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Full-Text Articles in Medicine and Health Sciences
A Role For P63 In The Regulati On Of Cell Cycle Progression And Cell Death, Eric Scott Helton
A Role For P63 In The Regulati On Of Cell Cycle Progression And Cell Death, Eric Scott Helton
All ETDs from UAB
p63 is a member of the p53 family of transcription factors that is a critical regulator of epithelial development. Studies have shown that p63 does not appear to function as a classical tumor suppressor like p53. Instead, the expression pattern of p63 in cancers suggests that p63 retains the potential to function as either a tumor suppressor or an onco-protein. Here, we provide evidence describing the transcriptional activity of the p63 isoforms and provide mechanisms whereby p63 function is regulated in a context dependent manner. Our data shows that both the ΔNp63 and TAp63 variants retain the potential to regulate …
Regulation Of The Human Heme Oxygenase-1 Gene, Thomas D. Hock
Regulation Of The Human Heme Oxygenase-1 Gene, Thomas D. Hock
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The heme oxygenase-1 (HO-1) gene encodes a microsomal enzyme that catalyzes the conversion of heme to carbon monoxide, Iron, and biliverdin. HO-1 transcription is induced upon a plethora of cellular stresses including heme, heavy metal exposure, hy-poxia, oxidative stress and many others. The goal of this work was to explore the molecu-lar regulation of HO-1 transcription. Four DNase 1 hypersensitive sites are detected within the HO-1 promoter extending from ~-40bp to ~-9.2kb relative to the transcription start site. Dimethylsulfate (DMS) in vivo footprinting is shown for two regulatory re-gions and reveals nine protected guanines in all. Mutational analyses indicates that …
Quantitation Of Antiretrovirals In Alternative Matrices, Chantelle Bennetto Hood
Quantitation Of Antiretrovirals In Alternative Matrices, Chantelle Bennetto Hood
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The human immunodeficiency virus (HIV) pandemic is a growing concern, affecting almost 40 million people worldwide. Treatment for HIV infection consists of highly active antiretroviral therapy (HAART) to block different steps in the viral lifecycle, ultimately reducing HIV RNA to undetectable levels in the plasma. However, HIV RNA can be detected in numerous reservoirs outside of the blood despite the use of HAART. Therefore, measurement of antiretroviral (ARV) drugs in other biological matrices is important to broaden our understanding of HIV transmission, the development of viral resistance with sub-optimal ARV exposure, and fetal and neonatal drug exposure. This work describes …
Prostate Cancer Chemoprevention With Genistein And Resveratrol In Models Of Spontaneously Developing Prostate Cancer, Curt E. Harper
Prostate Cancer Chemoprevention With Genistein And Resveratrol In Models Of Spontaneously Developing Prostate Cancer, Curt E. Harper
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Prostate cancer is the second leading cause of cancer-related death among men in the United States. The goal of this research was to investigate the potential of three nutriceutical polyphenols, genistein, resveratrol, and epigallocatechin-3-gallate (EGCG), to suppress prostate cancer. Cancer chemoprevention and mechanism of action studies were carried out in transgenic models of prostate cancer. In TRansgenic Adenocarcinoma of the Mouse Prostate (TRAMP) model, resveratrol suppressed poorly differentiated tumors by 86%, whereas EGCG suppressed precancerous lesions, but failed to prevent late-stage prostate cancer. Agents that were chemopreventive in the TRAMP model were subsequently evaluated alone, and in combination, in the …
Characterization Of A Global Regulatory Pathway In Streptococcus Pneumoniae, Greer E. Kaufman
Characterization Of A Global Regulatory Pathway In Streptococcus Pneumoniae, Greer E. Kaufman
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Streptococcus pneumoniae is a versatile organism that adapts to many different environments in the host. S. pneumoniae can asymptomatically colonize the nasopharynx of humans. However, dissemination of the bacterium from the nasopharynx to different locations in the body can lead to invasive diseases such as pneumonia, bacteremia, and meningitis. How S. pneumoniae modulates factors that are important for survival in these niches has not been well characterized. In the studies described here, we propose that S. pneumoniae may modulate gene expression in these niches by sensing the different glu-cose concentrations via carbon catabolite control protein A (CcpA). Initially we characterized …
On The Immunological Roles Of Tlt2 And Hsh2, R Glenn King
On The Immunological Roles Of Tlt2 And Hsh2, R Glenn King
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The evolution of multicellular organisms necessitated the ability to detect and remove harmful parasitic microorganisms from the host. This simple requirement for self non-self discrimination has evolved in vertebrates into an elaborate system consisting of a variety of effector mechanisms to perform this process. The immune system is often described as consisting of two distinct yet complimentary components, the innate and adaptive immune systems. It is now recognized that the immune system relies on the highly coordinated interplay between a variety of cell types which cooperate to maintain the health of the organism. The work outlined in this dissertation addresses …
The Effect Of The Aml1-Eto Translocation On Cell Cycle Tumor Suppressor Gene Function, Rose Marie Ko
The Effect Of The Aml1-Eto Translocation On Cell Cycle Tumor Suppressor Gene Function, Rose Marie Ko
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The t(8;21)(q22;q22) AML1-ETO translocation is one of the most frequent translocations in acute myeloid leukemia (AML), occurring in approximately 12% of cases. Our laboratory has generated a mouse model in which AML1-ETO is expressed in hematopoietic progenitor cells using a retroviral vector and assayed using bone marrow transplantation. Animals transplanted with AML1-ETO-expressing cells failed to develop leukemia. However, AML1-ETO promoted significant expansion of immature myeloid cells suggesting a “pre-leukemic” state that requires secondary mutations for disease progression. In addition, analysis of cell cycle kinetics in AML1-ETOexpressing myeloid progenitor cells showed that AML1- ETO slowed G1 to S phase progression compared …
The Role Of Complement In The Clearance Of Streptococcus Pneumoniae Through Immune Adherence, Jie Li
The Role Of Complement In The Clearance Of Streptococcus Pneumoniae Through Immune Adherence, Jie Li
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Streptococcus pneumoniae is the most frequently isolated pathogen causing bacteremia in young children and elderly adults. Complement-dependent opsonophagocytosis is thought to be essential to eliminate pneumococci from the circulation. Pneumococci are reported to attach to erythrocytes through immune adherence (IA), a complement and antibody- dependent process that facilitates phagocytosis of pneumococci. In these studies we have determined that protein (chapter 1) and polysaccharide (chapter 2) virulence factors of pneumococci can interfere with this process and that antibody to pneumococci can enhance this process. Using PspA and/or PspC negative strains and complement-deficient mouse sera, we demonstrated that PspA inhibits complement C1q …
Directing Akt And Gsk3ss: Molecular Insights Into Cell Signaling And Survival, Gordon P. Meares
Directing Akt And Gsk3ss: Molecular Insights Into Cell Signaling And Survival, Gordon P. Meares
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Proper regulation of survival signaling is critical for all organisms. One important signaling cascade involved in the coordinated effort to control signals influencing cell fate is the phosphatidylinositol 3-kinase (PI3K)-Akt-glycogen synthase kinase 3β (GSK3β) signaling cascade. Following activation by growth factors the PI3K-Akt pathway promotes cell survival and, cell death is facilitated following inhibition of Akt. Many factors influence the function of the Akt-GSK3β signaling dyad, including phosphorylation, protein complex formation and subcellular localization. Previous work had demonstrated that the 90kDa heat shock protein, HSP90, directly binds and stabilizes Akt. Furthermore, several heat shock proteins including HSP90 and HSP105 can …
Primer Selection Of E. Coli Trna Lys,3 By Human Immunodeficiency Virus Type-1, Anna Mcculley
Primer Selection Of E. Coli Trna Lys,3 By Human Immunodeficiency Virus Type-1, Anna Mcculley
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Human immunodeficiency virus (HIV) is the cause of acquired immunodeficiency syndrome (AIDS). HIV replication includes the notable process of reverse transcription, a conversion of RNA to DNA. Reverse transcription is initiated from a primer by a viral enzyme, reverse transcriptase. The primer, tRNALys,3, is selected from the cytoplasm of an infected cell, annealed via the 3’ terminal 18-nucleotides to the viral primer binding site (PBS), and used in a subsequent infection. The mechanism of primer selection has not been determined although numerous studies have been performed. This has been hampered by the challenge of tRNALys,3 manipulation in the cell and …
The Function Of Hiv-1 A-Loop On Primer Selection, Na Ni
The Function Of Hiv-1 A-Loop On Primer Selection, Na Ni
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Reverse transcription is the hallmark of retroviruses, such as HIV-1. A cellular tRNA bound to the primer binding site region (PBS) is used for initiation of reverse transcription. HIV-1 specially selects tRNALys3 as primer, although changing the PBS can force HIV-1 to use alternative tRNAs as a primer. However, HIV-1 reverts back to use tRNALys3 following in vitro replication. The A-loop, located upstream of PBS, interacts with the anti-codon of primer tRNA. The inclusion of A-loop modification has been shown to stabilize the utilization of some alternative tRNAs. The studies in this dissertation focus on further defining the role of …
Regulation Of Vertebrate Gastrulation By Erbb Signaling, Shuyi Nie
Regulation Of Vertebrate Gastrulation By Erbb Signaling, Shuyi Nie
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ErbB receptor tyrosine kinases have long been implicated in cancer formation and progression by regulating cell division, migration, and survival. ErbBs are also essential in multiple processes during invertebrate development; however, their activities during vertebrate embryogenesis are not well understood. For functional characterization of ErbB signaling during vertebrate development, frog model Xenopus laevis was used in our studies. The expression pattern and the general activities of ErbB receptors during early frog development were first analyzed and results shown that ErbBs regulate gastrulation, somite organization and head patterning. As gastrulation is the first major morphogenetic event in vertebrate development, I focused …
Surveying The Chromosomal Supercoiling Levels In Rapidly Growing Wild Type And Gyrase Mutant Strains Of Salmonella Enterica Serovar Typhimurium With Γδ Resolvase-Mediated Recombination Assay, Zhenhua Pang
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A gyrase mutant strain (gyrB652) has severe growth defect at 42°C. The survival at high temperature is dependent on DNA repair proteins. The purified mutant gyrase was assayed for supercoiling acitivity and quinolone-induced DNA cleavage activity. The results suggested that the mutant enzyme is not temperature-sensitive, but has slower kinetics than the wild type gyrase. The DNA supercoiling levels at multiple chromosomal loci in exponential phase cells were monitored with γδ resolvase-mediated recombination assay. The wild type cells showed homogenous supercoiling levels throughout most of the chromosome. But the superhelicity at dif locus was significantly lower than the other loci. …
The Role Of Complement In Experimental Autoimmune Uveitis, Russell W. Read
The Role Of Complement In Experimental Autoimmune Uveitis, Russell W. Read
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The complement system has been increasingly implicated in the pathophysiology of autoimmune disease. Complement expression in the normal human eye had not been previously completely defined. We performed immunohistochemical studies for membrane complement proteins in normal human retina to provide a baseline for future studies. We found expression of the anaphylatoxin receptors, CD55, and CD59 in the inner retina and CD46 in a polarized fashion on the retinal pigment epithelium. Previous studies in uveitis have shown activated fragments of complement in human eyes with uveitis and animal models have shown an effect on disease by complement depletion with cobra venom …
Pathogenesis And Therapeutic Potential Of Plasmacytoid Dendritic Cells In Siv/Shiv-Infected Macaques, R Keith Reeves Ii
Pathogenesis And Therapeutic Potential Of Plasmacytoid Dendritic Cells In Siv/Shiv-Infected Macaques, R Keith Reeves Ii
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Plasmacytoid dendritic cells (pDCs) are among the first responders during acute viral infections and are the primary producers of IFN-α, a cytokine known to inhibit viral replication and to activate natural killer (NK) cells. In HIV patients pDCs are decreased in number, are dysfunctional, and can harbor HIV-1 proviruses. However, since the time of transmission is usually unknown, pDC-virus interactions immediately after exposure to HIV remain unclear. Using the SIV/SHIV-macaque model, we showed that an acute and sustained loss of blood pDCs occurred during SIVmac239 infections, and when compared to those from naïve controls, pDCs were also significantly reduced in …
The Characterization Of The Subcellular Localization Of Bile Acid Coa: N-Acyltransferase, Nathan Allen Styles
The Characterization Of The Subcellular Localization Of Bile Acid Coa: N-Acyltransferase, Nathan Allen Styles
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The liver plays a central role in metabolism. It controls protein metabolism through deamination and transamination of amino acids, removal of ammonia through urea synthesis, synthesis of non-essential amino acids and synthesis of the majority of plasma proteins such as albumin. The liver regulates blood glucose levels through glyconeogenesis and glyconeolysis of glycogen, as well as gluconeogenesis from amino acids. It regulates fat metabolism through oxidation of triglycerides and fatty acids, as well as synthesis of cholesterol, lipoproteins, and phospholipids. Furthermore, the liver is the only site of formation of bile acids and their conjugates, physiologically important compounds that solubilize …
Genetic And Epigenetic Regulation Of Dihydropyrimidinase And Beta-Ureidopropionase In Individuals With Altered Uracil Catabolism And Normal Dihydro Pyrimidine Dehydrogenase Enzyme Activity, Holly Reed Thomas
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There remain a number of patients presenting with 5-fluorouracil (5-FU) toxicity despite normal dihydropyrimidine dehydrogenase (DPD) enzyme activity, suggesting possible deficiencies in the two enzymes downstream of DPD in the uracil catabolic pathway: dihydropyrimidinase (DHP), encoded by the DPYS gene, or β-ureidopropionase (BUP-1), encoded by the UPB1 gene. Unlike DPD, which is expressed in peripheral blood mononuclear cells (PBMCs), DHP and BUP-1 enzyme activity is detected in only the liver and kidney, thus requiring an invasive biopsy for determination of activity. This dissertation, therefore, focuses on the role of the genetic and epigenetic regulation of DPYS and UPB1. The genetic …
Effects Of Specific Alterations In Capsule Structure On Streptococcus Pneumoniae Capsule Assembly And Virulence, Bobbi Xayarath
Effects Of Specific Alterations In Capsule Structure On Streptococcus Pneumoniae Capsule Assembly And Virulence, Bobbi Xayarath
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The polysaccharide capsules of Streptococcus pneumoniae represent the most important virulence determinant produced by this organism. Ninety-one different serotypes have been identified, but only a small number of these serotypes are responsible for most of the infections caused by S. pneumoniae. The reasons why certain serotypes predominate in infections over others are not well understood. One common serotype found in invasive diseases is type 2, however, it is unclear what characteristics of a type 2 capsule makes strains producing it virulent. The type 2 capsule consists of repeat units made of a backbone of Glc-Rha-Rha-Rha, with a side chain Glc-GlcUA …
Characterization Of A Novel Acetyltransferase Found Only In Pathogenic Strains Of Mycobacterium Tuberculosis, David K. Crossman
Characterization Of A Novel Acetyltransferase Found Only In Pathogenic Strains Of Mycobacterium Tuberculosis, David K. Crossman
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Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), is still a major threat to the human population. Roughly one third of the world population is asymptomatically infected and two million people die each year of TB. Effective treatments are available as a multi-drug regimen, but there is an ever increasing problem with the rise of multi-drug resistant strains that newer drug targets and a better understanding of how M. tuberculosis affects the host need to be elucidated. The primary target of M. tuberculosis in the human host is the macrophage where M. tuberculosis secretes virulence factors that inhibit various signal …
Coupling Selection Of The Hiv- 1 Trna Primer Used For Reverse Transcription With Viral Translation And Encapsidation, Uros V. Djekic
Coupling Selection Of The Hiv- 1 Trna Primer Used For Reverse Transcription With Viral Translation And Encapsidation, Uros V. Djekic
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HIV-1 belongs to the Retroviridae family. A hallmark of retroviral replication is the process of reverse transcription. Viral reverse transcriptase requires placement of a cellular tRNA primer onto the primer binding site (PBS) in order to initiate conversion of the viral RNA genome into a double stranded DNA copy. Mutation of the HIV-1 PBS forces the virus to utilize the non-cognate primer. Even though extensive studies have been done over the past 15 years, the mechanism of HIV-1 primer selection has yet to be completely elucidated. HIV-1 captures free tRNA during a yet undefined step in viral replication. However, our …
Pneumococcal Choline-Binding Protein A: Its Role In Virulence And Its Utility As A Streptococcus Pneumoniae Vaccine Antigen, David Tawayne Glover
Pneumococcal Choline-Binding Protein A: Its Role In Virulence And Its Utility As A Streptococcus Pneumoniae Vaccine Antigen, David Tawayne Glover
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Streptococcus pneumoniae is a major cause of morbidity and mortality worldwide. S. pneumoniae is a leading cause of pneumonia, meningitis, septicemia, and otitis media. Although all age groups can be affected, children and the elderly are espccially susceptible to infection. Currently there is a conjugate vaccine available for use, but this vaccine only contains capsular polysaccahride antigens from the seven most prevelant S. pneumoniae serotypes. The use of the conjugate vaccine has led to serotype shift, with more disease being caused by non-vaccine serotype bacteria. The studies presented in this dissertation identify and characterize a novel S. penumoniae vaccine candidate …
Kainate Receptor Modulation Of Synaptic Transmission In Neocortex, Seena S. Mathew
Kainate Receptor Modulation Of Synaptic Transmission In Neocortex, Seena S. Mathew
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The actions of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) are tightly regulated to ensure effective information processing as well as prevention of excess excitatory activity, which can lead to seizures and neurological disorders such as epilepsy. Drugs which enhance the effects of GABA are used as anesthetics, sedatives and anticonvulsants. Using whole-cell patch clamp recordings from neocortical neurons, we examined the mechanisms of GABAergic modulation that occur when kainate receptors (KARs) are activated. First, we address a novel signaling mechanism for the KAR-mediated facilitation of GABAergic synaptic transmission. Our first observation involved the presence of presynaptic KARs located on the …
Trafficking Of Hantaviral Nucleocapsid Proteins, Harish N. Ramanathan
Trafficking Of Hantaviral Nucleocapsid Proteins, Harish N. Ramanathan
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Hantaviruses are enveloped, negative-sense RNA viruses belonging to genus Hantavirus, within the family Bunyaviridae. Hantaviruses include many serious human pathogens and are classified as Old and New World based on the geographic distribution of rodent reservoirs and their ability to in induce distinct illnesses in humans. Currently there are no reservoirs known for hantaviruses other than the rodents. Human transmission of hantaviruses occurs via inhalation of aerosolized rodent excreta leading to hemorrhagic fever with renal syndrome (HFRS) or hantavirus pulmonary syndrome (HPS). Hantavirus genome consists of small (S), medium (M) and large (L) segments that encode nucleocapsid (N) protein, two …
In Vivo Imaging Studies In Animal Models Of Myocardial Infarction With And Without Cell Injections, Balazs Ruzsics
In Vivo Imaging Studies In Animal Models Of Myocardial Infarction With And Without Cell Injections, Balazs Ruzsics
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After prolonged myocardial ischemia, myocardial infarction occurs. Several tissue changes are associated with myocardial infarction and iron labeled cell injections. In the present thesis our major aim was to develop methods to monitor these tissue changes with MRI and MDCT. In the first chapter we used transendocardial injection to deliver iron labeled allogen skeletal myoblasts one week after myocardial infarction. Our goal was to identify the cells and/or injection sites in the myocardium. We used our new Tissue Characterization Mapping method to delineate tissue edema and hemorrhage in the myocardium. The T2 weighted signal intensity enhancement, T2w SIE region was …
Relaxation Rate-Based Magnetic Resonance Imaging Quantification Of Myocardial Infarction, Pal Suranyi
Relaxation Rate-Based Magnetic Resonance Imaging Quantification Of Myocardial Infarction, Pal Suranyi
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Ischemic heart disease is the leading cause of mortality in western societies. Treatment needs to be tailored for each individual, which requires accurate assessment of the underlying pathology. Magnetic Resonance Imaging (MRI) is a relatively young modality in the field of cardiovascular imaging, and boasts with the lack of harmful radiation, excellent soft tissue contrast, and high spatial-temporal resolution. The very foundation of the concept of MRI was the finding that pathology causes changes in the relaxation rates of tissues. Measurement of relaxation rates is more time consuming than generating simple signal intensity images weighted by the longitudinal or transverse …
The Role Of Cd5 In Experimental Autoimmune Encephalitomyelitis, Robert C. Axtell
The Role Of Cd5 In Experimental Autoimmune Encephalitomyelitis, Robert C. Axtell
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The regulation of activation, differentiation and persistence of effector T-cells are critical for the development of Experimental Autoimmune Encephalomyelitis (EAE), the animal model of Multiple Sclerosis. Until now, the function of CD5 was accepted to be a negative regulator of T-cell activation. This dissertation reports that CD5 has an addi-tional role in T-cell responses, which is to promote cell survival. Observations from EAE experiments revealed that mice deficient in CD5 exhibited decreased disease severity which was associated with the inability of activated T-cells to survive. Moreover, block-ing the engagement of CD5 in mice led to enhanced activation induced cell death …
Modulation Of Cell Signaling By Tomoregulins In Embryogenesis And Cancer, Paul William Harms
Modulation Of Cell Signaling By Tomoregulins In Embryogenesis And Cancer, Paul William Harms
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Growth factor signals often regulate similar cellular processes both during embryogenesis and in adult homeostasis. Stringent control of these signals ensures proper embryonic development and correct cell physiology in mature individuals. Recently, a family of two members of Tomoregulin (or transmembrane protein with epidermal growth factor-like and two follistatin domains [TMEFF]) was found to interact with transforming growth factor-β (TGF-β) and ErbB signaling pathways, both of which are implicated in development and in cancer biology in the adult. The function as well as the mechanisms of TMEFFs in modulating these two signals has not been elucidated in detail. In this …
Increased Hexosamine Biosynthesis And Protein O-Glcnac Protect Isolated Rat Heart From Ischemia/Reperfusion Injury, Jia Liu
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Increased levels of protein-associated O-linked N-acetylglucosamine (O-GlcNAc) have been correlated with increased tolerance to stress. Therefore the goal of this study was to determine whether enhanced flux through the hexosamine biosynthesis pathway (HBP), which leads to elevated levels of O-GlcNAc, increased the tolerance of the heart to ischemia and reperfusion (I/R). Hearts from male rats were isolated and perfused with Krebs-Henseliet buffer containing 5mM glucose, and global, no-flow ischemia was induced for 20min followed by 60 min reperfusion. 20 min pre-treatment with 10 mM glucosamine, which enters the HBP directly, significantly improved functional recovery and decreased cardiac Troponin I release …
Regulation Of Ss-Catenin By Gli1 In Epithelial Transformation, Xingnan Li
Regulation Of Ss-Catenin By Gli1 In Epithelial Transformation, Xingnan Li
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Gli family members-mediated continuous Hedgehog (Hh) pathway activity plays a role in the growth of a number of human cancers, including the common malignancy of skin, basal cell carcinoma (BCC), and other highly aggressive tumor types. However, the mechanism by which Gli proteins act to promote the outgrowth of cancer in response to stimulation of Hh signaling is poorly understood. Identified as zinc finger transcriptional factors, the Gli family of proteins has been shown to be involved in multiple cellular processes through activating its target genes. Therefore, to study the function of Gli target genes is important for our understanding …
Klf4 Regulates Notch1 Expression And Signaling During Epithelial Transformation, Zhaoli Liu
Klf4 Regulates Notch1 Expression And Signaling During Epithelial Transformation, Zhaoli Liu
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Notch1 and KLF4 function in the specification of epithelial cell fates, and each can act as a context-dependent oncogene or tumor suppressor. We report that KLF4 directly regulates transcription of Notch1 and that cleavage of full-length Notch1 to the active intracellular form, N1IC, is necessary for transformation by KLF4. Paradoxically, KLF4 suppresses canonical Notch1-CSL signaling by up-regulating Hairless, an antagonist of this pathway. Dominant-negative inhibitors of the canonical Notch1 signaling pathway do not block transformation of epithelial cells by KLF4, while they greatly reduce the efficiency of transformation by N1IC. Thus, N1IC can transform cells by two distinct mechanisms: the …