Medicine and Health Sciences Commons^™

Regulation Of Clc-3 In Human Malignant Glioma, Vishnu Anand Cuddapah

All ETDs from UAB

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 …

Glutamate Release And Uptake At Cerebellar Synapses, Ming-Chi Tsai

All ETDs from UAB

Glutamate mediates excitatory synaptic transmission in the central nervous system (CNS). Regulation of glutamate release and uptake shapes the spatiotemporal dynamics of glutamate at and around synapses to influence information transfer between neural cells. This dissertation focuses on the modulation of glutamate release and uptake at excitatory synapses of cerebellar Purkinje cells (PC). In the first project we show that differential expression of PC glutamate transporters controls the amount of glutamate entering the extrasynaptic space, thereby influencing the excitatory responses in surrounding Bergmann glia. This work provides the first evidence that neuronal glutamate uptake affects glial glutamatergic signaling. In the …

Biochemical And Cellular Mechanisms For The Antineoplastic Properties Of Sulindac, Jason Derek Whitt

All ETDs from UAB

ABSTRACT The nonsteroidal anti-inflammatory drug (NSAID) sulindac has displayed the ability to inhibit the proliferation of colorectal cancer (CRC) cells and to increase the sensitivity of multidrug resistant (MDR) cancer cells to a wide variety of chemotherapeutic agents. The antineoplastic activity of sulindac has been attributed to inhibition of the prostaglandin producing enzyme COX-2, but the exact mechanism remains elusive and the inhibition of prostaglandin synthesis can result in gastrointestinal, hepatic, and cardiovascular toxicities. Enzymatic, cellular, and imaging assays were used to identify mechanisms that could contribute to the antiproliferative and apoptotic activity of sulindac. Screening of more than 500 …

Regulation And Function Of Interleukin-21-Producing T Cells And Immune-Mediated Control Of Hiv-1 Infection, Latonya Denise Williams

All ETDs from UAB

CD8 T cells play a critical role in controlling intracellular pathogens, particularly viruses. However, during persistent viral infections, such as human immunodeficiency virus-1 (HIV-1) infection, virus-specific CD8 T cells become increasingly impaired by poorly understood mechanisms. Massive CD4 T cell depletion is a hallmark of HIV-1 infection and is associated with CD8 T cell dysfunction and ineffective viral containment. CD4 T cells provide critical helper signals to CD8 T cells, especially during uncontrolled viral infections. Mouse models of chronic viral infection implicate interleukin-21 (IL-21), produced primarily by CD4 T cells, as a vital factor necessary for the maintenance of fully …

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

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 …

Evaluating The Efficacy Of Radiofrequency Amplitude-Modulated Electromagnetic Fields As A Novel Treatment For Hepatocellular Carcinoma, Jacquelyn Winifred Zimmerman

All ETDs from UAB

Hepatocellular carcinoma (HCC) incidence in the US is dramatically increasing. Five-year survival has remained 3-5% for the past several decades, demonstrating urgent need for additional therapies. Intrabuccal administration of amplitude-modulated radiofrequency electromagnetic fields (RF EMF) is a novel, minimally invasive treatment modality. Clinical evidence demonstrates this treatment approach elicits therapeutic responses in cancer patients. In vitro we have described a phenotype in HCC cells following RF EMF exposure that included proliferative inhibition, modulation of gene expression, and disruption of the mitotic spindle. This phenotype was specific for HCC cells exposed to HCC-specific RF EMF. We have demonstrated similar efficacy in …

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 …

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 …

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, …

Modulation Of Wzy-Dependent Capsule Production In Streptococcus Pneumoniae By The Phosphotyrosine-Specific Phosphatase Cpsb, Kimball Aaron Geno

All ETDs from UAB

Biosynthesis of capsule polysaccharide in the Gram-positive pathogen Streptococcus pneumoniae is regulated in part through the action of a phosphoregulatory system comprised of the products of the capsule biosynthetic operon genes cpsBCD. CpsC and CpsD together comprise an autophosphorylating tyrosine kinase whose homologs are implicated in chain length regulation in other systems in both Gram-positive and Gram-negative organisms. CpsB is the cognate phosphatase for the system. Unlike Gram-negative organisms, which use a low molecular weight phosphotyrosine phosphatase in phosphoregulation of capsule synthesis, Gram-positive organisms utilize a polymerase and histidinol phosphatase (PHP) superfamily phosphatase. Deletion of cpsB has resulted in conflicting …

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 …

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 …

The Formin Fmnl3 Is A Cytoskeletal Regulator Of Angiogenesis, Clare Hetheridge, Alice N. Scott, Rajeeb K. Swain, John W. Copeland, Henry N. Higgs

Dartmouth Scholarship

The process of angiogenesis requires endothelial cells (ECs) to undergo profound changes in shape and polarity. Although this must involve remodelling of the EC cytoskeleton, little is known about this process or the proteins that control it. We used a co-culture assay of angiogenesis to examine the cytoskeleton of ECs actively undergoing angiogenic morphogenesis. We found that elongation of ECs during angiogenesis is accompanied by stabilisation of microtubules and their alignment into parallel arrays directed at the growing tip. In other systems, similar microtubule alignments are mediated by the formin family of cytoskeletal regulators. We screened a library of human …

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.

Optical Imaging For Determination Of Apoptosis Medicated Therapeutic Efficacy, Kaijun Zhang, Bishnuhari Paudyal, Neil Mehta, Brian Gray, Koon Y. Pak, Eric Wickstrom, Mathew L Thakur

Department of Radiology Faculty Papers

No abstract provided.

Redefining Onyx Hd 500 In The Flow Diversion Era., Richard Tyler Dalyai, Ciro Randazzo, George Ghobrial, L Fernando Gonzalez, Stavropoula I Tjoumakaris, Aaron S Dumont, Robert H Rosenwasser, Pascal Jabbour

Department of Neurosurgery Faculty Papers

We report the largest US case series results using Onyx HD-500 (EV3), a new liquid embolic agent, in the successful treatment of 21 patients with wide-neck intracranial aneurysms (mean size 4.5 mm), which are at increased risk of incomplete occlusion or recanalization with standard endovascular intervention utilizing detachable platinum coils. All aneurysms were located in the anterior circulation, and three aneurysms presented as acute subarachnoid hemorrhages. Complete aneurysm occlusion was present in 19 of 21 patients (90%). On six-month followup, one patient with an initially small residual neck progressed to total occlusion. Aneurysm recanalization was not detected in any patients …

Complementary And Integrative Oncology In The Cross-Cultural Region Of The Middle East And South Asia., Eran Ben-Arye, Barrie Cassileth, Peter Heusser, Fatma Afifi, Bashar Saad, Senthamil R Selvan

Department of Medical Oncology 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, …

The Residency Cpc As A Means Of Faculty Development, Kathleen E. Kane Md, Kevin R. Weaver Do, Gavin C. Barr Jr. Md, Amy B. Smith Phd, Andrew C. Miller Do, Charles C. Worrilow Md, Terrence E. Goyke Do, Dawn M. Yenser, Bryan G. Kane Md

Department of Emergency Medicine

No abstract provided.

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 …

Severe Lamotrigine Neurotoxicity Treated With Intralipid Emulsion Therapy, Philip W. Moore Do, Megan C. Urquhart Do, Dale L. Mcmillion Do, Keith K. Burkhart Md, Louis R. Cantilena Jr, Md, J Ward Donovan Md

Department of Emergency Medicine

No abstract provided.

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, …

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 …