inherited. As abundant cellular macromolecules they are also major players of a wide variety of biological processes. They usually undergo post-transcriptional modifications and/or fold into higher order structures in order to accomplish their distinct functions. Most biological events involving nucleic acids are achieved by proteins that interact with them. The functionality requires specific recognition of nucleic acids by proteins at molecular level. Nucleic acid chaperones are a group of nucleic acids binding proteins that associate with structured RNAs or DNAs and assist correct folding of their …
Regulation Of P27kip1 By Trip6 And Its Implications In Cancer Progression, Victor T G Lin
Regulation Of P27kip1 By Trip6 And Its Implications In Cancer Progression, Victor T G Lin
All ETDs from UAB
TRIP6 is a focal adhesion molecule that functions as an adaptor protein to mediate diverse cellular functions, including motility and antiapoptotic signaling, through a wide variety of protein-protein interactions. We were able to characterize a novel interaction between TRIP6 and p27KIP1, a CDK inhibitor which can both suppress and promote tumorigenesis, depending on its regulation. TRIP6 expression specifically promotes the AKT-mediated phosphorylation of p27KIP1 at T157, which leads to its cytosolic retention, and accelerates the protein turnover rate of p27KIP1. We also found that phosphorylation of T157 by itself promotes cell motility and can be linked to the formation of …
Regulation Of Membrane Traffic By The Big2 Member Of Guanine Nucleotide Exchange Factors, Jason Lowery
Regulation Of Membrane Traffic By The Big2 Member Of Guanine Nucleotide Exchange Factors, Jason Lowery
All ETDs from UAB
Vesicular transport is an essential cellular process that facilitates the movement of molecules within a cell. The importance of vesicular transport is highlighted by numerous human diseases that result from mutations affecting protein trafficking. The Brefeldin A-inhibited guanine nucleotide exchange factor 2 (BIG2) has emerged as a key regulator of protein trafficking within the late secretory pathway, between the trans-Golgi Network (TGN) and endosomal compartments and within the recycling endosomal pathway. Mutations in BIG2 lead to Autosomal Recessive Periventricular Heterotopia with Microcephly (ARPHM), a disorder characterized by severe brain malformations. BIG2 stimulates nucleotide exchange of GDP for GTP on ADP-ribosylation …
Innate Immune Mechanisms Against The Atypical Fungal Pathogen Pneumocystis Murina, Michael Paul Nelson
Innate Immune Mechanisms Against The Atypical Fungal Pathogen Pneumocystis Murina, Michael Paul Nelson
All ETDs from UAB
Pneumonia caused by the fungal pathogen Pneumocystis continues to be the leading cause of morbidity and mortality in AIDS patients. In addition, there are a number of other non-HIV-associated diseases that render an individual susceptible to Pneumocystis infection, including chronic obstructive pulmonary disease. Innate immune mechanisms are important for controlling Pneumocystis lung infection. As alveolar macrophages serve the front lines of lung host defense, our goal was to elucidate their responses during lung Pneumocystis infection. Here, we established a role for Src family kinases in the lung immune response to Pneumocystis, which uncovered a role for alternatively activated alveolar macrophages. …
Characterizing The Transcriptional Complexity Of Pkhd1/Pkhd1, Ravindra Boddu
Characterizing The Transcriptional Complexity Of Pkhd1/Pkhd1, Ravindra Boddu
All ETDs from UAB
Mutations in PKHD1 gene cause autosomal recessive polycystic kidney disease. Our previous studies have shown that human PKHD1 and its mouse orthologue, Pkhd1, undergo an extensive pattern of alternative splicing. Pkhd1 is primarily expressed in renal and biliary tubular structures. Translation products of these alternative spliced transcripts are predicted to generate isoforms expressed in plasma membrane, primary cilium and cytoplasm. We have characterized the cyli mouse model of ARPKD and identified a frameshift mutation, c.7589delGGinsT, in Pkhd1 exon 48. In this thesis we have characterized the mouse Pkhd1cyli/cyli model (liver restricted phenotype) and evaluated the transcriptome in terms of alternative …
Structural Investigations Of Retinoid X Receptor Transcriptional Activation By Anti-Cancer Rexinoids, Leeann J. Boerma
Structural Investigations Of Retinoid X Receptor Transcriptional Activation By Anti-Cancer Rexinoids, Leeann J. Boerma
All ETDs from UAB
Nuclear receptor (NR) protein retinoid X receptor (RXR) is a ligand-inducible transcription factor that binds retinoids for regulation of target genes. Agonist binding induces a major structural rearrangement in the ligand binding domain (LBD) and formation of the coactivator binding interface. RXR-signaling pathways control proliferation, differentiation, and growth in epithelial tissues. To understand how RXR agonists enhance signaling at the molecular level requires an understanding of how agonists induce structural and dynamical changes in the LBD to recruit coactivators for activation of anti-cancer relevant transcription. While most studies of NR activation center on the position of Helix 12 (H12)/activation function-2 …
Discovery And Characterization Of Streptococcus Pneumoniae Serotype 11e Reveals A Novel Model Of Serotype Evolution, Juan Jose Calix
Discovery And Characterization Of Streptococcus Pneumoniae Serotype 11e Reveals A Novel Model Of Serotype Evolution, Juan Jose Calix
All ETDs from UAB
The facultative pathogen Streptococcus pneumoniae is capable of producing a polysaccharide (PS) capsule that prevents bacterial recognition and clearance by the host immune system. Over 90 antigenically distinct capsule serotypes have been identified. Because anti-capsule antibodies can mediate bacterial clearance, capsule diversity is critical to S. pneumoniae survival. However, the mechanisms of capsule evolution remain unclear. Due to the complex interaction of capsule synthesis (cps) genes, it is commonly thought that pneumococcal serotypes evolve once and that all clinically relevant serotypes are genetically derived from a single founding clone. In this dissertation we demonstrate a novel mechanism of capsule evolution …
Analysis Of Ergothioneine Production In Mycobacterium Tuberculosis, Loni Ann Guidry
Analysis Of Ergothioneine Production In Mycobacterium Tuberculosis, Loni Ann Guidry
All ETDs from UAB
Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis, currently infects more than two billion people worldwide. Mtb is a highly adaptable pathogen, capable of modifying its metabolism in response to its environment. We previously showed that Mtb WhiB3 is a redox-responsive regulator of core intermediary metabolism and lipid anabolism through which it maintains redox homeostasis. In this work, through the use of metabolomic analysis and a novel radioactive thin layer chromatography assay, we discovered that WhiB3 regulates the production of the intracellular thiol ergothioneine (ergo) when using immunomodulatory lipid precursors as the major carbon source. Our results suggest that this …
A Yeast Model For High Throughput Screening Of Gene-Gene Interactions Relevant To Cftrδf508 Protein Biogenesis, Jingyu Guo
All ETDs from UAB
Much remains unknown about gene interaction in the context of human disease. In cystic fibrosis (CF) a single mutation of the cystic fibrosis transmembrane conductance regulator (CFTR-deltaF508) accounts for most disease. In cell models, CFTR-deltaF508 causes defective protein biogenesis and degradation rather than proper trafficking to the plasma membrane where CFTR normally functions in ion transport. Numerous genes function in the biogenesis of CFTR and influence the fate of CFTR-deltaF508 in cell models. However it is not known whether natural genetic variation in such genes contributes to disease severity in patients. Moreover, there is no easy way to predict how …
The Role Of Histone Methylation In The Medial Temporal Lobe During Long-Term Memory Formation, Swati Gupta
The Role Of Histone Methylation In The Medial Temporal Lobe During Long-Term Memory Formation, Swati Gupta
All ETDs from UAB
Several studies have established the importance of epigenetic regulation of gene transcription in the brain during memory consolidation. Epigenetic mechanisms involve modifying the DNA or the associated histone proteins to determine the transcriptional outcome of a gene. The work encompassed in this dissertation serves as an initial investigation for the role of histone lysine methylation mechanisms in regulating gene activation and suppression in the medial temporal lobe that includes entorhinal cortex (EC), hippocampus, and amygdala during memory consolidation. To this end, we found that di-methylation of histone H3 at lysine 9 (H3K9me2) which promotes gene suppression was specific to associative …
The Role Of Vpr-1 Msp Signaling In C. Elegans, Sung Min Han
The Role Of Vpr-1 Msp Signaling In C. Elegans, Sung Min Han
All ETDs from UAB
In C. elegans, the major sperm protein (MSP) is the most abundant protein in sperm and functions as an intracellular cytoskeleton protein and a secreted extracellular signal that induces oocyte maturation and sheath contraction. Evolutionarily, MSP domain-containing proteins originate from the VAPs (VAMP/synaptobrevin-associated proteins), which comprise a highly conserved protein family with an MSP domain at the N-terminus and a transmembrane domain at the C-terminus. I have been studying the signaling role of VAP MSP domains using the C. elegans model system. In collaboration with Hugo Bellen's lab at Baylor College of Medicine, we have shown that C. elegans, Drosophila, …
A Study Of The Genetic Mechanisms Used To Regulate The Third Complementarity Determining Region Of The Immunoglobulin H Chain, Mohamed Khass
A Study Of The Genetic Mechanisms Used To Regulate The Third Complementarity Determining Region Of The Immunoglobulin H Chain, Mohamed Khass
All ETDs from UAB
Developing B cells exhibit sequential changes in the representation of immunoglobulin (Ig) heavy (H) chain sequences with excess hydrophobic or charged amino acids in complementarity determining region 3 (CDR-H3). To begin to elucidate the mechanisms by which this process occurs, we used Bromodeoxy Uridine (BrdU) incorporation and Annexin V binding to quantify B cell turnover and cell cycle progression in developing B cell subsets in the bone marrow, spleen and peritoneal cavity of wild-type BALB/c mice. To magnify the effects of hydrophobicity and charge, we included in this analysis mice limited to the use of an IgH allele with a …
Regulation Of Cell Death By Autophagy In Glial Neoplasms, Latika R. Kohli
Regulation Of Cell Death By Autophagy In Glial Neoplasms, Latika R. Kohli
All ETDs from UAB
Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive malignancies of the peripheral nervous system. The majority of MPNSTs arise in patients of the autosomal dominant genetic disorder neurofibromatosis type I (NF1) although they also arise sporadically. In the absence of any effective chemotherapeutic options and with surgery constituting the mainstay of treatment, MPNST patients face an extremely poor prognosis. This underscores the need to develop novel therapeutic strategies against this tumor type. It is well accepted that the crosstalk between autophagy and apoptosis can be exploited to derive maximal therapeutic benefit, especially through combinatorial therapies. However, this interaction is extremely …
Mechanism Of Nfi-C Functionin During Tooth Root Formation, Ejvis Lamani
Mechanism Of Nfi-C Functionin During Tooth Root Formation, Ejvis Lamani
All ETDs from UAB
Currently, very little is known regarding tissue-specific gene regulation during the later stages of tooth development, especially those associated with root formation. Re-cent studies have identified nuclear factor I-C (NFI-C) as a critical factor for root for-mation in mammals. NFI-C functions as a cellular transcription factor and adenovirus DNA replication factor. Its role in root formation first became evident when Nfi-c null mice were shown to lack molar roots. A similar phenotype of incomplete or absent root formation is observed in patients with the autosomal dominant disease Radicular Dentin Dysplasia (RDD; MIM125400) also known as Rootless Teeth or Dentin Dysplasia …
Retinoids And Abnormal Alveolar Development, Masheika L. James
Retinoids And Abnormal Alveolar Development, Masheika L. James
All ETDs from UAB
Extremely preterm infants are at high risk for a form of chronic lung disease called bronchopulmonary dysplasia (BPD), which is characterized by impaired alveolar development. Exposure to hyperoxia and deficiency of vitamin A (VA) contribute to the development of BPD in preterm infants. Randomized controlled trials indicate VA supplementation decreases BPD and/or death. However, 25% of preterm infants continue to remain VA deficient despite supplementation, probably due to impairment in VA transport, VA is stored in the liver as retinyl esters which are transported to the lung and irreversibly metabolized into all-trans-retinoic acid (ATRA), the active metabolite. A combination of …
The Role Of Endoplasmic Reticulum Stress Response In Glioma Cell Death, G Johnson
The Role Of Endoplasmic Reticulum Stress Response In Glioma Cell Death, G Johnson
All ETDs from UAB
Malignant gliomas, including glioblastomas, are the main primary adult brain tumor. Even with current therapies, the median survival time for patients diagnosed with glioblastomas is only about 12 months. Therefore, it is imperative to identify pathways that can induce glioma cell death. This dissertation provides evidence defining how Endoplasmic Reticulum Stress Response (ERSR) induction promotes cell death selectively in malignant glioma cells (MGCs). I present data showing a correlation between ER Ca2+ storage abnormalities, ER ribosome-translocon expression and activity, ERSR intensity and cell death in MGCs. These data show ERSR induction with thapsigargin (THAP) results in a larger loss of …
The Role Of C-Reactive Protein In Arthritic Disease, Nicholas Ryan Jones
The Role Of C-Reactive Protein In Arthritic Disease, Nicholas Ryan Jones
All ETDs from UAB
C-reactive protein (CRP) is an acute phase protein that is commonly used to evaluate systemic inflammation level. Blood CRP level also correlates very well with rheumatoid arthritis (RA) disease severity. However, CRP has many biological actions that lead one to suspect that it may be playing a role in the development or pathology of the disease. We have directly addressed whether this is the case by the use of novel mouse models (CRP deficiency or transgenic overexpression). We have shown that CRP positively affects collagen-induced arthritis development and progression. In order to thoroughly address the question, we have also reported …
Mycobacterial Iron Acquisition Systems, Christopher M. Jones
Mycobacterial Iron Acquisition Systems, Christopher M. Jones
All ETDs from UAB
Iron is an essential nutrient for the vast majority of organisms; yet, the availability of iron is limited to microorganisms due to the insolubility of ferric hydroxides and to pathogens by iron withholding strategies of their hosts. Many bacteria produce small, high-affinity iron chelators called siderophores to scavenge iron from the environment. In addition, many bacterial pathogens have evolved mechanisms to steal host iron contained in heme, hemoglobin, or transferrin. Mycobacteria are unique genera of bacteria represented by the notorious pathogens Mycobacterium tuberculosis and Mycobacterium leprae, the causative agents of tuberculosis (TB) and leprosy, respectively. Tuberculosis remains a global health …
Development Of Electrospun Bone-Mimetic Matrices For Bone Regenerative Applications, Matthew Christopher Phipps
Development Of Electrospun Bone-Mimetic Matrices For Bone Regenerative Applications, Matthew Christopher Phipps
All ETDs from UAB
Although bone has a dramatic capacity for regeneration, certain injuries and procedures present defects that are unable to heal properly, requiring surgical intervention to induce and support osteoregeneration. Our research group has hypothesized that the development of a biodegradable material that mimics the natural composition and architecture of bone extracellular matrix has the potential to provide therapeutic benefit to these patients. Utilizing a process known as electrospinning, our lab has developed a bone-mimetic matrix (BMM) consisting of composite nanofibers of the mechanically sta-ble polymer polycaprolactone (PCL), and the natural bone matrix molecules type-I colla-gen and hydroxyapatite nanocrystals (HA). We herein …
Targeting Mitochondrial Function In Diabetic Nephropathy, Colin Reily
Targeting Mitochondrial Function In Diabetic Nephropathy, Colin Reily
All ETDs from UAB
TARGETING MITOCHONDRIAL FUNCTION IN DIABETIC NEPHROPATHY The incidence of diabetes has increased to epidemic proportions over the last 50 years, due to a complex interaction of lifestyle and dietary factors. Changes in physical activity, caloric intake, and the composition of foods consumed over the last century are thought to interact with metabolic syndrome prone subpopulations leading ultimately to diabetes. It is widely accepted that chronic hyperglycemia in the blood characterizes the diabetic condition. Since the discovery of insulin therapy in the first half of the 20th century, diabetics have extended their lifespan considerably, but at the cost of increased morbitity …
Cystine/Glutamate Transporters As Prognostic & Therapeutic Markers Of Primary Brain Tumors, Stephanie Marie Robert
Cystine/Glutamate Transporters As Prognostic & Therapeutic Markers Of Primary Brain Tumors, Stephanie Marie Robert
All ETDs from UAB
Glioblastoma multiforme (GBM) are the most prevalent and aggressive malignant brain tumors. Current treatment - a combination of radiation, chemotherapy and resection - has limited effectiveness and offers poor prognosis. In this study, we examined the roles of system xc- (SXC) and excitatory amino acid transporters (EAATs), which transport the amino acids cystine and glutamate, on tumor growth, neurotoxicity, and peritumoral seizure activity. Tissue micro-arrays from 45 patients were examined by immuno-histochemistry, comparing tumor-bearing tissue and adjacent normal brain. Using a novel flank tumor propagation technique, we chose 3 glioma samples with varying SXC and EAAT expression levels to study …
Modulation Of Autoimmune Diabetes By B Cells Specific For N-Acetyl-D-Glucosamine, Brian L. Dizon
Modulation Of Autoimmune Diabetes By B Cells Specific For N-Acetyl-D-Glucosamine, Brian L. Dizon
All ETDs from UAB
Type I diabetes (T1D) is an autoimmune disease in which ß cells are destroyed by the immune system; however, role of infections in type I diabetes (T1D) pathogenesis is unclear. Reports suggesting that childhood Group A Streptococcal (GAS) infections protected against T1D prompted us to study how antibodies to N-acetyl-D-glucosamine (GlcNAc), which are induced by GAS infection, influenced T1D development. We found that GlcNAc-specific antibodies reacted with ß cell secretory granules, and neonatal NOD mice immunized with GAS or given GAS-immune sera were protected from spontaneous diabetes. Monoclonal GlcNAc-specific IgM blocked activation and effector responses to islet antigens by diabetogenic …
Modulation Of Capsule Production In Serotype 3 Streptococcus Pneumoniae, Melissa Ellis
Modulation Of Capsule Production In Serotype 3 Streptococcus Pneumoniae, Melissa Ellis
All ETDs from UAB
Streptococcus pneumoniae is a Gram-positive pathogen and an important cause of community-acquired pneumonia and meningitis, and it can also cause otitis media and bacteremia. A major virulence factor of S. pneumoniae is its polysaccharide capsule which functions to prevent complement-mediated opsonophagocytosis. At least 93 distinct serotypes that vary in sugar composition and structure exist. S. pneumoniae can asymptomatically colonize the nasopharynx and transition to other body sites such as the lungs and blood causing invasive disease. The ability to regulate capsule production in these vastly different environments is critical for survival as low levels of capsule are necessary for colonization, …
Cytokine Signaling In A Mouse Model Of Parkinson's Disease, Shuwen Cao
Cytokine Signaling In A Mouse Model Of Parkinson's Disease, Shuwen Cao
All ETDs from UAB
The protein alpha-synuclein (α-SYN), which is found in the Lewy bodies of dopaminergic (DA) neurons in the substantia nigra (SN), has an important role in the pathogenesis of Parkinson's disease (PD). Fcγ receptors (FcγR) are proteins present on the surface of microglia, which bind immunoglobulin G (IgG) and other ligands. Our studies in an AAV-synuclein mouse model of PD showed that over-abundance of α-SYN triggered the expression of NF-κB p65, and led to microglial activation and DA neurodegeneration; however, in mice deficient of gamma chain subunit of the Fc receptors (FcγR-/- mice), α-SYN-induced NF-κB signaling was blocked, while microglial activation …