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Susceptibility To Late-Onset Sepsis Is Controlled By The Neonatal Microbiome And Intestinal Immune System, Jeffrey Robert Singer
Susceptibility To Late-Onset Sepsis Is Controlled By The Neonatal Microbiome And Intestinal Immune System, Jeffrey Robert Singer
All ETDs from UAB
When mammals leave the womb, they encounter a world teeming with microbial life. Their intestinal tract, which will ultimately harbor an ecosystem of trillions of bacteria, must progress through a process called ecological succession. Late-onset sepsis (LOS) commonly occurs in preterm infants when pioneer members of the intestinal microbiome cause systemic infections. Both antibiotics and probiotics are used as prophylaxis for LOS, but mechanisms underlying susceptibility to the disease remain unclear. This is in large part due to a lack of animal models that mimic the relevant pathophysiology of LOS. This study begins with the development of a novel model …
The Role Of Astrocytes In The Development Of Central Chemosensitivity, Kelsey Patterson
The Role Of Astrocytes In The Development Of Central Chemosensitivity, Kelsey Patterson
All ETDs from UAB
In the two decades since MECP2 was identified as the causative gene in the majority of Rett Syndrome (RTT) cases, transgenic mouse models have played a critical role in our understanding of this X-linked neurodevelopmental disease. However, their exclusive use presents a limitation in translating findings from animal models to the clinic. Here, we characterized growth, anatomical, behavioral, and motor deficits in a novel zinc-finger nuclease murine RTT model from birth through adulthood. Male rats lacking the transcriptional regulatory protein, MeCP2 (Mecp2ZFN/y), are noticeably symptomatic as early as postnatal day (P) 21 and die prematurely, while females lacking one copy …
Elucidating The Role Of Hedgehog Signaling In Modulating Macrophage Function In Breast Cancer, Ann Hanna
Elucidating The Role Of Hedgehog Signaling In Modulating Macrophage Function In Breast Cancer, Ann Hanna
All ETDs from UAB
In the tumor microenvironment, breast cancer cells participate in crosstalk with the surrounding stroma. This tumoral-stromal interaction forms a balance that dictates tumor suppressing or tumor promoting response mechanisms. Macrophages in the tumor microenvironment are plastic and can mediate several functions depending on their activation states. Tumor associated macrophages co-exist as two major phenotypes: anti-tumorigenic and immune-eliciting classically activated M1 as well as tumor-promoting and immune-suppressive alternatively activated M2 macrophages. Alternatively activated macrophages are specifically associated with more aggressive stages and poor clinical outcomes in breast cancer patients as they suppress the tumoricidal properties of the immune system, thus facilitating …
Mitochondria-To-Nucleus Retrograde Signaling And Its Role In Cancer, Trevor Carden
Mitochondria-To-Nucleus Retrograde Signaling And Its Role In Cancer, Trevor Carden
All ETDs from UAB
Mitochondrial dysfunction is considered a hallmark of cancer. Mitochondria are essential, cellular organelles that participate in processes including energy production, calcium homeostasis and steroid metabolism. Mitochondria have been more recently appreciated for their role in cellular signaling, bringing about a greater understanding of their role in many diseases including cancer. Retrograde signaling is a mechanism by which the nucleus responds to mitochondrial dysfunction by modulating its own transcriptional programs to maintain metabolic and cellular processes. Many genes have already been identified as participants in or mediators of this signaling mechanism; these include cell signaling, metabolic and structural genes as well …
The Role Of Pim Kinases In Hepatoblastoma Tumorigenicity, Stem Cell-Like Cancer Cell Maintenance, And Chemoresistance, Laura Lee Stafman
The Role Of Pim Kinases In Hepatoblastoma Tumorigenicity, Stem Cell-Like Cancer Cell Maintenance, And Chemoresistance, Laura Lee Stafman
All ETDs from UAB
Hepatoblastoma is the most common primary liver malignancy in children. Despite increasing incidence, treatment has not changed significantly in the past 20 years, making the need for novel therapeutics imperative. Proviral Integration site for Moloney murine leukemia virus (PIM) kinases are a family of serine/threonine kinases that have been implicated in multiple other cancer types including the adult liver cancer, hepatocellular carcinoma. Emerging evidence has begun to elucidate a role for PIM kinases in stem-cell like cancer cells (SCLCCs). This subpopulation of cells is thought tobe responsible for tumor maintenance, recurrence, metastasis, and chemoresistance. Chemoresistance is a significant barrier to …
Novel Insights Into Neurofibromin Function And Human Neurofibromatosis Type 1 Mutations Using Genetically Engineered Mouse Models, Ashley Nicole Turner
Novel Insights Into Neurofibromin Function And Human Neurofibromatosis Type 1 Mutations Using Genetically Engineered Mouse Models, Ashley Nicole Turner
All ETDs from UAB
Loss of NF1 in different developmental and cellular contexts leads to unique physiological outcomes due to loss of neurofibromin function, including embryonic lethality, sporadic cancers, and the genetic disorder NF1. Neurofibromin acts as a tumor suppressor by modulation of RAS signaling, with other functions of this multi-domain protein being less clear. Even within the monogenic disorder of NF1, the clinical heterogeneity and mutational spectrum are immense, revealing the complexity underlying this disorder. There is a huge urgency and need for NF1 therapeutic treatments, and the same urgency to develop in vivo models to better understand NF1 that can be utilized …
Pharmacological Inhibition Of Thioredoxin-Interacting Protein To Protect Against Diabetes, Lance Thielen
Pharmacological Inhibition Of Thioredoxin-Interacting Protein To Protect Against Diabetes, Lance Thielen
All ETDs from UAB
The loss of functional beta cell mass represents a major factor in the pathogenesis of type 1 and type 2 diabetes. Inadequate production of insulin, a glucose-lowering hormone, and elevated glucagon production, a gluconeogenic hormone, contribute to impaired glycemic control and hyperglycemia. This promotes a vicious cycle involving glucotoxicity and additional beta cell dysfunction. Currently there are no therapies that halt this process; however, thioredoxin-interacting protein (TXNIP) has recently emerged as a promising therapeutic target. TXNIP was found to be the top glucose-induced gene in a human pancreatic islet microarray, is increased in mouse models of diabetes and diabetic human …
Evaluating Fty720 As An Anticancer Agent In Models Of Ovarian Cancer, Kelly Marie Kreitzburg
Evaluating Fty720 As An Anticancer Agent In Models Of Ovarian Cancer, Kelly Marie Kreitzburg
All ETDs from UAB
Despite satisfactory initial responses to frontline therapies that combine tumor debulking with platinum and taxane-based chemotherapies, ovarian cancer remains the principle cause of gynecological malignancies. Drug resistance at relapse contributes to poor outcomes for women diagnosed with advanced disease and underscores the need for novel therapeutic strategies. Compelling data have implicated bioactive sphingolipids and their metabolism in the development and progression of ovarian cancer. Aberrations in sphingolipid metabolism that limit levels of the tumor suppressor lipid ceramide contribute to chemotherapy resistance. This dissertation presents work investigating the anticancer efficacy of the immunomodulatory drug FTY720. The sphingosine analog FTY720 has shown …
Mucus Adhesion As A Therapeutic Target In Cystic Fibrosis, Courtney Fernandez Petty
Mucus Adhesion As A Therapeutic Target In Cystic Fibrosis, Courtney Fernandez Petty
All ETDs from UAB
Cystic fibrosis (CF) is a genetic disease resulting from mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. CFTR is an ion channel responsible for proper movement of chloride and bicarbonate ions across the apical cell surface. Defective CFTR results in an absence of bicarbonate transport, which functions in part to chelate Ca2+, a divalent cation found in abundance in mucin granules in normal conditions; this yields a hyperviscous and adhesive mucus on the respiratory and gastrointestinal tracts of patients with CF. Bronchial mucins are glycosylated proteins with neutral and negative sugars modified by negatively charged sialic and neuraminic …
Mechanistic Connections Between Metabolic And Differentiation Programs In T Cells, Danielle Alexandria Chisolm
Mechanistic Connections Between Metabolic And Differentiation Programs In T Cells, Danielle Alexandria Chisolm
All ETDs from UAB
Cellular metabolism is closely coupled to differentiation gene programs in many developmental systems. In part, this is due to a similar complement of transcription factors playing dual roles in regulating both the gene expression programs associated with specific metabolic pathways and the differentiation gene program of the cell. In T cells, T cell receptor- (TCR) and IL-2-sensitive transcription factors coordinate the programming of metabolic states with the effector and memory gene programs. Currently, our understanding of the mechanisms by which metabolic states contribute to the regulation of T cell differentiation gene programs is unclear. Metabolites are directly involved in epigenetic …
Molecular Characterization Of The Rare Cftr Mutation P67l As A Model For Genotype-Specific Drug Development And Personalized Medicine In Cystic Fibrosis, Carleen Mae Pomperada Sabusap
Molecular Characterization Of The Rare Cftr Mutation P67l As A Model For Genotype-Specific Drug Development And Personalized Medicine In Cystic Fibrosis, Carleen Mae Pomperada Sabusap
All ETDs from UAB
The traditional CFTR functional defect subcategories (i.e. protein misfolding, gating, conductance, etc.) are sometimes inadequate for determining patients most likely to benefit from emerging modulator treatment. We employ the P67L variant as emblematic of ways a thorough biochemical analysis of a rare CF defect can guide new therapeutic approaches, help predict drug response, and facilitate clinical precision. Historically, P67L has been designated a class IV conductance abnormality (i.e., malformed ion pore). In contrast, our studies demonstrate P67L disrupts CFTR protein maturation, prompts misfolding, causes gating defects, and exhibits wild-type like conductance. We show that P67L CFTR is robustly rescued by …
Epigenetic Regulation Of Stem Cell Fate Determination And Tumorigenesis, Kushani Shah
Epigenetic Regulation Of Stem Cell Fate Determination And Tumorigenesis, Kushani Shah
All ETDs from UAB
It is unclear how H3K4 methylation, an epigenetic modification associated with gene activation, regulates stem cell fate determination and tumorigenesis. DPY30 is one of the core subunits of the SET1/MLL complex in mammals responsible for H3K4me. DPY30 enhances the H3K4me activity of the SET1/MLL complex. Here, I sought to define role of DPY30 and H3K4me3 in postnatal neurogenesis and hematopoietic malignancies. Using a conditional knockout model, I found that Dpy30 deficiency halts the development of postnatal hippocampus, the subventricular zone, and cerebellum. Deficiency in cerebellum is most likely the cause of uncoordinated ataxia-like movements in these mice. By deleting Dpy30 …
Nf-Κb And Methyl-Lysine Signaling In The Epigenetic Regulation Of Memory, William Mitchell Webb
Nf-Κb And Methyl-Lysine Signaling In The Epigenetic Regulation Of Memory, William Mitchell Webb
All ETDs from UAB
Epigenetic mechanisms such as DNA methylation and histone methylation are critical regulators of gene transcription during memory consolidation and retrieval. However, the means by which these mechanisms are themselves initiated and directed to specific gene regions, and the extent to which these marks coordinate control of gene expression, remain poorly understood. In this dissertation, we explore the role of methyl-lysine signaling in the epigenetic regulation of gene expression in two contexts. First, we investigated the role of histone H3 lysine 4 tri-methylation (H3K4me3) and DNA 5-hydroxymethylation (5hmC) during memory retrieval, finding that these marks increased globally and at CpG-enriched coding …
Genetic Influences On Rheumatoid Arthritis In Global Populations, Vincent Albert Laufer
Genetic Influences On Rheumatoid Arthritis In Global Populations, Vincent Albert Laufer
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Rheumatoid arthritis (RA) is a complex disease having numerous genetic and environmental risk factors the interplay of which produces RA pathobiology. While the sheer number of genetic and environmental risk factors complicates understanding of disease biology, understanding has progressed far enough for insight into the most likely mechanisms for the development of the disease. Modern studies of the genetics of RA are massively parallel, enabling researchers to systematically interrogate variants throughout the human genome for associations in genome-wide association studies or GWAS. Such studies have been carried out in European and Asian cohorts many times, and the most recent RA …
St6gal-I Sialyltransferase Regulates The Activity Of Surface Receptors To Control Cell Signaling In Cancer And Immune Cells, Andrew Holdbrooks
St6gal-I Sialyltransferase Regulates The Activity Of Surface Receptors To Control Cell Signaling In Cancer And Immune Cells, Andrew Holdbrooks
All ETDs from UAB
Among the four classes of biological macromolecules, glycans are essential for proper cellular functioning. However, our knowledge of the contribution of these sugars, including the glycosyltransferases that add them, to cell signaling is limited. This dissertation focuses on the role of the ST6Gal-I sialyltransferase in modulating receptor-mediated signal transduction in cancer and inflammation. ST6Gal-I is a Golgi enzyme that conjugates α2-6-linked sialic acids to N-linked glycans on select glycoproteins. Through its sialylation of surface receptors, ST6Gal-I activity can significantly modify their function. The first section of this dissertation concentrates on the ST6Gal-I-mediated regulation of the signaling pathway of TNFR1, which …
Post-Transcriptional Regulation Of Myeloid Cell Leukemia 1 In Cancers, Jia Cui
Post-Transcriptional Regulation Of Myeloid Cell Leukemia 1 In Cancers, Jia Cui
All ETDs from UAB
Apoptosis, a highly regulated process of programmed cell death, is essential for maintaining normal tissue homeostasis. Myeloid cell leukemia 1 (MCL1), an anti-apoptotic BCL-2 family protein, lies at the center of apoptosis regulation. Overexpression of MCL1 has been identified as a key contributor to tumorigenesis and further enables resistance to anti-cancer chemotherapies and radiation. Due to the critical roles of MCL1 in cancer, it is essential to understand the regulatory mechanisms of MCL1 expression in cells. Previous studies have detailed how MCL1 expression is controlled by multiple mechanisms. However, characterization of the post-transcriptional regulation of MCL1 mRNA has been poorly …
The Effect Of Mitochondrial-Derived Ros On Calcium Handling And Cardiac Function In Heart, Kah Yong Goh
The Effect Of Mitochondrial-Derived Ros On Calcium Handling And Cardiac Function In Heart, Kah Yong Goh
All ETDs from UAB
Mitochondria are abundantly present in metabolic active organs such as the heart. The presence of mitochondria are crucial to provide energy in the form of ATP, regulate calcium handling, facilitate cell fate, and are involved in metabolic modulation. In the process of generating ATP through oxidative phosphorylation, mitochondria produce reactive oxygen species (ROS) as a side product. In the heart, mitochondria is a major source of ROS. Under normal conditions, ROS are kept at a physiologically relevant and healthy level. Unfortunately, excessive ROS levels during pathological states, such as pressure overload heart failure, appears as a threat to the whole …
Risk Factors Associated With Multiple Myeloma, Stephen Gragg
Risk Factors Associated With Multiple Myeloma, Stephen Gragg
All ETDs from UAB
Multiple myeloma (MM) is a hematologic malignancy in which clonal plasma cells accumulate in the bone marrow, leading to the formation of lytic bone lesions, hypercalcemia, anemia, renal insufficiency, and immunosuppression. It develops from a pre-malignant condition known as monoclonal gammopathy of undetermined significance (MGUS), which is prevalent in up to 3% of White populations over the age of 50 years, and twice that in Black populations. Although much progress has been made toward understanding the large scale genomic aberrations that facilitate the formation of MGUS clones and the various copy-number variations and mutations that trigger the development of MM, …
Identification Of Molecular Regulators Of Morphogenesis During Early Development Of Xenopus, Ivan Popov
Identification Of Molecular Regulators Of Morphogenesis During Early Development Of Xenopus, Ivan Popov
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During embryonic development of all animal species, dramatic changes in morphology occur to transform a single-celled zygote into a well-organized adult body that contains different organs positioned in stereotypical ways for the species. The processes that shape tissues and organs are called morphogenesis, and gastrulation is the first morphogenetic process in embryogenesis. During gastrulation, three germ layers are specified and a set of regionally specific cell movements act in concert to position these germ layers for proper establishment of future body plan of the developing animal. Although factors regulating cell lineage specification have been studied extensively, the molecular machinery controlling …
Transcriptional Changes Underpinning Poor Prognosis And Chemoresistance In Pancreatic Cancer, Ryne Ramaker
Transcriptional Changes Underpinning Poor Prognosis And Chemoresistance In Pancreatic Cancer, Ryne Ramaker
All ETDs from UAB
With a 5-year survival rate of 7% and only marginal improvements in recent dec-ades, pancreatic adenocarcinoma (PDAC) survival statistics present a disheartening chal-lenge. A majority of the high mortality rate associated with PDAC is due to late-stage diagnosis and limited efficacy of the current chemotherapeutic arsenal. This work is largely focused on the ~20% of tumors detected prior to metastasis for which curative surgical resection can be combined with chemotherapy and radiation therapy, increasing the 5 year survival rate to ~25%. Although a subset of these patients who undergo surgi-cal resection experience sustained remission, a majority of patients still relapse …
Overcoming Obesity-Induced Immunotherapeutic Impairment, Shannon Boi
Overcoming Obesity-Induced Immunotherapeutic Impairment, Shannon Boi
All ETDs from UAB
Obesity affects ~40% of United States adults and is linked to the development of multiple health-related complications. Obesity is a major risk factor for developing renal cell carcinoma (RCC), the most common type of renal cancer. Metastatic RCC has poor five-year survivals, therefore, new, efficacious therapeutics are needed. One avenue is immunomodulation to generate tumor-specific, systemic anti-tumor responses that are long-lasting against local, metastatic, and recurrent tumors. Despite encouraging results, immunotherapeutic treatment of RCC is underwhelming. Cytokine therapies are largely toxic, while newly FDA-approved ‘checkpoint blockade’ (CB) antibodies have responses <50%. Here, we present a strategy employing a T cell priming therapy (AdTR/CpG) upstream of CB administration. Combinatorial use resulted in improved anti-tumoral immune responses, significantly reduced tumor burdens, and extended overall survival in pre-clinical RCC. Importantly, this approach was more efficacious than either single agent(s). Pre-clinical therapy development is often accomplished using lean, healthy animals–thus, to improve translatability we examined immune responses in the context of obesity as a major patient comorbidity. Subsequently, we investigated AdTR/CpG/CB in diet-induced obese (DIO) mice. Tumor/treatment-naïve DIO mice exhibited obesity-associated features; i.e., increased leptin/insulin and serum cytokines. These effects were not dependent on high-fat diet administration as mice resistant to weight gain had minimal alterations in these factors, and were similar to mice maintained on standard chow. As previously identified, 80% of DIO mice bearing renal tumors failed to respond to AdTR/CpG. AdTR/CpG/CB-treatment dramatically improved response rates against DIO tumors, however, decreased obese responder percentages were observed in both combinatorial therapies and was independent of high fat diet administration alone. Impaired response rates were not model or immunotherapy-specific as similar reductions in tumor clearance were seen in models of melanoma and sarcoma. Furthermore, responses were not due to initial T cell priming or unequal precursor CD8+ T cell frequencies. Detrimental changes in the tumor microenvironment underscored failure in obese mice and revealed therapeutic success was defined by a T cell-myeloid cell-inversion profile, supported by immunogenetic and flow cytometric analyses. Thus, we demonstrate a novel combinatorial approach for improving checkpoint-based outcomes, and identify the ability of host obesity to impede therapy-induced anti-tumor immunity.
Neuropeptide Y Cells Regulate Anxiety Behavior, Katelynn Corder
Neuropeptide Y Cells Regulate Anxiety Behavior, Katelynn Corder
All ETDs from UAB
Dysregulation of the GABAergic system has long been implicated in anxiety disorders. Classic anxiolytic drugs, such as benzodiazepines, increase GABAergic transmission by modulating GABA¬A receptors, relieving anxiety symptoms. However, these treatments are not always effective and are often accompanied by negative side effects. Glutamate decarboxylase (GAD) is the enzyme responsible for producing GABA. Recent studies have shown that when the isoform GAD67 is reduced in specific brain regions or GABAergic subtypes, differential anxiety effects were found. These studies suggest that targeting specific GABAergic cell subtypes may provide a more effective treatment for anxiety disorders. Neuropeptide Y (NPY) is an abundant …
Cheminformatic Discovery And Characterization Of Copperdependent Bacterial Inhibitors, Alex Dalecki
Cheminformatic Discovery And Characterization Of Copperdependent Bacterial Inhibitors, Alex Dalecki
All ETDs from UAB
Deaths due to antibiotic-resistant bacteria are predicted to exceed 10 million per year by 2050, endangering our ability to conduct fundamental medical procedures such as immunosuppressive therapy or even basic surgery. Unfortunately, we are largely falling behind in the evolutionary arms race against common pathogens. Not only are we in sore need of new antibiotics, we also evidently need altogether new approaches to drug discovery itself, as our familiar avenues are increasingly failing to meet demands. In this dissertation, we describe a promising new source of antibacterials: copper-dependent inhibitors (CDIs), compounds that exert significant antibiotic activity only in the presence …
Pathological Changes In Hippocampal Synaptic Transmission And Neuronal Function During Early Disease In The Novel Tgf344-Ad Rat Model, Lindsey Allyson Smith
Pathological Changes In Hippocampal Synaptic Transmission And Neuronal Function During Early Disease In The Novel Tgf344-Ad Rat Model, Lindsey Allyson Smith
All ETDs from UAB
Alzheimer’s disease (AD) is the leading cause of dementia in those 65 years and older and the 6th leading cause of death in the United Sates. Current treatments only target symptoms of the disease and cannot slow or halt disease progression. The novel and comprehensive TgF344-AD rodent model may bridge the translational gap previous animal models have failed to traverse by providing the platform to probe pre-lesion synapse dysfunction, which is thought to result primarily from increased levels of toxic soluble amyloid beta and hyperphosphorylated tau. The most recently developed model, the TgF344-AD rat was created in 2013 by insertion …
The Primary Cilium Regulates Interstitial Immune Cells During Renal Cystogenesis, Cheng Song
The Primary Cilium Regulates Interstitial Immune Cells During Renal Cystogenesis, Cheng Song
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Renal cysts are a pathological condition that can lead to end-stage renal failure and death. The mechanisms that underlie renal cyst development are under active investigation, and emerging evidence has revealed defects in a number of proteins required for cilia assembly or signaling, such as intraflagellar transport (IFT) proteins and the polycystins. Characterization of mice harboring conditional IFT mutations suggests that the rate of cyst formation is dependent upon the timing of cilia loss. Induction of cilia loss in juvenile mice results in rapid cyst development, while induction of cilia loss in adult mice leads to a slower progressing form …
The Role Of Glycosylation Initiation By Galnac-Ts In Iga Nephropathy, Tyler Stewart
The Role Of Glycosylation Initiation By Galnac-Ts In Iga Nephropathy, Tyler Stewart
All ETDs from UAB
The autoimmune disease IgA nephropathy (IgAN) is a common cause of primary glo-merulonephritis, often resulting in end-stage renal disease. IgAN patients have elevated serum levels of immunoglobulin A1 (IgA1) with autoantigenic galactose-deficient (gd) O-glycans. The gd-O-glycans occur at specific sites within IgA1 hinge-region. We hy-pothesized that GalNAc-Ts play a role in the formation of gd-IgA1, due to their role in determining glycosylation sites and densities. To better understand how GalNAc-Ts may change O-glycans of IgA1 in IgAN we characterized the complex glycosylation mecha-nism involved in mucin-type O-glycan synthesis of IgA1 hinge-region. In the first section of this work, we explore …
The Mechanism Of Tgf-Β Function In Development Of The Axial Skeleton, Ga I Ban
The Mechanism Of Tgf-Β Function In Development Of The Axial Skeleton, Ga I Ban
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THE MECHANISM OF TGF-β FUNCTION IN DEVELOPMENT OF THE AXIAL SKELETON GA I BAN CELL, MOLECULAR DEVELOPMENTAL BIOLOGY ABSTRACT Back pain is caused by degeneration of intervertebral discs (IVD). IVD consists of two compartments: the annulus fibrosus (AF) and the nucleus pulposus (NP). One strategy for treatment of IVD degeneration is stem cell therapy, which would require an in-depth knowledge of how the IVD develops. Currently, the molecular mechanism of IVD development are not well defined. AF and vertebral bodies (VB) are derived from the same embryonic progenitor, sclerotome. Specification of sclerotome is determined by complex interactions among various growth …
Global Analysis Of Rpl12 Epistasis Within The Yor1-Δf Biogenesis Network, Mert Icyuz
Global Analysis Of Rpl12 Epistasis Within The Yor1-Δf Biogenesis Network, Mert Icyuz
All ETDs from UAB
In frame deletion of the phenylalanine residue at position 508 of the cystic fibrosis transmembrane conductance regulator (CFTR-ΔF508) results in protein misfolding and degradation, which reduces expression and function at the plasma membrane. The resulting loss of chloride and bicarbonate transport is the molecular basis of cystic fibrosis (CF). The F508-analogous mutation in the yeast oligomycin resistance 1 gene, yor1-ΔF670, has the same molecular consequences, but the phenotypic consequence is reduced resistance to growth inhibition by oligomycin. Comprehensive, systematic and quantitative analysis Yor1-ΔF gene modifiers has been demonstrated as a powerful way to further characterize known and to discover novel …
Endothelin-1 And The Diurnal Regulation Of Sodium Excretion, Jermaine Gajrae Johnston
Endothelin-1 And The Diurnal Regulation Of Sodium Excretion, Jermaine Gajrae Johnston
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Healthy individuals typically have a diurnal rhythm in sodium (Na+) excretion, with levels higher during the daytime and lower at nighttime. While the mechanism behind this rhythm is not yet fully understood, molecular clock genes such as Bmal1 may contribute to the diurnal variation in urinary Na+ excretion (UNaV). Endothelin-1 (ET-1) is a peptide that aids in the regulation of Na+ balance through activation of the endothelin B (ETB) receptor. Although the ETB receptor has been shown to play an important role in promoting natriuresis, whether this varies according to time of day is unknown. This dissertation examines the role …
An Investigation Of Sla Class Ii As A Xenoantigen, Joseph Ladowski
An Investigation Of Sla Class Ii As A Xenoantigen, Joseph Ladowski
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Xenotransplantation, using genetically-modified pigs as organ donors, is a potential solution to the growing transplant organ shortage. Avoiding antibody-mediated rejection (AMR) is the remaining hurdle to widespread application. The development of a triple glycan knockout pig reduced antibody binding to clinically acceptable levels, allowing for the screening of the history of antibodies to the major histocompatibility complex (MHC). In allotransplantation, the MHC is a group of proteins divided into two classes and anti-MHC antibodies possess the ability to cause both acute and chronic AMR. The pig MHC, the swine leukocyte antigen (SLA), is a hypothesized target of antibodies. This dissertation …