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Full-Text Articles in Medicine and Health Sciences
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 …
Fcrl5 Exerts Binary And Compartment-Specific Influence On Innate-Like B Cell Receptor Signaling, Zilu Zhu
Fcrl5 Exerts Binary And Compartment-Specific Influence On Innate-Like B Cell Receptor Signaling, Zilu Zhu
All ETDs from UAB
Innate-like splenic marginal zone (MZ) and peritoneal cavity (PEC)-derived B1 B lymphocytes are the major contributors to primary humoral responses and play an important role in connecting innate and adaptive immunity, but are known to significantly differ in their B cell receptor (BCR) signaling characteristics. In mice, FCRL5 is discretely expressed by innate-like MZ and B1 B cells and is furthermore equipped with cytoplasmic ITAM-like and ITIM elements, suggesting diverse signaling potential for it. Our results showed that FCRL5 markedly inhibited BCR-mediated activation in MZ B cells, but not in PEC B1 B cells. To characterize its signaling function, a …
Functional Collaboration Between Igf-1 Receptor And Growth Hormone Signaling Pathway, Yujun Gan
Functional Collaboration Between Igf-1 Receptor And Growth Hormone Signaling Pathway, Yujun Gan
All ETDs from UAB
GH receptor (GHR) binds GH in its extracellular domain (ECD) to activate the GHR-associated cytoplasmic tyrosine kinase, JAK2. IGF-1 binds IGF-1R, a disulfide-linked heterotetramer with tyrosine kinase activity in its intracellular domain (ICD). Classically, IGF-1 is a GH effector in a “linear” GH→GHR→IGF-1→IGF-1R pathway. Our recent studies suggest IGF-1R also subserves GH signaling in several novel ways: 1) GH induces a GHR-JAK2-IGF-1R complex, whose formation is independent of tyrosine phosphorylation of any of the partners; 2) Cotreatment with IGF-1 augments acute GH signaling; 3) deletion of IGF-1R in primary osteoblasts or human prostate cancer cells blunts acute GH signaling. In …
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 …
Neuropharmacology Of The Α2a Adrenergic Receptor In Disorders Of Mood And Cognition, Christopher Cottingham
Neuropharmacology Of The Α2a Adrenergic Receptor In Disorders Of Mood And Cognition, Christopher Cottingham
All ETDs from UAB
Depressive disorders carry relatively high lifetime risks of greater than 10%, and the antidepressant drugs used in the pharmacotherapy of these mood/cognitive disorders are among the most-prescribed pharmacological agents. However, a detailed understanding of both depressive etiology and the pharmacological mechanisms of action for antidepressant drugs remain elusive. The overall goal of this dissertation research is to provide novel in-sights through a detailed study of the neuropharmacology of the α2A adrenergic receptor (AR). α2ARs, as key regulators of noradrenergic neurotransmission, have been broadly understood to have some ill-defined role in both the neurobiology and neuropharmacology of depressive disorders. The studies …
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 …
Is P53 A Target Of Hpv-18 E6 In The Viral Life Cycle?, Eun-Young Kho
Is P53 A Target Of Hpv-18 E6 In The Viral Life Cycle?, Eun-Young Kho
All ETDs from UAB
The large family of human papillomaviruses (HPVs) infects the cutaneous or mucosal epithelia causing benign hyper proliferative diseases. Infections by the high-risk (HR) HPV genotypes in the anogenital tracts can progress to high grade lesions and cancers in men and women. Because the viral productive program requires squamous differentiation of epithelia, HPV encodes oncoproteins that recondition the differentiated cells that have withdrawn from the cell cycle to support viral DNA amplification. The HR HPV E6 and E7 oncogenes are selectively expressed in cervical carcinomas and are necessary to maintain the malignant state. In vitro, constitutive expression of the HR HPV …
Mechanism Of Nfi-C Functionin During Tooth Root Formation, Ejvis Lamani
Mechanism Of Nfi-C Functionin During Tooth Root Formation, Ejvis Lamani
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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 …
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 …
Antiphagocytic Factors Of Mycoplasma Pulmonis, Brandon Michael Shaw
Antiphagocytic Factors Of Mycoplasma Pulmonis, Brandon Michael Shaw
All ETDs from UAB
Mycoplasma pulmonis is a murine respiratory pathogen and is used as a model for studying chronic mycoplasmal respiratory disease. This organism has been used by many in vivo and in vitro studies to gain a better understanding of host-pathogen interactions in chronic respiratory infection. Studies have shown that alveolar macrophages play an important role in the removal of this pathogen from the host. Given that M. pulmonis is able to produce a chronic disease state, this organism should produce antiphagocytic factors that aid in avoidance of killing by alveolar macrophages. The Vsa proteins are involved in the avoidance of killing …
Effects Of Stress On Growth Hormone Receptor Signaling, Ryan Marshall Corrick
Effects Of Stress On Growth Hormone Receptor Signaling, Ryan Marshall Corrick
All ETDs from UAB
Growth hormone (GH) regulates body composition via stimulation of protein synthesis and catabolism of adipose tissue, generally promoting maintenance of lean body mass. Following severe injury, GH resistance contributes to muscle protein wasting, adversely impacting morbidity and mortality. In this dissertation research, we sought to determine the mechanisms of GH resistance following injury. To accomplish this, we evaluated GH signaling in a mouse model of severe injury. In the first section of this thesis, we demonstrate severe impairments in hepatic GH signaling occurring in association with an apparent, hemorrhage-dependent cleavage of the GH receptor (GHR). In the second section, we …
Regulation Of Clc-3 In Human Malignant Glioma, Vishnu Anand Cuddapah
Regulation Of Clc-3 In Human Malignant Glioma, Vishnu Anand Cuddapah
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Malignant gliomas are the most common and deadly form of primary brain cancer afflicting adults. Current treatment regimens, including surgical debulking, radiotherapy, and chemotherapy, have limited efficacy, and median patient survival remains only 14 months. Therefore, novel therapies must target different aspects of glioma biology. Two of the most striking features of this cancer are the unusual ability of glioma cells to robustly proliferate and migrate in the brain, and recent evidence suggests that ClC-3, a voltage-gated Cl- channel/transporter is implicated in both of these processes. We hypothesize that ClC-3 may facilitate proliferation and migration by promoting hydrodynamic shape and …
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 …
Finding A Cure For Venezuelan Equine Encephalitis Virus (Veev) Infection: The Search For The Antiviral Genes And Vaccine Development., Svetlana Atasheva
Finding A Cure For Venezuelan Equine Encephalitis Virus (Veev) Infection: The Search For The Antiviral Genes And Vaccine Development., Svetlana Atasheva
All ETDs from UAB
Venezuelan equine encephalitis virus (VEEV) is a re-emerging virus that causes a severe and often fatal disease in equids and humans. To date, despite a continuous public health threat, no vaccines or antiviral drugs against VEEV infection have been developed for human use. In this study we took advantage of accumulated knowledge of capsid protein function in viral replication, assembly and virus-host interactions. Besides being an integral part of the virion, capsid protein is the major determinant of VEEV pathogenesis. This protein is cytotoxic and induces cellular transcriptional shutoff as a countermeasure to the cellular antiviral response. We introduced targeted …
Identification, Molecular Cloning And Characterization Of Transmitted/Founder Hiv-1 Subtype A, D And Ad Viruses And Envelope Glycoproteins, Joshua Baalwa
All ETDs from UAB
A precise molecular identification of transmitted/founder (T/F) HIV-1 genomes responsible for productive infection in humans can be an enabling strategy for elucidating mechanisms of virus transmission, immunopathogenesis and prevention. Previously, we reported a single genome sequencing approach, which when combined with a mathematical model of early random virus diversification, allowed for an unambiguous identification of T/F HIV-1 subtype B and C envelope (env) genes. Here, we apply this method to the identification and molecular cloning of full-length HIV-1 genomes and env genes of the less well-studied, but nonetheless important, HIV-1 subtypes A and D. Twelve subtype A (n=5), D (n=5) …
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 …
The Role Of Primary Cilia In Articular Cartilage And Growth Plate, Ching-Fang Chang
The Role Of Primary Cilia In Articular Cartilage And Growth Plate, Ching-Fang Chang
All ETDs from UAB
Primary cilia are now considered an important organelle required for many key steps during developmental processes including skeletal development. Articular cartilage and growth plate are two cartilage compartments whose functions are important postnatally. Articular cartilage is a think cartilage layer which serves as a cushion to protect the joint space, whereas growth plate is important for postnatal long bone growth. Both articular cartilage and growth plate need to be developed properly to ensure the normal bone function. Here, we show an important role of primary cilia in development of both articular cartilage and growth plate using genetic modified mouse model …
Adhesion Molecule Interactions Influence The Implementation Of Immune Responses To Infection, Maureen Ann Cox
Adhesion Molecule Interactions Influence The Implementation Of Immune Responses To Infection, Maureen Ann Cox
All ETDs from UAB
Interactions mediated by intercellular adhesion molecule-1 (ICAM-1) enhance both the antigenic and cytokine signals that CD8 T cells perceive, and these interactions have been suggested to be required for the formation of memory CD8 T cells. Following acute lymphocytic choriomeningitis virus (LCMV) infection of ICAM-1-/- mice, we observe elevated numbers of "effector-phenotype" (CD127lo KLRG-1hi IL-2-) virus-specific CD8 T cells well into the memory phase, while the development of memory-phenotype CD8 T cells (CD127hi KLRG-1lo IL-2 producing) is not impaired. The enhanced maintenance of effector-phenotype cells is due to ICAM-1 deficiency on non-T cell subsets, suggesting a role for ICAM-1 mediated …
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 …
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, …
Proteomic Clues To The Pathogenesis Of Alexander Disease, Daniel L. Flint
Proteomic Clues To The Pathogenesis Of Alexander Disease, Daniel L. Flint
All ETDs from UAB
Since the initial report identifying mutations in GFAP as the primary genetic defect in the astrogliopathy Alexander Disease (AxD) much progress has been made in elucidating the molecular details underpinning the pathogenic role of mutant GFAP in astrocytes. In particular, data collected from mouse, fly, and cell culture models of AxD have isolated several prominent cellular changes that are associated with mutant GFAP expression including oxidative stress, proteasome inhibition, reduced expression of the astrocyte glutamate transporter GLT-1, and loss of neurons; these models have also successfully recapitulated the pathological hallmark of AxD--protein aggregates known as Rosenthal fibers (RFs). To date, …
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. …
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 …
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 …
Mitochondrial Morphology And Function In Neuronal Cells Under Stress, Lonnie Schneider
Mitochondrial Morphology And Function In Neuronal Cells Under Stress, Lonnie Schneider
All ETDs from UAB
Neurodegenerative disease encompasses a wide range of conditions and pathologies that can manifest at any age depending on the etiology. A major factor in both early onset and age-related neurodegeneration is mitochondrial dysfunction. To investigate how mitochondrial bioenergetics is affected by cellular stress, we used an in vitro culture system to examine mitochondrial function in response to oxidative stress. We also studied an in vivo model of neuronal ceroid lipofuscinosis to determine the impact of deficient autophagy-lysosomal activity on mitochondrial morphology, composition and function. In vitro we found that retinoic acid-induced differentiation of dopaminergic neuroblastoma SH-SY5Y cells exhibited increased mitochondrial …
A Role Of Angiogenin In Models Of Parkinson's Disease, Trent Steidinger
A Role Of Angiogenin In Models Of Parkinson's Disease, Trent Steidinger
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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 …
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 …