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Articles 31 - 52 of 52
Full-Text Articles in Medicine and Health Sciences
The Role Of Suppressor Of Cytokine Signaling 3 In Neuroinflammatory Disease, Zhaoqi Yan
The Role Of Suppressor Of Cytokine Signaling 3 In Neuroinflammatory Disease, Zhaoqi Yan
All ETDs from UAB
The Janus Kinase/Signal Transducers and Activators of Transcription (JAK/STAT) pathway plays a critical role in cytokine-mediated responses in both innate and adaptive immunity, and dysregulation of the JAK/STAT pathway is linked to many inflammatory disorders. Multiple Sclerosis (MS) is an inflammatory demyelinating disease that affects the central nervous system, and both innate and adaptive immunity are involved in disease progression. STAT3 signaling is critically involved in MS pathology and is negatively regulated by Suppressor Of Cytokine Signaling 3 (SOCS3). Both increased STAT3 activation and reduced SOCS3 expression are observed in immune cells from patients with MS. Although the role of …
Novel Biomarkers For Parkinson Disease, Shijie Wang
Novel Biomarkers For Parkinson Disease, Shijie Wang
All ETDs from UAB
Parkinson disease (PD) is the second most common neurodegenerative disorder with no reliable biochemical biomarkers for disease prediction or progression, nor disease-modifying treatments to slow the relentless progression. Mutations in the leucine-rich repeat kinase 2 (LRRK2) gene are known to increase LRRK2 kinase activity and increase the risk for late-onset PD. In this thesis, I discovered that LRRK2 is secreted into exosomes in urine and CSF, where LRRK2 kinase activity, reflected by autophosphorylation at pS1292 site, is preserved and reflective of cytosolic LRRK2 levels. In a cohort of biosamples from LRRK2 mutation carriers and matched controls, with and without PD, …
Context Fear Memory Formation Is Regulated By Hippocampal Lncrna-Mediated Histone Methylation Changes, Anderson Alan Butler
Context Fear Memory Formation Is Regulated By Hippocampal Lncrna-Mediated Histone Methylation Changes, Anderson Alan Butler
All ETDs from UAB
The post-translational modification of histones regulates gene expression and is critical for the formation and maintenance of hippocampus-dependent long-term memories. Changes in gene-specific expression of various epigenetic marks during the aging pro-cess are sufficiently consistent as to be used as an aging landmark or epigenetic clock in both humans and other species; however, the molecular mechanisms which govern the application of these marks aging are poorly explored. Recently, long noncoding RNAs (lncRNAs) have been implicated as regulators of histone methyltransferases and other chromatin-modifying enzymes (CMEs). Despite the relevance of such mechanisms to both aging and memory formation, the behavioral relevance …
Baf Chromatin Landscaping During Bone Formation And Maintenance, Tanner Cole Godfrey
Baf Chromatin Landscaping During Bone Formation And Maintenance, Tanner Cole Godfrey
All ETDs from UAB
Bone loss is a worldwide problem resulting in increased risk of fracture. Osteoblasts are responsible for bone synthesis; therefore, treatments promoting osteoblast differentiation and/or activity would result in increased bone formation. The regulation of DNA accessibility is a key mechanism controlling gene expression and cellular differentiation. BAF (BRG1 Associated Factor) mediated chromatin remodeling increases DNA accessibility by sliding or ejecting nucleosomes. This process can occur in a cell type specific manner based on the composition of BAF. In many tissue types, a unique combination of BAF subunits has been identified to be responsible for the maintenance or differentiation of that …
Genome Sequencing To Identify Novel Developmental Disorder Variation, Matthew Neu
Genome Sequencing To Identify Novel Developmental Disorder Variation, Matthew Neu
All ETDs from UAB
The ability to quickly and accurately catalog an individual's genetic variation through genome sequencing has ignited a new era of diagnostic and therapeutic development for heritable disease. Although genome sequencing can provide a molecular diagnosis in a significant number of patients with suspected genetic disease, there remain a number of unsolved cases for which no pathogenic cause can be determined. This uncertainty can create a "diagnostic odyssey" in which sequential tests fail to provide a diagnostic resolution and can often delay beneficial treatment, impact family planning, and be emotionally challenging for patients and their families. Clearly, there is an unmet …
Characterization Of Chemical Uptake And Aryl Hydrocarbon Receptor Mutations In Zebrafish, Jaclyn Paige Souder
Characterization Of Chemical Uptake And Aryl Hydrocarbon Receptor Mutations In Zebrafish, Jaclyn Paige Souder
All ETDs from UAB
In a society driven by technology and industry, we must be increasingly aware of how changes to our environment impact our health. This is especially true concerning embryonic development, which is easily influenced by extra-embryonic factors, including environmental contaminants. Determining how exogenous compounds are absorbed, which receptors they act through, and how these receptors act endogenously is important to fully understand to what extent developmental exposures impact fetal and adult health. I have used the zebrafish model system to address these questions for two classes of environmentally-relevant chemicals—estrogens and dioxins. First, I developed an assay to measure the uptake of …
Appropriately Timed Epigenetic Manipulation With Histone Deacetylase Inhibitors As A Platform Approach To Tumor Immunotherapy, Tyler Mccaw
All ETDs from UAB
In contrast to chemotherapy and radiotherapy, immunotherapy is able to respond in proportion to tumor burden and continue to evolve in parallel with the tumor mass and metastatic sites. In this way, immune-based cancer therapies are a living drug and hold enormous potential. In this work, we enforce expression of MHCII on a murine breast cancer model to study how changes in tumor biology can drive improved T cell-mediated responses. We next use histone deacetylase inhibitors to manipulate the microenvironment through a more clinically relevant, therapeutic approach. Herein, improvements in tumor control were driven by CD8 T cells and IFNγ, …
O-Glcnac Regulation Of Inhibitory Circuits, Kavitha Abiraman
O-Glcnac Regulation Of Inhibitory Circuits, Kavitha Abiraman
All ETDs from UAB
Post translational modification of proteins plays a crucial role in regulating their function, and the role of one such modification, termed O-GlcNAcylation, is understudied. O-GlcNAcylation involves the dynamic cycle of adding and removing an O-linked N-acetylglucosamine (O-GlcNAc) by the enzymes O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), which are highly expressed in the hippocampus. Enzymes that catalyze O-GlcNAcylation are found at both presynaptic and postsynaptic sites, and O-GlcNAcylated proteins localize to synaptosomes. We have shown that acute and selective increase in O-GlcNAcylation of AMPAR GluA2 subunits underlies expression of a novel form of LTD at CA3-CA1 synapses (O-GlcNAc LTD), as well …
Mechanisms Of Acute Kidney Injury: The Role Of Ferritin Heavy Chain In Renal Heme-Unology, Laurence Marie Black
Mechanisms Of Acute Kidney Injury: The Role Of Ferritin Heavy Chain In Renal Heme-Unology, Laurence Marie Black
All ETDs from UAB
The kidneys are complex, multi-faceted organs that are responsible for regulatory processes, such as fluid homeostasis, hormone production, blood pressure regulation, and systemic toxin removal. Sudden disruption of these processes by acute kidney injury (AKI) causes rapid decline in renal function as well as significant morbidity and mortality. AKI is a significant clinical concern, affecting up to 13.3 million people globally each year and has the propensity to progress to chronic kidney disease (CKD), though the mechanism remains undefined. One reason for this is due to the lack of understanding of models used to study both AKI and CKD, hindering …
Mechanisms Of Acute Kidney Injury: The Role Of Ferritin Heavy Chain In Renal Heme-Unology, Laurence Marie Black
Mechanisms Of Acute Kidney Injury: The Role Of Ferritin Heavy Chain In Renal Heme-Unology, Laurence Marie Black
All ETDs from UAB
The kidneys are complex, multi-faceted organs that are responsible for regulatory processes, such as fluid homeostasis, hormone production, blood pressure regulation, and systemic toxin removal. Sudden disruption of these processes by acute kidney injury (AKI) causes rapid decline in renal function as well as significant morbidity and mortality. AKI is a significant clinical concern, affecting up to 13.3 million people globally each year and has the propensity to progress to chronic kidney disease (CKD), though the mechanism remains undefined. One reason for this is due to the lack of understanding of models used to study both AKI and CKD, hindering …
The Impact Of Redox Stress In Primary Hyperoxaluria Type 1, Brianna Buchalski
The Impact Of Redox Stress In Primary Hyperoxaluria Type 1, Brianna Buchalski
All ETDs from UAB
Primary Hyperoxaluria (PH) is a family of three inborn errors of glyoxylate metabolism resulting in endogenous oxalate overproduction. PH1 is the most common and most severe form of the disorder when compared to PH2 and PH3. PH1 can result in systemic oxalosis or end stage renal disease, and there is currently no cure for this disorder. The only curative treatment is combined liver/kidney transplant. The difficulty in defining a cure for the disorder arises from poor knowledge of the sources of endogenous oxalate and a lack of understanding in the underlying pathophysiology of the disorder. For these reasons, we have …
St6gal-I Mediated Sialylation Promotes Pancreatic Ductal Adenocarcinoma Progression And Chemoresistance, Asmi Chakraborty
St6gal-I Mediated Sialylation Promotes Pancreatic Ductal Adenocarcinoma Progression And Chemoresistance, Asmi Chakraborty
All ETDs from UAB
ST6Gal-I adds α2-6 sialic acids to select N-glycosylated cell surface receptors, thereby modulating receptor function and intracellular signaling. ST6Gal-I is upregulated in various carcinomas and confers cancer stem cell (CSC) properties evidenced by tumorspheroid growth, chemoresistance and tumor initiating potential. In pancreatic ductal adenocarcinoma (PDAC), ST6Gal-I conferred gemcitabine resistance by abrogating DNA damage and altering expression levels of gemcitabine metabolism genes. Further, ST6Gal-I promoted resistance to chronic gemcitabine treatment. Additionally, metastatic clones of a PDAC cell line had increased ST6Gal-I expression and ST6Gal-I knockdown enhanced gemcitabine sensitivity. To investigate the physiological consequences of ST6Gal-I in PDAC, murine models were used. …
Dna Template Sequence Effects On Rna Polymerase I Transcription Elongation, Andrew Martin Clarke
Dna Template Sequence Effects On Rna Polymerase I Transcription Elongation, Andrew Martin Clarke
All ETDs from UAB
The production of ribosomes represents the major synthetic effort of a rapidly dividing cell, and is intimately linked to the regulation of cell growth and proliferation. Developing a greater understanding of the mechanisms that regulate ribosome biogenesis is therefore crucial to understanding cellular control of the growth cycle. Ribosome biogenesis begins with the synthesis of the 35S ribosomal RNA (rRNA) by RNA polymerase I (Pol I). This RNA is co- and post-transcriptionally processed to produce the 18S, 5.8S, and 25S rRNAs. These RNAs are critical components of ribosomes, and Pol I has been demonstrated to be a key regulation target …
Regulation Of St6gal-I In Cancer: Sox2 Identified As Novel Driver Of St6gal-I Expression, Kaitlyn Alexandra Dorsett
Regulation Of St6gal-I In Cancer: Sox2 Identified As Novel Driver Of St6gal-I Expression, Kaitlyn Alexandra Dorsett
All ETDs from UAB
ST6Gal-I is a sialyltransferase that functions to add an 2-6 linked sialic acid to N-linked glycoproteins. The expression of ST6Gal-I is upregulated in many cancers at both the mRNA and protein levels. ST6Gal-I has also been shown to promote cancer stem cell (CSC) characteristics including chemoresistance, tumor-initiating potential, and spheroid growth. However, the transcriptional drivers of ST6Gal-I expression in stem-like cells remain largely unknown. Herein we highlight that SOX2 and ST6GAL1 are both located on one of the most commonly amplified chromosomal segments in cancer, amplicon 3q26. Copy number gains in both SOX2 and ST6GAL1 are observed in roughly 25% …
Regulation Of Intestinal Innate Lymphoid Cells In Acute And Chronic Inflammation, Sarah Dulson
Regulation Of Intestinal Innate Lymphoid Cells In Acute And Chronic Inflammation, Sarah Dulson
All ETDs from UAB
The Innate Lymphoid Cell (ILC) population encompasses five subpopulations that are increasingly appreciated to participate in immune responses to inflammation and injury as well as directly influence homeostasis in tissues throughout the body. ILCs are enriched at mucosal surfaces, such as the gastrointestinal tract, where they are transcriptionally poised for rapid activation. Therefore, ILCs contribute significantly to protective responses to infection, and can exacerbate inflammation and disease when dysregulated. Herein, we demonstrate two pathways that regulate intestinal ILC phenotype and function and delineate the impact of these pathways on both protective and pathogenic roles of ILCs. Using a murine model …
Marcks Effector Domain: Functions In Glioblastoma Progression And Novel Cytolytic Therapy, Nicholas James Eustace
Marcks Effector Domain: Functions In Glioblastoma Progression And Novel Cytolytic Therapy, Nicholas James Eustace
All ETDs from UAB
Glioblastoma (GBM; grade IV astrocytoma) is the most common primary adult brain malignancy and remains incurable despite tremendous advances in our understanding of this heterogeneous disease. In this dissertation, we explore the challenges encountered in the treatment of GBM and discuss a promising new therapeutic approach gleaned from studies of the phospholipid binding “effector” domain (ED) of the protein Myristoylated alanine-rich protein C kinase substrate (MARCKS). Following an introduction to central nervous system (CNS) tumors and the grading of diffuse gliomas, we explain how recent advancements to our understanding of the cellular and molecular composition of CNS tu-mors, and the …
Bet Bromodomain Inhibition As An Approach For Treatment Of Cholangiocarcinoma, Samuel Charles Fehling
Bet Bromodomain Inhibition As An Approach For Treatment Of Cholangiocarcinoma, Samuel Charles Fehling
All ETDs from UAB
Cholangiocarcinoma (CCA) is a highly aggressive neoplasm which arises from the epithelial layer of the biliary tract. It is the second most common primary hepatic malignancy. As CCA is typically diagnosed at late disease stage, the current standard of care, resection followed by gemcitabine with cisplatin, is not effective. Further, up to 90% of CCA patients are ineligible for resection. Of those eligible for resection, postoperative chemotherapy does not prolong overall survival leading to a 5-year survival of ~30%. Previously, mutations have been identified in KRAS (17% of CCA cases), TP53 (44%) and SMAD4 (17%) but none have been recognized …
Identification Of Two Spop-Mediated Pathways In Prostate Cancer Progression, Joshua Fried
Identification Of Two Spop-Mediated Pathways In Prostate Cancer Progression, Joshua Fried
All ETDs from UAB
Prostate cancer is one of the most common malignancies and causes of cancer related death in men. Morbidity is primarily attributed to late-stage and metastatic disease. Re-cent genomic screening studies have revealed that the Speckle type Poz Protein (SPOP) is the most frequently altered gene by missense mutations in prostate cancer. Interestingly, all of the identified mutations were located in the substrate binding domain of SPOP. Here, two pathways highlighting the impact of SPOP mutation on prostate cancer are pre-sented. First, evidence showing that one of the naturally occurring SPOP mutations, ser-ine 119 to asparagine (S119N), induces radiosensitivity and an …
Characterizing The Hiv-1 Envelope N-Glycan Shield, Audra Ann Hargett
Characterizing The Hiv-1 Envelope N-Glycan Shield, Audra Ann Hargett
All ETDs from UAB
In 2017, there was an estimated 1.8 million new HIV-1 infections worldwide. Development of an effective HIV-1 vaccine would begin to quell this global pandemic. HIV-1 envelope (Env) glycoprotein is the main vaccine candidate target due to the immune systems ability to generate broadly neutralizing antibodies (bnAbs) against Env. Approximately 90 N-glycans form a glycan shield that is the primary interface between the virus and host immune system. Key glycan motifs within the glycan shield are targets for bnAbs and are necessary for HIV-1 infectivity. Herein, we explore how naturally occurring mutations alter the glycan shield and HIV-1 Env function. …
Investigating The Rho-Kinase (Rock) Signaling Pathway As A Therapeutic Target In Alzheimer’S Disease, Benjamin Wade Henderson
Investigating The Rho-Kinase (Rock) Signaling Pathway As A Therapeutic Target In Alzheimer’S Disease, Benjamin Wade Henderson
All ETDs from UAB
Current estimates project that there are approximately 5.4 million Americans affected by Alzheimer’s disease (AD). While this number is expected to dramatically increase in the years to come, there is currently no disease modifying therapeutic to prevent or slow AD progression. Cognitive decline is a clinical hallmark of AD, while accumulation of amyloid-β (Aβ) is a pathological hallmark. Work in the field has demonstrated that mitigating Aβ levels may serve as a rational therapeutic avenue to slow progression of the disease. Pharmacologic inhibition of the Rho-associated protein kinases (ROCK1 and ROCK2) is proposed to curb Aβ levels, and mechanisms that …
Bdnf/Trkb.T1 Signaling: A Novel Mechanism Of Astrocyte Morphological Maturation, Leanne Holt
Bdnf/Trkb.T1 Signaling: A Novel Mechanism Of Astrocyte Morphological Maturation, Leanne Holt
All ETDs from UAB
Astrocytic morphogenesis and maturation are critical steps in central nervous system (CNS) development. During morphological maturation, astrocytes extend fine peripheral processes which infiltrate the neuropil and form intimate partners with neuronal structures, including synapses, where they facilitate neurotransmitter and K+ uptake and contribute to synaptic development and stabilization. The developmental time window of astrocyte morphological maturation and refinement is well defined, but the molecular mechanisms that underlie this process are not understood. Brain derived neurotrophic factor (BDNF) is a critical growth factor involved in the development and maturation of neurons. We developed a novel technique for the specific isolation of …
Characterization Of The Tgfb Pathway And Its Role In Prostaglandin Metabolism In C. Elegans, Muhan Hu
Characterization Of The Tgfb Pathway And Its Role In Prostaglandin Metabolism In C. Elegans, Muhan Hu
All ETDs from UAB
Cell to cell communication is fundamental to all life processes, from fertilization to death. The TGFß superfamily is a large family of proteins that is involved in a wide array of physiological and pathological processes, including development, wound healing, immune system function, cancer, and reproduction. This group of signaling peptides is well conserved across many organisms, from basic nematode to humans. While many studies have aimed to delineate the functions of TGFß, they have also unveiled the complexity of this multifunctional family of ligands. In this thesis, I take advantage of the simple C. elegans model system to study the …