• Gene regulation by the putative Campylobacter jejuni diguanylate cyclase CbrR

      Fulmer, Claudia; Department of Biochemistry and Cancer Biology (Augusta University, 2020-05)
      As a leading cause of bacterial gastroenteritis, Campylobacter jejuni incurs health care costs estimated at $290 million a year in the US and up to 40,000 deaths in children aged 5 and younger worldwide. As such, determining those proteins that regulate C. jejuni virulence factors are prime targets to possibly develop a prophylactic therapy, that as of yet does not exist. CbrR is a C. jejuni response regulator that is annotated as a diguanylate cyclase (DGC), the class of enzyme that catalyzes the synthesis of cyclic di-GMP, a universal bacterial second message molecule, from GTP. In C. jejuni strain DRH212, an unmarked deletion mutant, cbrR-, and complemented mutant, cbrR+, were constructed. Soft agar motility tests, biofilm formation assays, transmission electron microscopy (TEM), and scanning electron microscopy (SEM) were performed. Site-directed mutagenesis was performed on cbrR to make alanine substitutions in both the autoinhibitory site (I-site) and active site and differential radial capillary of action ligand (DRaCALA) assays were performed to determine nucleotide binding by wild-type CbrR and the CbrR point mutants. Soft agar motility assays indicated a hyper-motile phenotype associated with the C. jejuni cbrR- mutant, whereas motility was all but negated in the cbrR+ complement. Biofilm assays and SEM demonstrated similar formation and robustness of biofilms between wild type and cbrR- mutant, however cbrR+ was unable to form significant biofilms in 72 hours. TEM images showed similar cellular morphology between cbrR-, wild type, and cbrR+, however cbrR+ cells had fewer flagella. DRaCALA assays showed wild-type CbrR and the active site mutant were both able to bind GTP and cyclic di-GMP, whereas the I-site mutant lost the ability to bind cyclic di-GMP, indicating the product binding site on CbrR. The highly conserved diguanylate cyclase CbrR is the only annotated DGC in the C. jejuni genome. Though the active site sequence is highly variant when compared to the consensus sequence, this protein is able to bind both substrate and product of the chemical synthesis of cyclic di-GMP and has now been shown to be a negative regulator of motility, a critical virulence factor in C. jejuni pathogenesis.
    • A gene-based approach for testing association of rare alleles

      Xu, Hongyan; George, Varghese; Department of Biostatistics and Epidemiology (2011-11-29)
      Rare genetic variants have been shown to be important to the susceptibility of common human diseases. Methods for detecting association of rare genetic variants are drawing much attention. In this report, we applied a gene-based approach to the 200 simulated data sets of unrelated individuals. The test can detect the association of some genes with multiple rare variants.
    • Gene-Environment Interaction Modulates Schizophrenic Endophenotypes in Heterozygous Reeler Mice

      Howell, Kristy R.; Department of Psychiatry and Health Behavior (2013-07)
      Aim 1: To determine the effect of chronic stress on the VEGF signaling pathway. Aim 2: To determine the effects of prenatal hypoxia on VEGF signaling, behavioral activities, blood flow, and brain volume in heterozygous reeler mice during early adulthood. Aim 3: To evaluate long lasting effects of prenatal hypoxia on VEGF signaling, behavioral activities, blood flow, and brain volume in heterozygous reeler mice. Aim 4: To determine the correlation between serum VEGF levels and brain volumes in schizophrenia subjects.
    • General Anesthesia in an Ex-Utero Intrapartum Treatment (EXIT) Procedure for a Neonate with NAGER Syndrome

      Grinage, Brandon C; O'Bannon, Robert Toney; Department of Anesthesiology and Perioperative Medicine (American Society of Anesthesiologists, 2010-10)
      In the ex-utero intrapartum treatment (EXIT) procedure, an incision is made similar to that for a cesarean section. Following uterine incision, the baby is partially delivered by the obstetrician but remains attached to the maternal-fetal unit, allowing the pediatric surgeon to establish or secure an airway while the baby maintains oxygen saturation on utero-placental support. Once the airway has been secured, the obstetric team resumes control of the procedure, the umbilical cord is cut and clamped, and the delivery of the baby is completed. We report on an EXIT procedure performed for fetal craniofacial abnormalities secondary to Nager Syndrome.
    • Genetic Ablation of CD68 Results in Mice with Increased Bone and Dysfunctional Osteoclasts

      Ashley, Jason W.; Shi, Zhenqi; Zhao, Haibo; Li, Xingsheng; Kesterson, Robert A.; Feng, Xu; McNeil, Paul L.; Department of Cellular Biology and Anatomy; College of Graduate Studies (2011-10-3)
      CD68 is a member of the lysosome associated membrane protein (LAMP) family that is restricted in its expression to cells of the monocyte/macrophage lineage. This lineage restriction includes osteoclasts, and, while previous studies of CD68 in macrophages and dendritic cells have proposed roles in lipid metabolism, phagocytosis, and antigen presentation, the expression and function of CD68 in osteoclasts have not been explored. In this study, we investigated the expression and localization of CD68 in macrophages and osteoclasts in response to the monocyte/macrophage-colony stimulating factor (M-CSF) and the receptor activator of NF-κB ligand (RANKL). We found that M-CSF stimulates CD68 expression and RANKL alters the apparent molecular weight of CD68 as measured by Western immunoblotting. In addition, we explored the significance of CD68 expression in osteoclasts by generating mice that lack expression of CD68. These mice have increased trabecular bone, and in vitro assessment of CD68â /â osteoclasts revealed that, in the absence of CD68, osteoclasts demonstrate an accumulation of intracellular vesicle-like structures, and do not efficiently resorb bone. These findings demonstrate a role for CD68 in the function of osteoclasts, and future studies will determine the mechanistic nature of the defects seen in CD68â /â osteoclasts.
    • Genetic Ablation of PLA2G6 in Mice Leads to Cerebellar Atrophy Characterized by Purkinje Cell Loss and Glial Cell Activation

      Zhao, Zhengshan; Wang, Jing; Zhao, Chunying; Bi, Weina; Yue, Zhenyu; Ma, Zhongmin Alex; Mei, Lin; Department of Neurology (2011-10-28)
      Infantile neuroaxonal dystrophy (INAD) is a progressive, autosomal recessive neurodegenerative disease characterized by axonal dystrophy, abnormal iron deposition and cerebellar atrophy. This disease was recently mapped to PLA2G6, which encodes group VI Ca2+-independent phospholipase A2 (iPLA2 or iPLA2b). Here we show that genetic ablation of PLA2G6 in mice (iPLA2b-/-) leads to the development of cerebellar atrophy by the age of 13 months. Atrophied cerebella exhibited significant loss of Purkinje cells, as well as reactive astrogliosis, the activation of microglial cells, and the pronounced upregulation of the pro-inflammatory cytokines tumor necrosis factor-a (TNF-a) and interleukin-1b (IL-1b). Moreover, glial cell activation and the elevation in TNF-a and IL-1b expression occurred before apparent cerebellar atrophy. Our findings indicate that the absence of PLA2G6 causes neuroinflammation and Purkinje cell loss and ultimately leads to cerebellar atrophy. Our study suggests that iPLA2b-/- mice are a valuable model for cerebellar atrophy in INAD and that early antiinflammatory therapy may help slow the progression of cerebellar atrophy in this deadly neurodegenerative disease.
    • Genetic and gene expression analyses of the polycystic ovary syndrome candidate gene fibrillin-3 and other fibrillin family members in human ovaries.

      Prodoehl, Mark J; Hatzirodos, Nicholas; Irving-Rodgers, Helen F; Zhao, Zhen Z; Painter, Jodie N; Hickey, Theresa E; Gibson, Mark A; Rainey, William E; Carr, Bruce R; Mason, Helen D; et al. (2009-11-13)
      Several studies have demonstrated an association between polycystic ovary syndrome (PCOS) and the dinucleotide repeat microsatellite marker D19S884, which is located in intron 55 of the fibrillin-3 (FBN3) gene. Fibrillins, including FBN1 and 2, interact with latent transforming growth factor (TGF)-beta-binding proteins (LTBP) and thereby control the bioactivity of TGFbetas. TGFbetas stimulate fibroblast replication and collagen production. The PCOS ovarian phenotype includes increased stromal collagen and expansion of the ovarian cortex, features feasibly influenced by abnormal fibrillin expression. To examine a possible role of fibrillins in PCOS, particularly FBN3, we undertook tagging and functional single nucleotide polymorphism (SNP) analysis (32 SNPs including 10 that generate non-synonymous amino acid changes) using DNA from 173 PCOS patients and 194 controls. No SNP showed a significant association with PCOS and alleles of most SNPs showed almost identical population frequencies between PCOS and control subjects. No significant differences were observed for microsatellite D19S884. In human PCO stroma/cortex (n = 4) and non-PCO ovarian stroma (n = 9), follicles (n = 3) and corpora lutea (n = 3) and in human ovarian cancer cell lines (KGN, SKOV-3, OVCAR-3, OVCAR-5), FBN1 mRNA levels were approximately 100 times greater than FBN2 and 200-1000-fold greater than FBN3. Expression of LTBP-1 mRNA was 3-fold greater than LTBP-2. We conclude that FBN3 appears to have little involvement in PCOS but cannot rule out that other markers in the region of chromosome 19p13.2 are associated with PCOS or that FBN3 expression occurs in other organs and that this may be influencing the PCOS phenotype.
    • Genetic labeling reveals novel cellular targets of schizophrenia susceptibility gene ERBB4 and neuregulin-1 – ERBB4 signaling in monoamine neurons

      Bean, Jonathan C; Department of Neuroscience and Regenerative Medicine (2015)
      Neuregulin 1 (NRG1) and its receptor ErbB4 are schizophrenia risk genes. NRG1-ErbB4 signaling plays a critical role in neural development and regulates neurotransmission and synaptic plasticity. Nevertheless, its cellular targets remain controversial. ErbB4 was thought to be expressed in excitatory neurons although recent studies have disputed this view. Utilizing mice that express a fluorescent protein under the promoter of the ErbB4 gene, I determined in what cells ErbB4 is expressed and their identity. ErbB4 was widely expressed in the mouse brain, being highest in amygdala and cortex. Almost all ErbB4-positive cells were GABAergic in cortex, hippocampus, basal ganglia, and most of amygdala in neonatal and adult mice, suggesting GABAergic transmission as a major target of NRG1-ErbB4 signaling in these regions. Non-GABAergic, ErbB4-positive cells were present in thalamus, hypothalamus, midbrain and hindbrain. In particular, ErbB4 was expressed in both dopamine neurons in the substantia nigra and ventral tegmental area and in serotoninergic neurons of raphe nuclei, but not in norepinephrinergic neurons of the locus coeruleus. In hypothalamus, ErbB4 was present in neurons that express oxytocin. ErbB4 was expressed in a group of cells in the subcortical areas that are positive for S100β. These results identify novel cellular targets of NRG1-ErbB4 signaling. Finally, perfusion of NRG1 into the medial prefrontal cortex enhanced both dopamine and serotonin release but with differing time courses.
    • Genetic Modeling and Pathophysiological Analysis of FAM109A, a Putative Human Disease Gene

      Ates, Kristin Marie; Department of Neuroscience and Regenerative Medicine (Augusta University, 2019-05)
      A critical barrier in the treatment of endocytic diseases is the lack of information and understanding of the in vivo mechanisms of endocytosis. Part of this is due to the diverse array of endocytic adaptor proteins that have not yet been studied. We address this by investigating a key endocytic adaptor protein, FAM109A, which interacts with OCRL1, a causative gene for Lowe syndrome. Previous in vitro studies have identified FAM109A as a regulator for endosomal trafficking, particularly in the recycling of receptors in endosomes and sorting of cargo to lysosomes, based on knock-down studies. Here we conduct the first study into the developmental and physiological functions of FAM109A in vivo, utilizing the zebrafish model. We find that depletion of both zebrafish orthologs, zFAM109A and zFAM109B, in our maternal-zygotic homozygous mutant models (AB mutant) disrupts fluid-phase endocytosis and ciliogenesis in the pronephros. Partial knockdown of OCRL1 in the AB mutants exacerbates the endocytosis deficit, confirming that OCRL1 and FAM109 proteins are linked in a common endocytic pathway. In addition, we discover that zFAM109A/B mutant animals exhibit reduced jaw size and delay in chondrocyte maturation, indicating a novel role for zFAM109A and zFAM109B in craniofacial development. This is consistent with the phenotype in a patient within the NIH’s Undiagnosed Diseases Program (UDP). The UDP patient carries a de novo arginine (R) to cysteine (C) mutation (R6C) in FAM109A and presents with craniofacial abnormalities, developmental delay, auditory and vision impairments, and renal dysfunction. Expressing zFAM109A with the R6C mutation in zebrafish exacerbated craniofacial deficits, suggesting that the R6C allele acts in a dominant-negative manner. Together, these results show that FAM109A is involved in fluid-phase endocytosis and ciliogenesis in vivo. Moreover, we provide further insight into the potential pathogenesis of a UDP patient’s disease in association with a de novo mutation in FAM109A.
    • Genetic mutations cause primary aldosteronism

      Hattangady, Namita G; Department of Physiology (2014-10)
      The human adrenal glands are complex endocrine organs that are physiologically located above the kidney. The cortex of the adrenal gland may be considered as a combination of three different steroidogenic tissue-types which form concentric zones within each adrenal. The three cortical zones include zona glomerulosa (ZG), zona fasciculata (ZF) and zona reticularis (ZR). Each zone, under independent regulation, produces unique steroid(s) which exhibit specific functions. The outermost ZG layer secretes the steroid, aldosterone due to ZG specific expression of aldosterone synthase (CYP11B2). Aldosterone regulates sodium reabsorption, and therefore, blood pressure. Aldosterone production is tightly regulated by the renin-angiotensin-aldosterone system. Thus, aldosterone levels are in direct proportion with renin levels. Other known physiological regulators of aldosterone production include serum K+ and adrenocorticotrophic hormone. A type of endocrine hypertension termed ‘Primary Aldosteronism’ (PA), is characterized by aldosterone secretion under suppressed renin levels. PA accounts for almost 10 % of hypertension. More recently, genetic mutations in an inward rectifying K+ channel (KCNJ5) that occur as both, somatic and germline cases, have been implicated in the pathology of PA. The goal of this dissertation is to define the role of KCNJ5 mutations in PA. In this dissertation, I will summarize my studies that describe the acute and chronic events involved in mutated KCNJ5 mediated aldosterone excess. In addition, I will define a novel mutation in KCNJ5 of germline nature identified at Georgia Regents University. Finally, I will also describe some interesting lessons we learnt from the expression of mutated KCNJ5 in primary cultures of human adrenals. The prevalence of a hereditary form of PA termed as Familial Hyperaldosteronism type III (FH III) is very rare. Thus far, only a few mutations in the KCNJ5 gene, including T158A, G151R, G151E and I157S, are confirmed as causing FH III, following Mendelian genetics. Perhaps the most interesting feature of this disease is the varied phenotype between the different mutations. T158A-affected patients present with massive hyperplasia and require bilateral adrenalectomy. In contrast, patients affected by the G151E mutation have more severe hypertension, although their adrenals are near normal in appearance. In this study we identify a new germline mutation (Y152C). The index case was a 61 year old woman who underwent unilateral adrenalectomy. The patient with the Y152C mutation exhibited a milder hypertension phenotype (like the G151E-affected patient) with extensive hyperplasia (as seen in the T158A-affected patient). In vitro analyses of the Y152C mutation indicated a pathology similar to other known mutations in KCNJ5, including change in conductance to Na+ ions and elevated calcium levels, and increase in CYP11B2 mRNA and aldosterone production. The inherent challenge presented by current studies utilizing constitutive expression of KCNJ5 mutations is the limitation in studying acute temporal events such as post translational modifications of steroidogenic enzymes and transcription factors. To address this issue, we generated a doxycycline inducible cell model system for the T158A harboring KCNJ5 transgene. Herein, we demonstrate a useful system that was amenable to the study of acute and chronic events involved in mutant-KCNJ5 mediated aldosterone excess. Our findings suggest that mutant KNCJ5 increases CYP11B2 expression through the activation of transcriptional activators of CYP11B2. Additionally, this is the first study to demonstrate that mutant KCNJ5 also activates steroidogenic acute regulatory protein (StAR) at the levels of translation and post translational phosphorylation. We also demonstrate calcium channel blocker, verapamil as an efficient blocker of mKCNJ5 mediated aldosterone production. Finally, one of the sharp advantages of our study was the use of primary cultures of human adrenal cells to confirm the effects of mutated KCNJ5. Interestingly, transduction of cells with constitutive viruses for mutant KCNJ5, confirmed an increase in KCNJ5 mRNA, although no change in CYP11B2 expression levels was observed. Pilot data including treatment of primary cells with calcium ionophores indicated that ZF/ZR cells may have a phenotype that is ‘muted’ for calcium mediated pathways. We could also speculate that this may disprove some current hypotheses that APA harboring KCNJ5 mutations may originate from the ZF. Overall, this study has improved our knowledge regarding the pathogenesis of PA caused by KCNJ5 mutations and has identified verapamil as a potentially effective therapeutic strategy in the inhibition of aldosterone excess in this type of PA.
    • Genetic Variation of the Serotonin 2a Receptor Affects Hippocampal Novelty Processing in Humans

      Schott, Bjorn H.; Seidenbecher, Constanze I.; Richter, Sylvia; Wustenberg, Torsten; Debska-Vielhaber, Grazyna; Schubert, Heike; Heinze, Hans-Jochen; Richardson-Klavehn, Alan; Duzel, Emrah; Department of Neurology; et al. (2011-01-18)
      Serotonin (5-hydroxytryptamine, 5-HT) is an important neuromodulator in learning and memory processes. A functional genetic polymorphism of the 5-HT 2a receptor (5-HTR2a His452Tyr), which leads to blunted intracellular signaling, has previously been associated with explicit memory performance in several independent cohorts, but the underlying neural mechanisms are thus far unclear. The human hippocampus plays a critical role in memory, particularly in the detection and encoding of novel information. Here we investigated the relationship of 5-HTR2a His452Tyr and hippocampal novelty processing in 41 young, healthy subjects using functional magnetic resonance imaging (fMRI). Participants performed a novelty/familiarity task with complex scene stimuli, which was followed by a delayed recognition memory test 24 hours later. Compared to His homozygotes, Tyr carriers exhibited a diminished hippocampal response to novel stimuli and a higher tendency to judge novel stimuli as familiar during delayed recognition. Across the cohort, the false alarm rate during delayed recognition correlated negatively with the hippocampal novelty response. Our results suggest that previously reported effects of 5-HTR2a on explicit memory performance may, at least in part, be mediated by alterations of hippocampal novelty processing.
    • Genistein attenuates retinal inflammation associated with diabetes by targeting of microglial activation

      Ibrahim, Ahmed S.; El-Shishtawy, Mamdouh M.; Pena, Alejandro Jr.; Liou, Gregory I.; Department of Ophthalmology; Department of Medicine (2010-10-08)
      Purpose: Diabetic retinopathy (DR) is associated with microglial activation and increased levels of inflammatory cytokines. Genistein, a tyrosine kinase inhibitor, has been shown to possess anti-inflammatory potential that so far untested in animal models of diabetes. The aims of this study are to evaluate the efficacy of genistein for alleviation of diabetes-induced retinal inflammation and also to gain insight into the molecular mechanisms involved therein by analyzing the effect of genistein on concomitant microglia activation in the diabetic retina and in isolated cells.
    • Genomic analysis reveals clinical significance of PGK1 in head and neck cancer

      Crystal, Evan; Department of Biological Sciences (Augusta University, 2021-05)
      The underlying abnormality that yields cancer development is the unregulated growth and proliferation of cancer cells. Phosphoglycerate kinase-1 (PGK1) is a key regulator for cell metabolism and is encoded by the gene PGK1. The protein translated by this gene is a glycolytic enzyme that catalyzes the conversion from 1,3-Bisphosphoglyceric acid to 3-Phosphoglyceric acid. This enzyme takes part in the first energy-producing step of glycolysis. High intracellular expression of PGK1 has been linked to tumor cell proliferation, and high PGK1 mRNA expression predicts poor survival in head and neck cancer. Therefore, the role of PGK1 in cancer cell metabolism could potentially display clinical significance in the treatment of head and neck squamous cell carcinoma (HNSCC). The study that I will conduct under the advisement of Dr. Teng will investigate the role and importance of PGK1 in HNSCC through bioinformatics analysis with RNA sequencing data. The goal of this project is to reveal the clinical relevance/significance of PGK1 in head and neck cancer. In addition, a goal is to provide a strong rationale for further studying PGK1’s role and molecular regulations in head and neck cancer development and progression.
    • GET THEM HERE: KEEP THEM HERE: A STUDY OF THE RECRUITMENT AND RETENTION OF BLACK STUDENTS AT GREENWOOD UNIVERSITY

      Hodges, Jamel Antwon; Department of Advanced Studies and Innovation (Augusta University, 2019-05)
      Greenwood University, a Predominantly White Institution (PWI), has had difficulty recruiting Black students and retaining them throughout their undergraduate careers to graduation. Research shows the significant link between students’ perceptions of belonging and satisfaction at a university and their retention at that university. Race on a college campus is complex and requires intentional efforts to understand within the framework of higher education. The aim of this study is to determine specific causes that explain why Black students are not being recruited and retained at the same rate as their non-Black peers at Greenwood University. In doing so, the authors employed a mixed methods approach in which they conducted interviews from Black second and third year students, as well as faculty and staff, to explain the responses gathered from a recent Campus Climate Survey. A focus group of students also highlighted factors that impact the recruitment and retention of Black students. Among the responses received, factors such as support, connection, and representation among Black faculty and staff were shown to have a strong impact on Black students’ feelings of belonging, thus in many cases, their retention at Greenwood University. Based on the findings, it is recommended that universities prioritize intentional incentives to provide specialized support services and “spaces” for its students and to grow the numbers of faculty and staff who represent all of their institution’s student body. Keywords: enrollment, recruitment, retention, Black students, faculty, staff, Predominantly White Institution (PWI), Historically Black College or University (HBCU), Higher Education, Administrators
    • GET THEM HERE: KEEP THEM HERE: A STUDY OF THE RECRUITMENT AND RETENTION OF BLACK STUDENTS AT GREENWOOD UNIVERSITY

      Green, Garrett; Department of Advanced Studies and Innovation (Augusta University, 2019-05)
      Greenwood University, a Predominantly White Institution (PWI), has had difficulty recruiting Black students and retaining them throughout their undergraduate careers to graduation. Research shows the significant link between students’ perceptions of belonging and satisfaction at a university and their retention at that university. Race on a college campus is complex and requires intentional efforts to understand within the framework of higher education. The aim of this study is to determine specific causes that explain why Black students are not being recruited and retained at the same rate as their non-Black peers at Greenwood University. In doing so, the authors employed a mixed methods approach in which they conducted interviews from Black second and third year students, as well as faculty and staff, to explain the responses gathered from a recent Campus Climate Survey. A focus group of students also highlighted factors that impact the recruitment and retention of Black students. Among the responses received, factors such as support, connection, and representation among Black faculty and staff were shown to have a strong impact on Black students’ feelings of belonging, thus in many cases, their retention at Greenwood University. Based on the findings, it is recommended that universities prioritize intentional incentives to provide specialized support services and “spaces” for its students and to grow the numbers of faculty and staff who represent all of their institution’s student body. Keywords: enrollment, recruitment, retention, Black students, faculty, staff, Predominantly White Institution (PWI), Historically Black College or University (HBCU), Higher Education, Administrators
    • GIP-Overexpressing Mice Demonstrate Reduced Diet-Induced Obesity and Steatosis, and Improved Glucose Homeostasis

      Kim, Su-Jin; Nian, Cuilan; Karunakaran, Subashini; Clee, Susanne M.; Isales, Carlos M.; McIntosh, Christopher H. S.; Department of Orthopaedic Surgery; Department of Cellular Biology and Anatomy (2012-07-3)
      Glucose-dependent insulinotropic polypeptide (GIP) is a gastrointestinal hormone that potentiates glucose-stimulated insulin secretion during a meal. Since GIP has also been shown to exert b-cell prosurvival and adipocyte lipogenic effects in rodents, both GIP receptor agonists and antagonists have been considered as potential therapeutics in type 2 diabetes (T2DM). In the present study, we tested the hypothesis that chronically elevating GIP levels in a transgenic (Tg) mouse model would increase adipose tissue expansion and exert beneficial effects on glucose homeostasis. In contrast, although GIP Tg mice demonstrated enhanced b-cell function, resulting in improved glucose tolerance and insulin sensitivity, they exhibited reduced diet-induced obesity. Adipose tissue macrophage infiltration and hepatic steatosis were both greatly reduced, and a number of genes involved in lipid metabolism/inflammatory signaling pathways were found to be down-regulated. Reduced adiposity in GIP Tg mice was associated with decreased energy intake, involving overexpression of hypothalamic GIP. Together, these studies suggest that, in the context of over-nutrition, transgenic GIP overexpression has the potential to improve hepatic and adipocyte function as well as glucose homeostasis.
    • Give Rise

      Visintainer, Rachel; Communications (Augusta University Libraries, 2020-05-04)
      This item presents the abstract for an oral presentation at the 21st Annual Phi Kappa Phi Student Research and Fine Arts Conference.
    • GLYCOSAMINOGLYCANS, CHONDROITINASE, AND MOLECULAR SUBTYPES IN BLADDER CANCER

      Morera, Daley S; Department of Biochemistry and Molecular Biology (Augusta University, 2020-05)
      There is a need for novel prognostic biomarkers and targeted treatments in bladder cancer (BC), even more so for muscle-invasive disease (MIBC). Discovery of molecular markers to predict outcome in BC patients may lead to identification of impactful therapeutic targets. The hyaluronic acid (HA) family of molecules and distinct molecular subtypes have both been investigated as potential prognostic markers. HA family and chondroitin sulfate proteoglycans, such as CD44, have been implicated in driving aggressiveness of disease; however, a chondroitinase enzyme that cleaves chondroitin sulfate proteoglycans has not been identified in any eukaryotic system. We evaluated molecular markers of BC and the first known eukaryotic/human chondroitinase, that we identified, for their ability to predict clinical outcome in patients, and for their roles as drivers of disease. We also investigated the anti-tumor effects of HA synthesis inhibitor 4-methylumbelliferone (4MU), a non-toxic orally bioavailable supplement. This study demonstrates that transcript levels of HA family members can predict metastasis and poor survival in BC patients. HA- family expression also correlated with epithelial mesenchymal transition (EMT) markers β -Catenin, Twist, Snail, and E-Cadherin. HA signaled through its receptors CD44/RHAMM and the PI3-K/AKT axis. 4MU targeted HA signaling, inhibiting proliferation and motility/invasion, inducing apoptosis in vitro, and preventing tumor growth in vivo. We discovered that a previously unidentified splice variant of HYAL-4 was elevated in bladder tumors. We named this variant "V1". Our studies showed that V1 had chondroitinase activity, cleaved chondroitin-6-sulfate from CD44, and consequently increased CD44 secretion. In vivo, V1-expressing urothelial cells formed muscle-invasive tumors and V1-expressing cancer cells developed metastatic tumors. Evaluation of the prognostic significance of the molecular subtypes of MIBC that were recently identified by other groups, showed the subtypes to have little to no predictive ability for clinical outcome in multivariate analyses that included standard clinical parameters. Consistently, clinical parameters such as histopathologic tumor grade, T-stage, and lymph node status, outperformed the molecular subtypes. Contrarily, V1 levels could independently predict metastasis and survival with high efficacy, suggesting that focusing on V1 as a functional biomarker may be a better strategy to improve clinical outcome of BC patients.
    • Gods and Heroism: Ares and Hercules from Classics to Comic Books

      Lane, Joshua; Department of History, Anthropology, & Philosophy (Augusta University, 2018-12)
    • Granulomatous Conduit for Intrathecal Infusion of Morphine and Bupivacaine

      Webb, David M; Schneider, John R; Lober, Robert M.; Vender, John R.; Department of Anesthesiology and Perioperative Medicine; Department of Neurosurgery (American Society of Regional Anesthesia and Pain Medicine, 2010-11)
      Intrathecal Drug Delivery Systems (IT-DDS) have gained widespread acceptance as a therapeutic alternative to high dose parenteral opioids for unremitting chronic pain. Granuloma formation has been reported as a side effect in association with the greater use of IT-DDS. Etiological factors include infection, reaction to catheter material, and trauma at the site of implantation. The most widely accepted etiology is the use of intrathecal morphine, with granuloma formation dependent on morphine dosage. We present the case of a woman with unremitting GI pain and IT-DDS placement who developed a granuloma at the hub of the catheter which formed a sealed conduit that re-established drug flow between the pump and catheter.