Digital Commons Network^™

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 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 …

Hcn Channels And Regulation Of Neocortical Network Activity, Asher Albertson

All ETDs from UAB

Hyperpolarization activated non-specifc cation (HCN) channels are unique channels that activate following membrane hyperpolarization. Expressed primarily along the apical dendrites of pyramidal neurons, they pass a non-inactivating, inward current (Ih). HCN channel activation at resting membrane potentials profoundly impacts the synaptic and intrinsic properties of pyramidal neurons. Activated channels decrease intrinsic membrane excitability, hyperpolarize the resting membrane potential, and increase excitatory post-synaptic potentials (EPSP) summation. Loss of HCN channels is commonly observed in models of epilepsy. This dissertation tests the hypothesis that the influence of HCN channels on individual neuron excitability translates to an influence on network excitability. Furthermore, we …

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, …

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 …

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) …

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 …

Serotonin Signaling In Angiogenesis, Ali Zamani

All ETDs from UAB

Serotonin (5-hydroxytryptamine, 5-HT) is a well-known "happy" neurotransmitter. Selective serotonin reuptake inhibitors (SSRIs) are the most prescribed class of antidepressant medications to raise the serotonin level in the brain. However, the majority of serotonin in the human body is present outside of the brain and stored in platelets in blood circulation. Blood coagulation is a common feature of malignant solid tumors and leads to significant serotonin release from activated platelets into tumor environment. Due to the unique feature of platelet in lacking nucleus, the impact of platelet and serotonin on cancer progression has been overlooked by studies focusing on cancer …

Determining Efficacy Of Breast Cancer Therapy By Pet Imaging Of Her2 Mrna, Bishnuhari Paudyal, Kaijun Zhang, Changpo Chen, Neil Mehta, Eric Wickstrom, Brian Gray, Jeffrey Mattis, Koon Pak, Mathew L Thakur

Department of Radiology Faculty Papers

No abstract provided.

Increasing Parity Is Associated With Cumulative Effects On Memory, Laura M. Glynn

Psychology Faculty Articles and Research

BACKGROUND: The purpose of this investigation was to determine if reproductive experience is associated with cumulative effects on human memory performance during pregnancy and if these effects persist into the postpartum period.

METHODS: Verbal recall memory performance was assessed in 254 women four times during pregnancy and at 3 months postpartum. The relation between parity and memory function was evaluated with hierarchical linear modeling and analysis of covariance (ANCOVA).

RESULTS: The data indicate that the previously documented adverse effects of pregnancy on memory performance are compounded with successive pregnancies. During gestation and postpartum, multiparity was associated with poorer memory function, …

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 …

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 …

Regulation Of Neuronal Cell Death By Bh3-Only Proteins, Arindam P. Ghosh

All ETDs from UAB

Apoptosis in metazoan organisms plays critical roles in normal development, tissue homeostasis and immunity, and its disturbed regulation leads to many pathological states, including cancer, autoimmunity, infection and degenerative disorders. Apoptosis can be triggered by the engagement of `death receptors' of the tumor necrosis factor receptor family on the cell surface or by diverse intracellular signals that act upon the BCL2 (B-cell CLL/lymphoma 2) protein family, which controls the integrity of the mitochondrial outer membrane through the complex interactions of family members. Both the pathways lead to cellular demolition by dedicated proteases termed caspases. Different BH3-only proteins (or combinations of …

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 …

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 …

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 …

Suppression Of A Nonsense Mutation In A Mouse Model Of Hurler Syndrome, Dan Wang

All ETDs from UAB

Nonsense suppression therapy utilizes compounds that suppress translation termination at disease-causing premature termination codons (PTCs) to restore full-length, functional protein synthesis. This approach may provide a treatment for many diseases caused by nonsense mutations including Hurler syndrome (mucopolysaccharidosis type I - Hurler, MPS I-H). MPS I-H is a lysosomal storage disease caused by severe &alpha-L-iduronidase deficiency and subsequent lysosomal glycosaminoglycan (GAG) accumulation. In this work, we investigated the effectiveness of nonsense suppression therapy as a treatment for MPS I-H. We first generated a targeted knock-in mouse model that carries the Idua-W392X nonsense mutation homologous to the human IDUA-W402X mutation frequently …

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, Guyla 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

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

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 …

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 …

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

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 …

Development Of An Adenoviral Vector Platform For Selective Gene Delivery To Neurons, Travis Benjamin Lewis

All ETDs from UAB

Parkinson disease (PD) is a devastating movement disorder affecting between 500,000 and 1,000,000 individuals in the United States alone, and for which there is currently no cure. Therapies such as dopamine replacement help initially, but with disease progression these lose efficacy and do not alter the underlying degenerative process. Gene therapy is the delivery of exogenous genetic material to correct an underlying disorder. A major advantage of this approach is the ability to distribute potent therapies to specific targets over an extended duration, properties necessary for the treatment of progressive degenerative diseases such as PD. A number of clinical trials …

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 …

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

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

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 …

Transcriptional Regulation Of Gfap, Sujeong Yeo

All ETDs from UAB

Glial fibrillary acidic protein (GFAP) is an astrocytic intermediate filament protein whose levels are increased in response to CNS injuries. Aim one of my thesis is to find the regulatory elements of the GFAP promoter responsible for its expression properties using a transgenic approach, since previous studies showed inconsistent results between in vitro and in vivo approaches. Two contiguous DNA segments previously implicated in transcriptional control of the GFAP gene, the B region (bp -1612 to -1489), and the C1.1 and C1.2 regions (bp -1488 to -1399), were analyzed. Block mutation of each of 4 contiguous sequences together spanning the …