Digital Commons Network^™

The Role Of Fc Receptor-Like 2 In B Cell Signaling, Tanisha Anne Jackson

All ETDs from UAB

Fc receptor-like 2 (FCRL2) is a transmembrane protein with immunomodulatory potential that is preferentially expressed by memory B cells in humans. It has two consensus immunoreceptor tyrosine-based inhibitory motifs (ITIM) in addition to a putative immunoreceptor tyrosine-based activation motif (ITAM) sequence in its cytoplasmic domain. We have confirmed the cellular distribution of FCRL2 and ana-lyzed its functional potential to show that coligation with the B cell receptor (BCR) leads to tyrosine phosphorylation of its ITIM motifs and subsequent SHP-1 recruitment to facilitate inhibition of BCR signaling. Mutational analysis indicates that the tyrosine residues in both inhibitory motifs of FCRL2 are …

Molecular Mechanisms Of Hepatic Insulin Resistance Following Injury, Shaoning Jiang

All ETDs from UAB

Insulin resistance commonly occurs following injuries or critical illness independent of previous diabetic status. The development of insulin resistance and hyperglycemia is associated with increased mortality and morbidity in critically ill patients. However, the molecular mechanisms underlying the acute insulin resistance following injuries remain poorly understood. With an animal model of trauma and hemorrhage, we have previously demonstrated the rapid development of insulin resistance in liver, and a critical role of TNFα in hemorrhage-induced defects in insulin signaling following resuscitation. However, hepat-ic insulin signaling is impaired prior to a significant increase in plasma TNFα, suggesting the initial development of hemorrhage-induced …

In Vitro Elucidation Of The Role And Mechanism Of Rankl In Tnf-And Il-1-Mediated Osteoclast Formation And Function, Joel Jules

All ETDs from UAB

The receptor activator of NF-қB (RANK) ligand (RANKL) and its receptor RANK play a critical role in osteoclast biology. RANK has three tumor necrosis factor receptor associated factor (TRAF)-binding motifs [PFQEP369-373 (Motif 1), PVQEET559-564 (Motif 2), and PVQEQG604-609 (Motif 3)] that regulate osteoclast formation and function. RANK also contains a TRAF-independent motif (IVVY535-538) that commits bone marrow macrophages (BMMs), which are osteoclast precursors, to the osteoclast lineage for osteoclastogenesis. Notably, tumor necrosis factor-α (TNF) and interlukin-1 (IL-1) utilize TRAFs to initiate most of the signaling pathways known to be activated by RANKL but fail to form osteoclasts unless attended by …

The Role Of The Intracellular Signaling Pathway In Ehrlichia Canis Infection In Vitro, Chang-Hyun Kim

All ETDs from UAB

Ehrlichia canis is a pleomorphic obligatory intracellular gram-negative bacterium that causes tick-borne canine ehrlichiosis. A systematic investigation on the pathogenesis of the disease has been hindered largely by lack of a reliable quantitative assay. Using quantitative real time PCR (qPCR), a quantitative assay for E. canis was developed and validated. Using the qPCR, the intracellular proliferation kinetics of E. canis in the canine 030F cell-line was studied for the first time. Many intracellular bacterial pathogens have been shown to use Ca2+ signaling in the host cells to induce their own internalization and proliferation. However, it is not clear how Ca2+ …

Identification And Characterization Of Downstream Target Genes Of The Bmp Signaling Pathway, Nam Chul Kim

All ETDs from UAB

During nervous system development, neurons proliferate, differentiate, project their axons to their targets and make synapses with them. At the neuromuscular junction of Drosophila, these functional synapses enlarge as the body grows to maintain physiologically effective synaptic transmission with the muscles. Drosophila Bone Morphogenetic Protein (BMP) type II receptor, Wishful thinking (Wit), is important in this proper synaptic growth and function. To identify transcriptional targets of Wit signaling, we performed microarray experiments comparing normal controls to wit mutants. Through this study, we found that some of the verified target genes showed isoform-specific regulation in wit mutants, and that several neuropeptide …

Role Of 14-3-3&Tau In Autophagy And Role Of Edd In P53 Regulation, Shiyun Ling

All ETDs from UAB

Unrestricted cell proliferation and suppression of cell death are two essential events for tumor development. My dissertation research involves two proteins, 14-3-3 &tau and EDD which are involved in diverse pathways related to these two fields in recent studies. Previous study demonstrates that 14-3-3ô regulates p21 degradation. Up-regulation of 14-3-3ô is seen in breast cancer and is correlated with the down-regulation of p21 in breast cancer. Amplification or overexpression of EDD was observed in breast cancer and ovarian cancers. Illustrating the new roles of these two proteins in proliferation and cell death will advance our knowledge in tumorigenesis and help …

Identification And Characterization Of Virulence Factors Of Mycoplasmas, Wenyi Luo

All ETDs from UAB

Mycoplasmas cause a group of diseases that are characterized by their chronicity and resistance to treatment. Diseases caused by the murine pathogens Mycoplasma pulmonis and Mycoplasma arthritidis are often studied as models of human diseases caused by a variety of chronic pathogens that induce a similar pathology. Among several candidate pathogenic factors, superantigens and degradative enzymes such as glycosidases are potentially important but not well characterized. The M. arthritidis mitogen (MAM) is a superantigen secreted by M. arthritidis. Its role with respect to arthritogenicity and toxicity is unclear. To improve the efficiency of transformation and hence enhance efforts to generate …

Lim Kinase 1 And Twinstar In Synaptic Plasticity Of Drosophila Motoneurons, James Brian Machamer

All ETDs from UAB

Modification of the actin cytoskeleton is essential for synaptic plasticity, which is believed to underlie the brain's capacity for learning and memory. Regulation of the actin cytoskeleton by LIM Kinases (LIMK1 and LIMK2) and their downstream targets Actin Depolymerization Factor/Cofilin (ADF/Cofilin) in the mouse forebrain modulates dendritic spine morphology, synaptic function, long-term potentiation (LTP), and learning and memory, but appear dispensable for the regulation of most forms of presynaptic plasticity. However, these analyses were performed in mice mutant for single members of these gene families, and thus the interpretation of these results is confounded by potential compensatory activity of homologous …

Translocation And Function Of Akt In The Mitochondria, Keri A. Mans

All ETDs from UAB

The ubiquitously expressed kinase Akt is a known survival protein, and is involved in multiple cell signaling cascades, notably the phosphatidylinositol 3-kinase (PI3K) pathway. Active Akt translocates from the plasma membrane to different subcellular compartments, including mitochondria, where it phosphorylates compartment-specific substrates. The mechanism of this translocation and the specific function of Akt within the mitochondria remains a mystery. The goals of this study were to elucidate the mechanism by which Akt enters the mitochondria and examine the role of Akt in mitochondrial function. Finally, the possibilities of using post-mortem human brain tissue to study mitochondrial function in normal and …

Translation Initiation Signaling Components Altered By Mechanical Load Dictate Skeletal Muscle Hypertrophy, David Lawrence Mayhew

All ETDs from UAB

The regulation of protein synthesis (i.e., mRNA translation) is an energetically costly and extensively regulated process, which is primarily regulated at the initiation step. Mechanical load is a potent stimulus of translation in skeletal muscle, and thus this tissue provides an excellent model system to study the plasticity of the translational apparatus. We investigated the effects of alterations in translation initiation cell signaling pathways in skeletal muscle using a variety of in vitro and in vivo mouse and human model systems. Collectively, our results suggest that, although many proteins in translational signaling pathways are responsive to mechanical load, the response …

The Contribution Of Different Mechanisms Of Viral Sequence Variation To The Evolution Of Positive-Sense Single-Stranded Rna Viruses, Brett Earl Pickett

All ETDs from UAB

The Flaviviridae family of positive-sense single-stranded RNA (+ssRNA) viruses includes viral taxa which greatly impact public health worldwide. To explore how the viruses within the Flaviviridae family evolve, we examined the extent to which these viral taxa use nucleotide covariance, spontaneous mutation, and/or homologous recombination to vary their genotype as well as the resulting phenotype. We developed and used CovarView to assist us in simultaneously viewing and inspecting the results from whole genome covariance analyses. This resulted in the identification of previously-characterized RNA functional structures in the genomes of hepatitis C virus (HCV), as well as a new RNA functional …

Regulation Of Glycogen Synthase Kinase 3 In The Pathophysiology And Treatment Of Mood Disorders, Abigail Marie Polter

All ETDs from UAB

Mood disorders are devastating psychiatric illnesses that will affect as many as one in every five persons worldwide over the course of their lifetime. Significant gaps still remain in our understanding of these illnesses and outcomes for many patients are far from optimal. Glycogen Synthase Kinase 3 (GSK3) is a protein kinase that is increasingly recognized as playing an important role in a number of neuronal functions, as well as in pathological states such as mood disorders. GSK3 is inhibited in the brain by phosphorylation on an N-terminal serine. Several treatments for mood disorders, including lithium, antidepressants, and atypical antipsychotics …

Heparanase Drives The Aggressive Myeloma Phenotype: Preclinical Development Of A Heparanase Inhibitor For The Treatment Of Multiple Myeloma, Joe Ritchie

All ETDs from UAB

Heparanase, an endoglycosidase which cleaves heparan sulfate chains at specific sites, is rarely expressed in normal tissues but becomes evident in many human cancers. We have previously shown that heparanase promotes myeloma growth and angiogenesis through modulation of the tumor microenvironment. Recognition that heparanase drives the aggressive myeloma phenotype has led to new strategies designed to therapeutically target this enzyme. SST0001, a non-anticoagulant heparin that is 100% N-acetylated and 25% glycol split, was previously described as a potent inhibitor of heparanase activity in vitro, and, in limited in vivo experiments, SST0001 was identified to have efficacy as an anti-tumor agent …

The Role Of Map Kinase Cascade In Msp Signaling Response, Youfeng Yang

All ETDs from UAB

The MSP domain is an evolutionarily conserved immunoglobulin-like structure of about 120 amino acids (Miller et al., 2001). A P56S missense mutation in the MSP domain of the human vapb gene is associated with a dominantly inherited form of Amyotropic Lateral Sclerosis (ALS) or Spinal Muscular Atrophy (SMA) (Nishimura et al., 2004). In C. elegans, secreted MSP binds to the VAB-1 Eph receptor and other receptors on oocyte and ovarian sheath cell surfaces (Miller et al., 2003). We have recently shown that the P56S mutation prevents secretion of the VAPB MSP domain, suggesting that the signaling function is important in …

Il-21 Dictates The Quality Of The Cd8 T Cell Response During Acute And Chronic Infections, John Seung-Hoon Yi

All ETDs from UAB

CD8 T cells contribute to the control of intracellular pathogens including viruses and certain bacteria. Recognition of foreign antigens by antigen-specific CD8 T cells initiates a differentiation process by which CD8 T cells gain effector functions including the ability to rapidly produce cytokines and kill infected cells. Currently, it is not well understood what signals dictate the generation of robust CD8 T cell responses, however it has been demonstrated that without CD4 T cell help CD8 T cell responses are compromised. CD4 T cells are the primary producers of interleukin-21 (IL-21), which has broad immunological actions. Thus for this dissertation, …

A Ck2-Dependent Mechanism For Activation Of The Jak-Stat Signaling Pathway: Implications For Cancer Biology, Ying Zheng

All ETDs from UAB

Janus Kinase (JAK)-Signal Transducer and Activator of Transcription (STAT) signaling is involved in regulation of cell survival, proliferation and differentiation. JAK tyrosine kinases can be transiently activated by cytokines or growth factors in normal cells, while they become constitutively activated as a result of mutations that affect their function in tumors. Specifically, the JAK2V617F mutation is present in the majority of patients with myeloproliferative disorders (MPDs) and is implicated in the pathogenesis of these diseases. In this dissertation, we report the identification of the serine/threonine kinase CK2 as a novel interactor and important regulator of activation of the JAK-STAT signaling …

Effect Of Overexpressing Apolipoprotein A-I In An Animal Model Of Alzheimer's Disease, Terry L. Lewis

All ETDs from UAB

Apolipoprotein A-I (apoA-I) is the major protein component of high density lipoprotein (HDL) in circulation and is expressed mainly by the liver and intestine. The levels of apoA-I/HDL are inversely related to the incidence of cardiovascular disease. Because of the connections between heart disease and Alzheimer's disease (AD), it is conceivable that high levels of apoA-I/HDL may be protective against AD. However, the limited literature shows mixed results on the role of apoA-I/HDL in the development of AD. It is hypothesized that increased expression of human apoA-I will ameliorate the behavioral deficits and characteristic amyloid-ß (Aß) plaque formation in a …

Protective Antibodies To The Proline-Rich And Alpha Helical Regions Of Pneumococcal Surface Protein A And Their Detection In An In Vitro Surrogate Assay, Calvin Clay Daniels

All ETDs from UAB

Current pneumococcal vaccines containing pneumococcal capsular polysaccharide antigens protect against infection by pneumococci. However, this protection is limited to strains expressing the capsule types included in the vaccine. Since the introduction of these vaccines, the increase in incidence of infection by serotypes not targeted by the vaccine, a process called "serotype replacement," and the growing antibiotic resistance of replacement strains both stress the need for vaccines with broader protection. The alpha-helical region of a protein present on all clinical isolates of pneumococci, Pneumococcal Surface Protein A (PspA), elicits protective immunity. Downstream of the alpha-helical region is a highly conserved region …

Poxvirus Evolution: The Role Of Horizontal Gene Transfer, Mary Rebecca Odom

All ETDs from UAB

We have investigated the set of all poxvirus proteins for information about the origins of protein coding genes of the Poxviridae family of viruses. A global assessment of all poxvirus proteins for levels of similarity to proteins of other organisms, including eukaryotes, viruses, and prokaryotes, has suggested trends and relationships informative about poxvirus evolution and poxvirus interactions with hosts. Our research has focused on the poxvirus proteins subset this assessment identified as likely to have evolutionary histories involving horizontal gene transfer (HGT). We have used phylogenetic reconstructions to individually determine the sources of more than 70 horizontally transferred genes present …

Identification Of A Novel Cytokine Inducible Stat5 Phosphoserine Site (Ps193) That Positively Regulates Its Transcriptional Activity And Is Found Constitutively Activated In Certain Hematopoietic Cancers, Abhisek Mitra

Open Access Theses & Dissertations

Hematological malignancies such as leukemia and lymphoma, can develop from aberrant changes in the cell signaling molecules to drive their uncontrolled cellular proliferation and differentiation. Activation, maturation, expansion and differentiation of T cells are critically regulated by the dynamics of various transcription factors activated by a variety of cytokines. Additionally, multiple effector molecules that mediate these T cells dependent signals include the JAK (Janus Kinase)-STAT (Signal transducer and activator of transcription) cascade. These signaling proteins are activated in response to a broad array of cytokines. Constitutively activated JAKs and STATs have been described in several T cell malignancies. A growing …

Morphological Development Of The Axial Skeletons Of Esox Lucius And Esox Masquinongy (Euteleostei: Esociforms), With Comparisons In Developmental And Mineralization Rates., Amanda Maria Burdi

Master's Theses

Developmental morphology of the axial skeleton of Esox lucius (i.e., northern pike and type species) and E. masquinongy (i.e., muskellunge) was investigated. More than 1,000 specimens were examined ranging in size from approximately 10 mm notochordal length (NL) post-hatching juveniles to over 80 mm standard length (SL) foraging sub-adults. Results show that regardless of individual variation, the relative sequence of bone formation and mineralization is consistent between the two species. This consistent developmental pattern enabled construction of an ontogenetic staging scheme of eight developmental stages, each characterized by one defining criterion. The first appearance in cartilage and/or first sign of …

The Globin Gene Family Of The Cephalochordate Amphioxus: Implications For Chordate Globin Evolution, Bettina Ebner, Georgia Panopoulou, Serge N. Vinogradov, Laurent Kiger, Michael C. Marden, Thorsten Burmester, Thomas Hankeln

Wayne State University Associated BioMed Central Scholarship

Abstract

Background

The lancelet amphioxus (Cephalochordata) is a close relative of vertebrates and thus may enhance our understanding of vertebrate gene and genome evolution. In this context, the globins are one of the best studied models for gene family evolution. Previous biochemical studies have demonstrated the presence of an intracellular globin in notochord tissue and myotome of amphioxus, but the corresponding gene has not yet been identified. Genomic resources of Branchiostoma floridae now facilitate the identification, experimental confirmation and molecular evolutionary analysis of its globin gene repertoire.

Results

We show that B. floridae harbors at least fifteen paralogous globin genes, …

Mapping Haplotype-Haplotype Interactions With Adaptive Lasso, Ming Li, Roberto Romero, Wenjiang J. Fu, Yuehua Cui

Wayne State University Associated BioMed Central Scholarship

Abstract

Background

The genetic etiology of complex diseases in human has been commonly viewed as a complex process involving both genetic and environmental factors functioning in a complicated manner. Quite often the interactions among genetic variants play major roles in determining the susceptibility of an individual to a particular disease. Statistical methods for modeling interactions underlying complex diseases between single genetic variants (e.g. single nucleotide polymorphisms or SNPs) have been extensively studied. Recently, haplotype-based analysis has gained its popularity among genetic association studies. When multiple sequence or haplotype interactions are involved in determining an individual's susceptibility to a disease, it …

Comparison Of Mitotic Cell Death By Chromosome Fragmentation To Premature Chromosome Condensation, Joshua B. Stevens, Batoul Y. Abdallah, Sarah M. Regan, Guo Liu, Steven W. Bremer, Christine J. Ye, Henry H. Heng

Wayne State University Associated BioMed Central Scholarship

Abstract

Mitotic cell death is an important form of cell death, particularly in cancer. Chromosome fragmentation is a major form of mitotic cell death which is identifiable during common cytogenetic analysis by its unique phenotype of progressively degraded chromosomes. This morphology however, can appear similar to the morphology of premature chromosome condensation (PCC) and thus, PCC has been at times confused with chromosome fragmentation. In this analysis the phenomena of chromosome fragmentation and PCC are reviewed and their similarities and differences are discussed in order to facilitate differentiation of the similar morphologies. Furthermore, chromosome pulverization, which has been used almost …

Molecular And Therapeutic Implications Of Notch1 Signaling In Pediatric T-Cell Acute Lymphoblastic Leukemia, Amanda Larson Gedman

Wayne State University Dissertations

T-cell acute lymphoblastic leukemia (T-ALL) accounts for 15% of pediatric ALL cases and is associated with early relapse and inferior outcome. The poorer prognosis of T-ALL compared to B-precursor ALL may in part reflect the lack of unique features on which to base therapy. NOTCH1 mutations are of particular interest since these were reported in 37-71% of T-ALLs. The prognostic value of NOTCH1 mutations remains controversial as both favorable and unfavorable associations were reported, whereas in other studies, there were no associations between NOTCH1 mutations and treatment outcome. We explored the impact of mutations in NOTCH1, FBW7 and PTEN on …

The Role Of Synaptically Evoked Plateau Potentials In Retinogeniculate Development, Emily Dilger

Theses and Dissertations

We study the activity-dependent refinement of sensory systems by using the mouse retinogeniculate system as a model. Spontaneous retinal waves lead to robust excitatory post-synaptic activity in developing relay cells in the dorsal lateral geniculate nucleus (dLGN) of the thalamus and are reportedly needed to help guide the segregation of retinal inputs into eye-specific domains as well as for the pruning of extraneous retinal inputs onto single dLGN relay cells. The composition of retinally evoked post-synaptic activity activated by these retinal waves in dLGN is largely unknown, but based on our in vitro recordings, such activity seems well suited to …

Expanding The Treatment Window Raising The Bar For Patient Safety, Claranne Mathiesen Rn, Msn, Cnrn

Patient Care Services / Nursing

No abstract provided.

The Development Of A Formal Preceptor Model To Improve Departmental Mentorship, Angela Lutz Bs, Rrt-Nps, Kenneth Miller Med, Rrt-Nps, Linda Cornman Bs, Rrt-Nps, Uma Bhatt Rrt, Bryn Surgeoner Rrt

Patient Care Services / Nursing

No abstract provided.

Subacute Neural Stem Cell Therapy For Traumatic Brain Injury, Mikhail Bogdanov, Philip N Heacock, William Dowhan

Faculty, Staff and Student Publications

A protocol is described using lipid mutants and thiol-specific chemical reagents to study lipid-dependent and host-specific membrane protein topogenesis by the substituted-cysteine accessibility method as applied to transmembrane domains (SCAM). SCAM is adapted to follow changes in membrane protein topology as a function of changes in membrane lipid composition. The strategy described can be adapted to any membrane system.

The Role Of The L-Type Calcium Channel And Its Carboxyl-Terminus, Miranda Jean Byse

University of Kentucky Doctoral Dissertations

In the heart, the primary role of the L-type calcium channel (LTCC) Ca_V1.2 is to conduct calcium into cardiomyocytes and initiate contraction. However, part of the Ca_V1.2 channel itself, the cleaved carboxyl-terminus (CCt) can also localize to the nucleus and regulate gene transcription. Therefore, the goal of this dissertation project was to determine the role and regulation of CCt in the embryonic and adult heart. The global hypothesis of my dissertation project is that CCt localizes to the nucleus in embryonic and adult cardiomyocytes via a calcium-mediated mechanism and regulates transcription. A model of pharmacological LTCC …