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Bioenergetics As A Biomarker Of Health And Disease, Philip Kramer Jan 2015

Bioenergetics As A Biomarker Of Health And Disease, Philip Kramer

All ETDs from UAB

The increasing prevalence of metabolic syndrome, diabetes, atherosclerosis, and many other diseases only recently associated with aberrant metabolism, have led to a de-mand for clinical assays to determine a patient’s mitochondrial health. With the rapidly growing interest in personalized medicine, such an assay would ideally be able to capture the metabolic changes associated with oxidative stress, inflammation, and therapy of a patient in a swift and non-invasive manner. Short of tissue biopsies, this burgeoning field of Translational Bioenergetics has had minimal success in obtaining sufficient human cells and the means to assess them both accurately and swiftly. The purpose of …

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Defining The Role Of Trps1 In Phosphate Mediated Mineralization, Maria Kuzynski Jan 2015

Defining The Role Of Trps1 In Phosphate Mediated Mineralization, Maria Kuzynski

All ETDs from UAB

Mineralization is a tightly controlled bi-phasic process that occurs when crystals of calcium and phosphate (Pi) are laid down within the extracellular matrix. However, the molecular networks regulating the initiation and progression of this process have not been well characterized. Pi, as one of the components of mineral crystals and a signaling molecule that regulates expression of mineralization-related genes, is essential to the mineralization process. In our studies, we discovered a novel function for Pi in this process: Pi is sufficient to induce secretion of matrix vesicles, which support the initiation of mineralization. Furthermore, we determined that this induction is …

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Transient-State Kinetic Analysis Of The Rna Polymerase I Nucleotide Incorporation Mechanism, Francis Dean Appling Jan 2015

Transient-State Kinetic Analysis Of The Rna Polymerase I Nucleotide Incorporation Mechanism, Francis Dean Appling

All ETDs from UAB

The diversity of enzymes and the reactions which they catalyze is enormous. Careful study of enzymatic reaction mechanisms has taught us a great deal about chemical reactivity and has given us insight into the chemical and physical basis of life. One particularly ubiquitous class of enzymes, the RNA polymerases, are expressed in all forms of life. RNA polymerases are central components of nucleic acid metabolism and display a variety of distinctive enzymatic features; two points which solicit their thorough study. The central theme of this dissertation is the use of kinetic techniques to describe enzymatic reaction mechanisms. Although the main …

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Transcriptional Regulation Of The Human Ribosomal Rna Gene, Blake L. Atwood Jan 2015

Transcriptional Regulation Of The Human Ribosomal Rna Gene, Blake L. Atwood

All ETDs from UAB

The ribosome has the major role of synthesizing almost all the proteins of the cell. One of the main structural components of the ribosome are the ribosomal RNAs 18S, 28S, 5.8S and the 5S which are bound by numerous proteins to make up a fully functional unit. In the human genome there are approximately 400 copies of the rRNA gene, which contains all but the 5S rRNA in one long transcription unit. This gene is found in tandem repeats on the acrocentric arm of chromosomes 13, 14, 15, 21 and 22. It is critical that this gene is tightly regulated …

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The I507-Atc→Att Silent Codon Change Contributes To The Misfolding Of ∆F508 Cftr, Vedrana Bali Jan 2015

The I507-Atc→Att Silent Codon Change Contributes To The Misfolding Of ∆F508 Cftr, Vedrana Bali

All ETDs from UAB

Synonymous codon changes (SCCs) do not alter the amino acid sequence of proteins, but may significantly change the phenotype. The frequency of synonymous codons is species- and gene-specific, described as codon usage bias (CUB). Over the past 50 years, research has shown that SCCs affect protein biogenesis, development of human disorders and the function of recombinant proteins developed for therapeutic applications. However, the molecular mechanisms by which SCCs alter the function of gene products are not completely understood. In Chapter 2 we summarize present knowledge in this field. The most common cause of cystic fibrosis (CF) is the deletion of …

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The Mspa Nanopore As A Sensor For Dna Sequencing, Mikhail Pavlenok Jan 2015

The Mspa Nanopore As A Sensor For Dna Sequencing, Mikhail Pavlenok

All ETDs from UAB

Nanopore sequencing is a novel and promising DNA sequencing method. This single molecule technique is capable of long reads, retains epigenetic information, and is inexpensive and fast. In this method ionic current is measured while single-stranded DNA is electrophoretically translocated through a nanometer-scale pore. Each passing nucleotide blocks current with characteristic amplitude and duration which are used to identify DNA sequence. MspA is the primary porin of M. smegmatis and mediates the diffusion of small, hydrophilic nutrients across the outer membrane. MspA is an octameric, channel-forming protein and represents the founding member of a new class of mycobacterial outer membrane …

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Exploiting Novel Interactions With Parp1 In Dna Repair Proficient Human Breast Cancers, Jennifer Anne Stanley Jan 2015

Exploiting Novel Interactions With Parp1 In Dna Repair Proficient Human Breast Cancers, Jennifer Anne Stanley

All ETDs from UAB

Breast cancer remains the most frequently diagnosed cancer amongst women worldwide. Despite advances in treatment, patients with more aggressive basal-like and HER2-positive cancer experience high rates of recurrence and necessitate novel therapeutic approaches. A class of inhibitors targeted against poly (ADP-ribose) polymerases (PARP), important DNA repair proteins, are effective in cancers with a defective DNA repair response. As such, extensive preclinical and clinical research has examined their efficacy in these cancers. Although this data is promising, it is only applicable to a lim-ited patient population. The main goal of this dissertation is to expand the utility of these well-tolerated drugs …

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C-Reactive Protein, Autoimmunity, And Inflammation In The Central Nervous System, Tyler T. Wright Jan 2015

C-Reactive Protein, Autoimmunity, And Inflammation In The Central Nervous System, Tyler T. Wright

All ETDs from UAB

C-reactive protein (CRP) is an acute phase reactant whose blood concentration rises in response all types of inflammation. And while CRP is widely used as a clinical marker of inflammation, it has several biological functions, e.g. activation of the classical complement cascade and binding Fcγ receptors in order to mediate multiple immune processes. The full extent of CRP’s physiological activities has not yet been fully elucidated, but there is significant evidence to establish that CRP plays an important role in the onset and progression of autoimmune disease. Seminal work from our lab showed that human CRP, hepatically expressed in transgenic …

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Faculty Publications 2014, Lsu Health Sciences Center New Orleans Jan 2015

Faculty Publications 2014, Lsu Health Sciences Center New Orleans

Historical Faculty Publications

This Faculty bibliography contains 898 publications.

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Development Of Cytotoxic Natural Killer Cells For Ovarian Cancer Treatment, Veethika Pandey Jan 2015

Development Of Cytotoxic Natural Killer Cells For Ovarian Cancer Treatment, Veethika Pandey

Electronic Theses and Dissertations

Ovarian cancer is a leading cause of gynecological malignancy. Cytoreductive surgery and frontline platinum/taxane-based chemotherapy provides good initial efficacy in the treatment, but poor long-term patient survival. This is mainly caused by tumor relapse due to intraperitoneal spreading and ineffective alternate therapies to treat these resistant tumors. The challenge in the field is to develop strategies that would prove effective in these patients and extend overall survival. Over the years, various treatments have been developed for the treatment of cancer amongst which, adoptive cell immunotherapy has shown promising results. But despite the efficacy seen in the clinic, there are concerns …

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The Role Of A Highly Conserved Eubacterial Ribosomal Protein In Translation Quality Control, Anusha Naganathan Jan 2015

The Role Of A Highly Conserved Eubacterial Ribosomal Protein In Translation Quality Control, Anusha Naganathan

Electronic Theses and Dissertations

The process of decoding is the most crucial determinant of the quality of protein synthesis. Ribosomal protein L9 was first implicated in decoding fidelity when a mutant version of L9 was found to increase the translation of a T4 phage gene. Later studies confirmed that the absence of L9 leads to increased translational bypassing, frameshifting, and stop codon readthrough. L9 is part of the large subunit of the prokaryotic ribosome and is located more than 90 Å from the site of decoding, making it difficult to envision how it might affect decoding and reading frame maintenance. Twenty years after the …

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Proteomic Analysis Delineates The Signaling Networks Of Plasmodium Falciparum, Brittany Pease Jan 2015

Proteomic Analysis Delineates The Signaling Networks Of Plasmodium Falciparum, Brittany Pease

Electronic Theses and Dissertations

Malaria is a life-threatening disease caused by Plasmodium parasites that are spread through the bites of infected mosquito vectors. It is a worldwide pandemic that threatens 3.4 billion people annually. Currently, there are only a few validated Plasmodium drug targets, while drug resistance continues to rise. This marks the urgency for the development of novel parasite-specific therapeutics. Plasmodium falciparum diverges from the paradigm of the eukaryotic cell cycle by undergoing multiple rounds of DNA replication and nuclear division without cytokinesis. A better understanding of the molecular switches that coordinate the progression of the parasite through the intraerythrocytic developmental stages will …

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Predicting Aqueous Solubility Of Pharmaceutical Agents By Solid Dispersion Prepared By Solvent Evaporation Method, Karthik Reddy Patlolla Jan 2015

Predicting Aqueous Solubility Of Pharmaceutical Agents By Solid Dispersion Prepared By Solvent Evaporation Method, Karthik Reddy Patlolla

University of the Pacific Theses and Dissertations

Solubility of active pharmaceutical agents is a crucial process that determines drug absorption and ultimately its bioavailability. Many of the new therapeutically beneficial compounds discovered are lipophilic requiring various solubility enhancement strategies to improve their solubility. Among these strategies, solubility enhancement using solid dispersions is a leading method. To obtain a desirable increase in the solubility of a poorly-soluble compound, a good understanding of the molecular descriptors influencing the enhancement of solubility is essential. Therefore, the major research objective was to determine the descriptors which significantly influence the solubility enhancement by solid dispersions. After enhancing the solubility of selected poorly-soluble …

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Regulation Of System XC- By Pharmacological Manipulation Of Cellular Thiols, Rebecca Albano, Nicholas J. Raddatz, Julie Hjelmhaug, David A. Baker, Doug Lobner Jan 2015

Regulation Of System XC- By Pharmacological Manipulation Of Cellular Thiols, Rebecca Albano, Nicholas J. Raddatz, Julie Hjelmhaug, David A. Baker, Doug Lobner

Biomedical Sciences Faculty Research and Publications

The cystine/glutamate exchanger (system xc-) mediates the transport of cystine into the cell in exchange for glutamate. By releasing glutamate, system xc- can potentially cause excitotoxicity. However, through providing cystine to the cell, it regulates the levels of cellular glutathione (GSH), the main endogenous intracellular antioxidant, and may protect cells against oxidative stress. We tested two different compounds that deplete primary cortical cultures containing both neurons and astrocytes of intracellular GSH, L-buthionine-sulfoximine (L-BSO), and diethyl maleate (DEM). Both compounds caused significant concentration and time dependent decreases in intracellular GSH levels. However; DEM caused an increase …

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The Regulation Of Vitamin A Metabolism, Mark Adams Jan 2015

The Regulation Of Vitamin A Metabolism, Mark Adams

All ETDs from UAB

Bioactive vitamin A takes form as several molecules, among them all-trans-retinoic acid (RA) is the major form and influences a wide range of biological processes. RA must be synthesized through a two-step mechanism, where all-trans-retinol is first oxidized to all-trans-retinaldehyde by retinol dehydrogenases (RDHs) and retinaldehyde is further oxidized to RA by retinaldehyde dehydrogenases (RALDHs). The first step, retinol to retinaldehyde conversion is the rate limiting step and therefore a likely target of mechanisms that modulate RA synthesis. Despite this, many of the enzymes that are involved in retinol and retinaldehyde interconversion have yet to be identified and thus many …

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Competition From New Neurons Drives Circuit Refinement In The Adult Dentate Gyrus, Elena W. Adlaf Jan 2015

Competition From New Neurons Drives Circuit Refinement In The Adult Dentate Gyrus, Elena W. Adlaf

All ETDs from UAB

The hippocampus encodes sensory information into memories. The dentate gyrus (DG) region is viewed as the entry point into the hippocampus, receiving sensory and spatial signals from perforant path axons of the entorhinal cortex (EC). Ever since researchers discovered a neurogenic niche in the subgranular zone (SGZ) of the DG in adult animals and humans, many studies have been aimed at discovering how these continually proliferating granule cells (GCs) contribute to the network. Immature GCs have dendrites that project densely into the molecular layer alongside mature GCs and there is morphological evidence that immature excitatory spines preferentially synapse onto existing …

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Pathophysiology And Metabolic Dysfunction Following Polytrauma, Robert Mackay Akscyn Jan 2015

Pathophysiology And Metabolic Dysfunction Following Polytrauma, Robert Mackay Akscyn

All ETDs from UAB

Polytrauma, a combination of injuries to more than one body part or organ system, is common in modern warfare and in automobile and industrial accidents. The combination of injuries can include burn, fracture, hemorrhage, trauma to the extremities, and trauma to specific organ systems. These injuries are highly survivable when occurring singly. However, when they occur in combination the prognosis is worsened. To investigate the effects of combined injuries, we have developed a new and highly reproducible model of polytrauma. This model combines burn injury with soft tissue and gastrointestinal (GI) tract trauma. Male Sprague Dawley rats were subjected to …

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The Effect Of Thioredoxin-Interacting Protein Induced Microrna-200 Family Members On Pancreatic Beta Cells, Stephen Filios Jan 2015

The Effect Of Thioredoxin-Interacting Protein Induced Microrna-200 Family Members On Pancreatic Beta Cells, Stephen Filios

All ETDs from UAB

Pancreatic beta cells secrete insulin to maintain normal blood glucose levels and allow cells of the body to use glucose. However, in diabetes, there is beta cell dysfunction and pancreatic beta cells undergo programmed cell death leading to inadequate insulin production and secretion. Thioredoxin-Interacting Protein (TXNIP) is a ubiquitously expressed protein, 46 kDa in size, which is an arrestin protein family member. Unique to this member of the arrestin family, however, is its ability to bind to, and reduce, thioredoxin. The TXNIP gene is increased in pancreatic islets more than any other gene in response to high levels of glucose. …

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Hiv-1 Adaptation To T-Cell Responses During Infection, Victor Yimin Du Jan 2015

Hiv-1 Adaptation To T-Cell Responses During Infection, Victor Yimin Du

All ETDs from UAB

recommended vitamin D intake, and perceived barriers to adequate calcium intake

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Exploiting The Glioblastoma Tumor Microenvironment For Enhanced Oncolytic Herpes Simplex Virus Therapy, Tyrel Talbert Smith Jan 2015

Exploiting The Glioblastoma Tumor Microenvironment For Enhanced Oncolytic Herpes Simplex Virus Therapy, Tyrel Talbert Smith

All ETDs from UAB

Gliomas are the most common and fatal malignancy of the adult central nervous system. The need for new therapeutic options is clear, as standard of care therapies only extend median survival 12-14 months beyond diagnosis. Conditionally replication-competent oncolytic herpes simplex type-1 viruses (oHSV) have emerged as promising therapeutics for treating malignant gliomas. However, two factors that contribute to the dismal prognosis of malignant gliomas, immunosuppression and invasive growth, are also thought to limit virotherapeutic efficacy. We examined these factors in tumor microenvironments to explore novel strategies to treat malignant gliomas with oHSV for improved therapeutic response. In a Phase 1b …

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The Role Of Ribosome Biogenesis In Exercise-Induced Skeletal Muscle Anabolism In Aging, Michael Stec Jan 2015

The Role Of Ribosome Biogenesis In Exercise-Induced Skeletal Muscle Anabolism In Aging, Michael Stec

All ETDs from UAB

Numerous chronic medical conditions, as well as normal aging result in a significant loss of skeletal muscle mass. This has profound effects on quality of life and can increase the risk of all-cause mortality. Currently, the most potent treatment for reversing the loss of muscle mass is resistance exercise training (RT); however, the human muscle fiber growth (hypertrophy) response to this treatment is quite variable, and older adults do not respond as favorably to this treatment as younger adults. The focus of this dissertation is to elucidate the role that ribosome biogenesis plays in regulating the RT-induced hypertrophic response. We …

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The Role Of Mammalian Tribbles Homolog 3 (Trb3) In Macrophage Biology; Evidence For Reciprocal Regulation Of Macrophage Function In Foam Cell Formation, Dennis Steverson Jan 2015

The Role Of Mammalian Tribbles Homolog 3 (Trb3) In Macrophage Biology; Evidence For Reciprocal Regulation Of Macrophage Function In Foam Cell Formation, Dennis Steverson

All ETDs from UAB

Atherosclerosis is disease characterized by dysregulated lipid metabolism and chronic inflammation. Macrophages are critical to the progression of the disease and are involved in the pathophysiology at all stages of the disease. In the early stages, macrophages are responsible for fatty streak formation by becoming foam cells through lipid uptake. In the later stages, macrophages contribute to the degradation of the fibrous cap and are largely responsible for chronic inflammation in atherosclerotic plaques. Tribbles homolog 3 (TRB3) is a pseudokinase that inhibits Akt activation by blocking its phosphorylation site. TRB3 is expressed on numerous cell types in the body (pancreatic …

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Characterization Of The Gtpase Rac1 As An Electrophilic-Sensitive Protein In Vascular Cells, Stephanie Brook Wall Jan 2015

Characterization Of The Gtpase Rac1 As An Electrophilic-Sensitive Protein In Vascular Cells, Stephanie Brook Wall

All ETDs from UAB

The GTPase Rac1 is a protein which has been shown to be dysregulated in the context of a number of inflammatory diseases including atherosclerosis. Rac1 responds to extracellular signals and is involved in cellular cytoskeletal rearrangement, reactive oxygen species generation and cell cycle progression. When activated Rac1 interacts with effector proteins on the plasma membrane. This activation has recently been shown to be modulated by redox signaling via an active site cysteine. However, it is not known whether other redox signaling compounds can modulate Rac1 activity. An important redox signaling mediator is the electrophilic lipid, 15-deoxy-Δ12,14-prostaglandin J2 (15dPGJ2). This lipid …

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Mechanisms Of Heme Oxygenase-1-Mediated Protection Against Tissue Injury, Travis David Hull Jan 2015

Mechanisms Of Heme Oxygenase-1-Mediated Protection Against Tissue Injury, Travis David Hull

All ETDs from UAB

Heme oxygenase-1 (HO-1) catalyzes the rate-limiting step in the catabolism of heme, which is released by necrotic cells in injured tissue. HO-1 expression is protective in cardiac and renal injury because it coordinates the degradation of pro-oxidant heme with the generation of equimolar quantities of iron (Fe2+) and the cytoprotective mole-cules carbon monoxide and biliverdin. While many studies have demonstrated that HO-1 expression is protective in numerous disease states, relatively few have examined the specific cellular compartment(s) through which HO-1 expression confers its protective effects. Our objective was to define the cellular compartments in which HO-1 expression is critical to …

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Mechanisms Of Resistance To Oncolytic Herpes Simplex Viruses In Malignant Peripheral Nerve Sheath Tumors, Joshua Douglas Jackson Jan 2015

Mechanisms Of Resistance To Oncolytic Herpes Simplex Viruses In Malignant Peripheral Nerve Sheath Tumors, Joshua Douglas Jackson

All ETDs from UAB

Malignant peripheral nerve sheath tumors (MPNSTs) are rare but highly aggressive cancer of the peripheral nervous tissue. Median patient survival is approximately two years following diagnosis due in part to the ineffective options for treatment. As an alternative therapeutic approach to conventional radio- and chemotherapy, oncolytic herpes simplex viruses type-1 (oHSVs) have been proposed to treat MPNSTs. These oHSVs have been shown safe in clinical trials with associated tumor regression. However, there is evidence that resistance to the therapy should be anticipated in a subset of patients. Therefore, the goal of this dissertation has been to identify the primary obstacles …

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Regulation Of Cks1 Protein Turnover In Cancer Cells, Vinayak Khattar Jan 2015

Regulation Of Cks1 Protein Turnover In Cancer Cells, Vinayak Khattar

All ETDs from UAB

Cks1 is a crucial cell cycle regulator which plays pleiotropic roles in cancer cell growth and is highly expressed at both the protein, and mRNA levels, in cancer cells. In contrast, normal cells exhibit barely detectable levels of this protein, even though they express substantial Cks1 mRNA. One reason for high Cks1 protein in cancers appears to be its stabilization in these cells. Cks1 is known to be ubiquitinated and degraded by the proteasome. Coordinated ubiquitination dependent proteasomal degradation of cell cycle proteins is a major mechanism that regulates their activity. Therefore aberrant accumulation of Cks1, frequently observed in cancer, …

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Impairment Of The Gliovascular Unit In Neurological Disease, Ian Kimbrough Jan 2015

Impairment Of The Gliovascular Unit In Neurological Disease, Ian Kimbrough

All ETDs from UAB

Cerebral blood flow is regulated by vasoactive molecules released by astroglial cell processes that ensheath the entire cerebrovasculature. This regulation of blood flow in response to neuronal activity is a process known as functional hyperemia. Astrocytes, along with their associated neurons and microvessels, are organized into a functional system called the gliovascular unit (GVU). The astroglial component of the GVU is integral in both regulation of blood flow and maintenance of the blood-brain barrier (BBB). In disease, this system can be disrupted. We found that glioma cells displace astrocytic processes, called endfeet, and prevent their communication with associated vessels, leading …

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An Nphp-4 Enhancer Mutagenesis Screen For Modifiers Of Cilia Phenotypes Reveals Novel Mks Alleles, Uncovers, A Specific Genetic Interaction Between Osm-3 And Nphp-4, And A Novel Ciliary Calcium Channel., Dawn Landis Jan 2015

An Nphp-4 Enhancer Mutagenesis Screen For Modifiers Of Cilia Phenotypes Reveals Novel Mks Alleles, Uncovers, A Specific Genetic Interaction Between Osm-3 And Nphp-4, And A Novel Ciliary Calcium Channel., Dawn Landis

All ETDs from UAB

Nephronophthisis (NPHP) is a ciliopathy with diverse clinical features likely caused by genetic modifiers. To identify NPHP modifiers, a screen was conducted on nphp-4(tm925) mutant C. elegans to reveal mutations that exacerbate the NPHP ciliary defects. Ten loci were generated, five of which have now been identified. Three are mutations in ciliopathy genes mks-1, mks-2, and mks-5. The fourth allele (yhw66) is a missense mutation (S316F) in OSM-3, a kinesin required for cilia distal segment assembly. As in osm-3 null mutants, nphp-4(tm925);osm-3(yhw66) mutants lack distal segments, are dye-filing defective (Dyf), and have osmotic avoidance defects (OSM). The osm-3(yhw66) mutant alone …

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14-3-3 Proteins Regulate Mutant Lrrk2 Kinase Activity And Neurite Shortening, Nicholas Lavalley Jan 2015

14-3-3 Proteins Regulate Mutant Lrrk2 Kinase Activity And Neurite Shortening, Nicholas Lavalley

All ETDs from UAB

Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common known cause of inherited Parkinson’s disease (PD), and LRRK2 is a risk factor for idiopathic PD. How LRRK2 function is regulated is not well understood. Recently, the highly-conserved 14-3-3 proteins, which play a key role in many cellular functions including cell death, have been shown to interact with LRRK2. In this study, we investigated whether 14-3-3s can regulate mutant LRRK2-induced neurite shortening and kinase activity. In the presence of 14-3-3θ overexpression, neurite length of primary neurons from BAC transgenic G2019S-LRRK2 mice returned back to wildtype levels. Similarly, 14-3-3θ overexpression …

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The Jak/Stat Pathway In Neuroinflammatory Diseases, Yudong Liu Jan 2015

The Jak/Stat Pathway In Neuroinflammatory Diseases, Yudong Liu

All ETDs from UAB

Dysregulation of the Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) pathway is critically involved in the pathogenesis of multiple sclerosis (MS)/experimental autoimmune encephalomyelitis (EAE). Suppressor Of Cytokine Signaling (SOCS) proteins are the negative regulators of the JAK/STAT pathway. To determine the role of SOCS3 in myeloid cells in EAE, mice with conditional SOCS3 deletion in myeloid cells (LysMCre-SOCS3fl/fl) were created and tested. LysMCre-SOCS3fl/fl mice develop a severe, non-resolving atypical form of disease, characterized by lesions and extensive neutrophil and other inflammatory cell infiltrates in the cerebellum and brainstem, elevated STAT activation, elevated cytokine, chemokine and iNOS expression, and prominent …

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