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1
Omodho, Becky. "Early growth response gene (Egr) 2 and 3 control inflammatory responses of tolerant T cells." Thesis, Brunel University, 2016. http://bura.brunel.ac.uk/handle/2438/13516.
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This study investigated the role of tolerance induction in an inflammatory setting in regard to the early growth response genes Egr2 and Egr3. T cells robustly respond to pathogenic antigens during infection, but are tolerant to stimulation by self-antigens. The intrinsic mechanisms for self-tolerance in the periphery are still not clear. Egr2 and 3 are induced in tolerant T cells in response to antigen stimulation by NFAT-medicated tolerant signalling; however, their function in tolerant T cells is still unknown. The study demonstrated that Egr2 and 3, induced in tolerant T cells, are not directly involved in defective proliferation and IL-2 production, the hallmarks of T cell tolerance. However, they are essential for preventing inflammatory response of tolerant T cells. In the absence of Egr2 and 3, tolerant T cells show impaired proliferation and production of IL-2, but produce high levels of IFN-γ, a key inflammatory cytokine. This phenotype resembles CD4 T cells from autoimmune diseases such as lupus which show poor proliferative response, but hyper-inflammation. Our study demonstrated, for the first time, a distinctive mechanism to control inflammation from proliferative tolerance regulated by Egr2 and 3, which may be an important mechanism for the control of autoimmune diseases.
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Kasneci, Amanda. "Early growth factor response 1 (Egr-1) negatively regulates expression of calsequestrin (CSQ) on cardiomyocytes in vitro." Thesis, McGill University, 2008. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=112521.
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Heart failure represents an important cause of death in Western Countries. The pathophysiology of heart failure is mainly associated with abnormalities in intracellular calcium control. We previously showed that Egr-1 negatively regulates expression of sodium-calcium exchanger (NCX) in vivo and in vitro. Here we tested the hypothesis that Egr-1 regulates expression of calcium storage proteins in the sarco-endoplasmic reticulum (SER), calsequestrin (CSQ) and/or ER, calreticulin (CRT) directly or indirectly via Egr-1:NFAT (nuclear factor of activated T-cells) formation. Secondarily, we hypothesized that this will reduce calcium mobilization. We found that undifferentiated 1293F cells, overexpressing Egr-1, have reduced CSQ compared to control H9c2 cells. We demonstrated that Egr-1 negatively regulates CSQ but not CRT expression. The Egr-1 mediated decrease in CSQ is linked to decreased calcium availability. Repression is by a novel NAB-independent (NGFI-A binding protein) activity localized to a.a. region 1-307. We conclude that Egr-1-mediated reductions in calcium storage protein expression alter calcium availability for cardiac contraction/relaxation.
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Symonds, Alistair. "The zinc finger transcription factor Early Growth Response 2 (Egr-2) is an intrinsic regulator of T cell tolerance and homeostasis." Thesis, Queen Mary, University of London, 2009. http://qmro.qmul.ac.uk/xmlui/handle/123456789/409.
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Tolerance of T cells to self-antigen is crucial to prevent the development of autoimmune disease. How self-tolerance is controlled at the transcriptional level is, however, unknown. We discovered that the transcription factor Early Growth Response 2 (Egr-2) was expressed by tolerant T cells, and by CD4+CD44high T cells in the absence of overt antigen stimulation, in vivo. To investigate the roles of Egr-2 in T cells, we generated CD2 cell specific Egr-2 deficient (Egr-2 cKO) mice. The proliferation of Egr-2 cKO CD44high T cells in vivo was markedly increased leading to progressive accumulation as the mice aged. By 15 months of age CD4+CD44high cells constituted the predominant T cell population in the peripheral lymphoid organs of Egr-2 cKO mice and expressed high levels of the activation markers CD25 and CD69. In addition to this lymphoproliferative disorder, 15 month old Egr-2 cKO mice showed signs of lupus-like autoimmune disease. This autoimmune syndrome was characterised by glomerulonephritis and proteinuria, infiltration of T cells into internal organs and, crucially, auto-antibodies directed against nuclear components; the hallmark of lupus. We observed decreased expression of the cyclin-dependent kinase inhibitor p21cip1 in Egr-2 cKO CD4+CD44high T cells while TCR stimulation induced IFN-γ, and, in particular, IL-17A and IL-17F expression was markedly increased. Consistent with these findings, we observed increased numbers of IFN-γ and IL-17 producing CD4+ T cells in Egr-2 cKO mice. The numbers of IFN-γ and IL-17 producing CD4+ T cells further increased as the mice aged in parallel with the gradual development of symptoms of lupus-like disease. These results demonstrate that Egr-2 is an intrinsic regulator of both T cell homeostasis and T cell tolerance.
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Pagel, Judith-Irina Carola. "Functional characterization of the transcription factor early growth response 1 (Egr1) in arteriogenesis." Diss., Ludwig-Maximilians-Universität München, 2014. http://nbn-resolving.de/urn:nbn:de:bvb:19-178078.
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The number of patients suffering from obstructive arterial disease is still increasing. Stimulation of a patient’s collateralization (arteriogenesis), though an auspicious therapeutic approach, is still not part of current therapy regimes. Further studies on the molecular level are needed to understand the genetic regulation in this process. The transcription factor early growth response 1 (Egr1) was shown to partic-ipate in leukocyte recruitment and cell proliferation in vitro. This work contributes to the acquisition of new insights into its mode of action in vivo.
Using a model of peripheral arteriogenesis, Egr1 was found significantly upregulated in growing col-laterals of wild-type mice (WT), both on mRNA (2.24fold) and protein level (2.3fold). Egr1 stained positive in EC and vSMCs of collaterals as well as in nerves. In LDI measurements conducted over the period of 21 days evidenced a delayed perfusion recovery after femoral artery ligation in Egr1-/- mice compared to WT mice (day7: 0.46±0.05 in Egr1-/- vs. WT (0.73±0.04), day 14: 0.65±0.02 in Egr1-/- vs. 0.88±0.04 in WT and day 21: 0.79 ±0.03 in Egr1-/- vs. 0.96±0.02 in WT). Under baseline conditions, Egr1-/- showed increased levels of monocytes (521.89±52.9 cells/µl vs. 326.56±21.6 cells/µl in WT) and granulocytes (811.79±79.96 cells/µl vs. WT 559.88±34.57 cells/µl) in the circulation but reduced levels in adductor muscles (18.14±2.73 cells/µl vs. 51.22±4.38 cells/µl in WT) as evidenced by FACS analyses. After femoral artery ligation, more macrophages were detected in the perivascular space of collateral arteries in Egr1-/- (8.10±0.99 per vessel) vs. WT (6.12±0.45 per vessel) mice. The mRNA of leukocyte recruitment mediators monocyte chemoattractant protein 1 (MCP-1), intercellular adhesion molecule 1 (ICAM-1) and urokinase plasminogen activator (uPA) were found upregulated in both groups. Whereas other Egr family members (Egr2-4) did not show an upregulation in WT collateral arteries, they were found significantly upregulated in Egr1-/- mice suggesting a mechanism of counter-balancing Egr1 deficiency. A closer look at cell cycle regulators revealed that cyclin E and cdc20 were found upregulated in WT as well as in Egr1-/- mice. However, cyclin D1 was hardly detectable under Egr1 deficiency conferring Egr1 an unique role for cyclin D1 transcription. vSMC phenotype switch is a critical step towards vSMC proliferation and therefore arteriogenesis. In this context, the downregu-lation of alpha smooth muscle actin (αSM-actin) and of the transcriptional repressor, splicing factor-1 (SF-1) has been shown to be critical in vitro. During arteriogenesis, SF-1 has been found downregulat-ed in collaterals of WT mice but was 1.64fold upregulated in Egr1-/-. Similar was true for αSM-actin. Whereas in WT mice αSM-actin is downregulated at 12h after ligation Egr1 deficient mice evidenced an upregulation of αSM-actin. The strong upregulation of the nonselective proliferation marker ki67 in WT mice was not detectable under Egr1 deficiency evidencing furthermore a delay in vascular cell proliferation. Conclusion: Compensation for deficiency of Egr1 function in leukocyte recruitment can be mediated by other transcription factors; however, Egr1 is indispensable for effective vascular cell cycle progression and phenotype switch in arteriogenesis.
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Mohamad, Trefa Salih. "EARLY GROWTH RESPONSE 1 (EGR1) AS A TUMOR SUPPRESSOR AND APOPTOSIS INDUCER IN RHABDOMYOSARCOMA." OpenSIUC, 2017. https://opensiuc.lib.siu.edu/dissertations/1375.
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EGR1, one of the immediate-early response genes, plays an important role as a mediator for transmitting extracellular stimuli. EGR1 is down regulated in many cancers. Many studies show that it functions as a tumor suppressor gene in a variety of cancers. EGR1 also acts as an oncogene in number of cancers. We found that in rhabdomyosarcoma (RMS), which is a muscle derived pediatric cancer, EGR1 was expressed in both RMS subtypes, embryonal and alveolar, but with a much higher expression profile in embryonal RMS. This suggests different mechanisms of down regulation of EGR1 in these two subtypes. Molecular and cellular approaches were used to characterize the functional role of EGR1 in RMS. We found that over expression of EGR1 in alveolar RMS significantly decreased cell proliferation, mobility, and anchorage-independent growth. We showed that exogenous EGR1 up regulated the cell cycle regulator, p21, which is normally repressed in RMS. EGR1 also promoted differentiation in RMS cells by up regulating several genes involved in muscle differentiation including myosin heavy chain (MyHC), MyoD and myogenin. We found that EGR1 interacts with the oncogene TBX2 in RMS cells and that TBX2 inhibits EGR1 function. To understand how TBX2 inhibits EGR1, we depleted TBX2 in RMS and we found an up regulation of the EGR1 targeted tumor suppressor gene, PTEN, and the cysteine protease inhibitor gene, CST6. Also, we performed luciferase assays and found that TBX2 decreased the expression of luciferase constructs fused with the PTEN promoter when TBX2 was co-transfected with EGR1. Our novel findings on the EGR1 function in RMS highlights the significant role of EGR1 in muscle development and tumor growth. Significantly, our work also suggests the EGR1 could promote tumor regression in RMS through inducing programmed cell death, or apoptosis. We found that EGR1 induced apoptosis through triggering the intrinsic apoptosis pathway and activating caspase cascades involving caspase 3 and caspase 9, which are essential mitochondrial apoptotic factors. Also, we observed the activation of two pro-apoptotic factors, BAX and dephosphorylated BAD, which are both located upstream of the caspase cascades in the intrinsic pathway. Also, we found in our study that EGR1 is repressed by the catalytic subunit of PRC2 complex, EZH2, which mediates gene silencing through methylation of lysine 27 on histone 3 (H3K27me3). EGR1 also sensitized RMS cells to chemotherapeutic agents, which could be a future direction for improved therapeutic targeting. Therefore, this work provides a novel and powerful molecular therapeutic target for RMS cancer.
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Young, Ada. "IL-1β Amplification of Nitric Oxide Production and Its Inhibitory Effects on Glucose Induced Early Growth Response-1 Expression in INS-1 Cells." Digital Commons @ East Tennessee State University, 2012. https://dc.etsu.edu/etd/1463.
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The pathophysiology of cytokines released by infiltrating white blood cells upon pancreatic beta cells is not fully understood. Early growth response gene-1 (Egr-1) expression is specifically and transiently up regulated in pancreatic beta cells in response to glucose. We hypothesized that interleukin-1 beta (IL-1▀) induction of nitric oxide alters glucose induced Egr-1 transcription levels. Egr-1 levels were assessed via western blot, nitric oxide was measured with a Griess Reagent kit and insulin levels via ELISA. Glucose induced both insulin and Egr-1 production in INS-1 cells. IL-1▀ dose dependently increased nitric oxide production over time and significantly attenuated glucose induced Egr-1 expression. Sodium nitroprusside dose dependently reduced glucose induced Egr-1 production. The data suggest a strong relationship between IL-1▀ induced nitric oxide production and the reduction of glucose stimulated Egr-1 production. The pathways altered by this cytokine could provide a better understanding of the pathophysiology leading to pancreatic beta cell death.
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Murray, Alexander James. "The Interaction of Early Growth Response Gene 1 and Myocyte Enhancer Factor 2C in the Murine Brain Cortex." Thesis, Virginia Tech, 2021. http://hdl.handle.net/10919/105007.
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Early growth response gene – 1 (Egr1) encodes a protein widely present in mammalian body, such as connective tissue, cardiac tissue, the liver, and the brain. As a transcription factor (TF), it is involved in processes that take place in the endocrine, digestive, immune, musculo-skeletal and central nervous systems, for instance, B cell maturation upon B cell receptor activation, tendon repair upon mechano-stimulation, and long-term spatial memory formation. In mammalian brains, EGR1 controls the responses to environmental stimuli such as chronic stress and physical contact. It also participates in processes such as long-term memory consolidation and synapse re-structuring. It plays a role in enacting responses and qualities of gene transcription cascades upon neuronal stimulation. Inside the epigenetic realm, EGR1 recruits Ten-eleven translocation methylcytosine dioxygenase 1 (TET1) to remove DNA methylation at target loci. Due to its critical functions during brain development and upon neuronal activation, mis-regulation of EGR1 is associated with neuropsychological disorders such as post-traumatic stress disorder (PTSD) and schizophrenia (SCZ) in humans. In this study, we performed bioinformatics analysis with brain methylomes and predicted EGR1 may interact with myocyte enhancer factor 2C (MEF2C), which is known to be involved in many similar processes as EGR1, such as synapse architecture, cell migration, and learning and memory. EGR1 and MEF2C ChIP-seq data derived from mouse frontal cortex suggest these two proteins may regulate a common set of downstream genes. To begin, co-immunoprecipitation experiments were performed with HEK293T cells co-transfected with EGR1-FLAG and MEF2C-HA tagged constructs, allowing for specific interaction identification without endogenous protein expression interference. Furthermore, co-immunoprecipitation experiments performed with brain tissues additionally indicated the two proteins interact with each other endogenously. Altogether, this study provides protein-protein interaction evidence for EGR1 and MEF2C in cultured HEK293 cells and in the cortices of adult male mice. This information provides a foundation for future examinations of how these two TFs interact to initiate cascading events following neuronal stimulation.Master of Science
Early growth response gene – 1 (EGR1) encodes a protein that can be found in animals such as fruit flies, mice, rats, and humans. In mammals, it is widely expressed in the cardiovascular, endocrine, digestive, immune, musculo-skeletal and central nervous systems (CNS). Within the CNS, EGR1 is known as an essential transcription factor involved in brain development. More specifically, EGR1 plays a role in how the early brain develops in response to environmental stimuli, formation of synapse architecture and certain types of memories. Many gene networks involved in growth and development rely on EGR1 to regulate functions such as synapse reformation after exposure to the environment. EGR1 is known to have numerous partners with whom it interacts to execute its functions. It is also involved in epigenetic regulation, which is a process by which genes are silenced or activated without changing DNA sequences in the genome. EGR1 may directly interact with TET1 to demethylate EGR1 target sites in the genome, and to increase gene transcription. In memory development, EGR1 plays a key role ensuring short-term auditory fear memory can be converted to long-term memory, and also ensures long-term spatial memory. In this study, our computational analyses suggest that EGR1 may interact with MEF2C. This work provides evidence of a protein-protein interaction of EGR1 and MEF2C in cultured cells and in the brain cortical areas of mice. Such an interaction may explain why these two genes regulate overlapped biological processes within the brain and sheds lights on how cascading events are initiated following neuronal stimulation.
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Lejard, Véronique. "Etude de la régulation transcriptionnelle du collagène de type I dans les fibroblastes tendineux." Paris 6, 2007. http://www.theses.fr/2007PA066465.
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L’expression du gène codant pour la chaîne1 du collagène I (Col1a1) dans les tendons nécessite la coopération des éléments cis-activateurs TSE1, TSE2 et d’éléments localisés entre – 1537 et – 220 pb du promoteur proximal de Col1a1. Mon travail de thèse avait pour but d’identifier les facteurs de transcription qui, en se liant à ces séquences, activent le promoteur de Col1a1 dans les tendons. J’ai montré (1) que scleraxis (SCX), dont l’expression est spécifique des tendons, active le promoteur de Col1a1 en se liant à TSE2 sous forme d��hétérodimère SCX/E47 ; (2) que des facteurs de transcription NFATc sont exprimés dans les fibroblastes tendineux, peuvent se lier à TSE1 et augmenter l’expression de Col1a1 ; et (3) que la protéine Egr2 active le promoteur de Col1a1 probablement en se liant à un élément localisé entre – 1537 et – 220 pb. L’ensemble de ces résultats suggère que l’expression du gène Col1a1 dans les fibroblastes tendineux nécessite la coopération de SCX et de NFATc avec Egr2.
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Billah, MD Muntasir. "Cardioprotective effect of remote ischaemic preconditioning and the role of Early growth response-1 as a master switch regulator." Thesis, The University of Sydney, 2017. http://hdl.handle.net/2123/18248.
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Once the blood supply is restored after heart attack by opening up the coronary artery, the heart is insulted by ischemia-reperfusion (I/R) injury. Direct ischaemic preconditioning has the ability to protect the heart against this injury for a brief period of time. Direct ischaemic preconditioning involves cycles of non-lethal occlusion of the coronary artery and releasing. Preconditioning other organs remote to the heart such as the limbs can protect the heart from I/R injury. This new therapeutic technique, known as remote ischaemic preconditioning (RIPC) is non-invasive and easy to apply compared to direct ischaemic preconditioning. However, we still do not know the mechanism through which RIPC protects the heart. This thesis explores the underlying mechanism of RIPC-induced cardioprotection from myocardial I/R injury, in experimental in vitro and in vivo models. Both intrinsic and extrinsic pathways of apoptosis contribute to cell death during heart attack. This thesis explores the relative contribution of the apoptotic pathways in I/R injury. Moreover, autophagy is associated with myocardial I/R injury sparing effect of direct ischaemic preconditioning and postconditioning. It is hypothesized that autophagy plays a key role in RIPC-mediated cardioprotection and autophagy stimulation provides therapeutic benefit. There is evidence that preconditioning can decrease the level of early growth response-1 (Egr-1), a master regulator highly expressed in heart tissue followed by heart attack. Once Egr-1 is highly expressed, a number of downstream inflammatory signalling molecules get expressed, which are well known to cause myocardial damage. It is shown that Egr-1 downregulation in the hind limb prior RIPC abolishes RIPC-induced cardioprotection. In addition, it augmented certain a number of process that are attenuated by RIPC including apoptosis, cytokine expression. This work identifies a key role for Egr-1 in the signalling mechanism of RIPC through its regulation of a number of crucial downstream genes and cardioprotective pathways. In addition, it identifies IL-6 as a potential mediator of RIPC to mitigate myocardial I/R injury.
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Pfaffenseller, Bianca, Flavio Kapczinski, Amelia L. Gallitano, and Fábio Klamt. "EGR3 Immediate Early Gene and the Brain-Derived Neurotrophic Factor in Bipolar Disorder." FRONTIERS MEDIA SA, 2018. http://hdl.handle.net/10150/627052.
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Bipolar disorder (BD) is a severe psychiatric illness with a consistent genetic influence, involving complex interactions between numerous genes and environmental factors. Immediate early genes (IEGs) are activated in the brain in response to environmental stimuli, such as stress. The potential to translate environmental stimuli into long-term changes in brain has led to increased interest in a potential role for these genes influencing risk for psychiatric disorders. Our recent finding using network-based approach has shown that the regulatory unit of early growth response gene 3 (EGR3) of IEGs family was robustly repressed in postmortem prefrontal cortex of BD patients. As a central transcription factor, EGR3 regulates an array of target genes that mediate critical neurobiological processes such as synaptic plasticity, memory and cognition. Considering that EGR3 expression is induced by brain-derived neurotrophic factor (BDNF) that has been consistently related to BD pathophysiology, we suggest a link between BDNF and EGR3 and their potential role in BD. A growing body of data from our group and others has shown that peripheral BDNF levels are reduced during mood episodes and also with illness progression. In this same vein, BDNF has been proposed as an important growth factor in the impaired cellular resilience related to BD. Taken together with the fact that EGR3 regulates the expression of the neurotrophin receptor p75NTR and may also indirectly induce BDNF expression, here we propose a feed-forward gene regulatory network involving EGR3 and BDNF and its potential role in BD.
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Pagel, Judith-Irina Carola [Verfasser], and Elisabeth [Akademischer Betreuer] Deindl. "Functional characterization of the transcription factor early growth response 1 (Egr1) in arteriogenesis / Judith-Irina Carola Pagel. Betreuer: Elisabeth Deindl." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2014. http://d-nb.info/1066206422/34.
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Gernon, Grainne Mary. "Investigation into Early Growth Response 1 in colorectal disease : a study of EGR1 expression in colorectal tissue and novel protein interactions in cancer cells." Thesis, University of Edinburgh, 2012. http://hdl.handle.net/1842/9899.
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Introduction: Early growth response 1 (EGR1) is a zinc-finger transcription factor involved in the regulation of cell growth. It can act as either a tumour suppressor or a tumour promoter with a role in the induction of apoptosis in cancer cells by various pathways and is likely to play a role in colorectal cancer (CRC). EGR1 also appears to play a significant role in inflammatory pathways, therefore a possible role in Inflammatory Bowel Disease (IBD) is hypothesised. Patients with IBD have a greater risk of developing CRC, which is increased with duration of symptoms and severity of inflammation and dysplasia. The aim of this study is to determine whether EGR1 is differentially expressed in diseased colon tissue and to investigate novel EGR1-protein interactions in CRC cell lines. Methods: The relative EGR1 expression in CRC cell lines and in normal mucosa and tumours of colorectal cancer patients was determined by qRT-PCR. IBD patient samples were also examined for differential EGR1 expression levels by qRT-PCR, before and after stimulation with inflammatory mediators. Statistical analysis of the data was performed using ‘R’ statistical package, with the mixed-model ANOVA. Statistical significance was set at < 0.05. The genotype of three EGR1 variants was determined in the samples using PCR and sequencing, and the methylation status of regions of the EGR1 promoter was determined using bisulfite sequencing. A yeasttwo hybrid screen was conducted with EGR1 as bait, and screened against a SW480 CRC cell line library. Interesting novel interactions were investigated using immunocytochemistry and immunoprecipitation, as was the novel interaction between EGR1 and NOD2 and between EGR1 and components of the cytoskeleton. Results: Investigation into the relative EGR1 mRNA expression in CRC has shown that there is differential expression of EGR1 between matched normal mucosa and tumour. EGR1 expression is decreased in IBD patients compared with healthy controls. Induction of EGR1 by inflammatory stimuli also appears to be aberrant in these patients. The differential expression of EGR1 was not associated with aberrant methylation of a large region of the EGR1 promoter in either the CRC or IBD patients or with the genotype of EGR1 variants. EGR1 localises to both the cytoplasm and the nucleus in CRC cell lines and this study demonstrate interactions with the IBD susceptibility protein NOD2 and with components of the cyotskeleton. A yeast-two hybrid screen conducted with EGR1 as bait using a CRC cell line library has identified several other novel protein interactions of EGR1 in CRC cell lines. Conclusion: EGR1 is differentially expressed in both CRC and IBD, and in the case of IBD shows aberrant activity, suggesting that EGR1 may play a role in both colorectal diseases. EGR1 interacts with the IBD protein NOD2, and components of the cytoskeleton in CRC cells. Several novel protein interactions with EGR1 have been identified and warrant further study.
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Kim, Julia Heewon. "Growth factor regulation of early growth response factor 3 localization and function in neurons." Thesis, Boston University, 2012. https://hdl.handle.net/2144/12448.
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Thesis (Ph.D.)--Boston University
PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.The brain is a complex system of membrane-dependent cellular responses that utilize flexible and adaptive regulatory cascades to represent the presence or absence of extracellular signals. Many neurological diseases occur due to the sustained activation of signaling pathways that disturb important gene regulatory networks. Our initial studies have focused on temporal lobe epilepsy (TLE) where balance between excitatory and inhibitory synaptic transmission is most affected. Using in vitro and in vivo models of TLE, the Russek and Brooks-Kayal laboratories identified a crucial role for altered GABA-A receptor function that occurs in response to increased levels of α4 subunits. Increases in α4 are controlled by brain-derived neurotrophic factor (BDNF) and synthesis of early growth response factor 3 (Egr3), transcriptional activator of the a4 subunit gene. In the work of this thesis, we show that Egr3 also regulates expression of the excitatory n-methyl-D-aspartate receptor type 1 subunit (NMDAR1), providing an additional mechanism for increased synaptic activity associated with epileptogenesis. Recent evidence suggests that in addition to epilepsy, Egr3 plays a role in complex brain disorders, like schizophrenia and depression. Expression of Egr3 is critical for spatial memory like other important activity-dependent molecules such as cyclic adenosine monophosphate (cAMP)-response element-binding protein (CREB). Unlike these molecules that are found predominantly in the nucleus, this thesis reports that Egr3 may play a unique role in activity-dependent gene expression based on its unique cytoplasmic presence. Furthermore, mutation in the T12 residue of Egr3 that abolishes a putative protein kinase C/mitogen activated protein kinase (PKC/MAPK) phosphorylation site confers BDNF-induced regulation that is relevant to endogenous NMDAR1 gene expression. These results are the first demonstration that post-translational modification of Egr3 may be an important feature of its gene regulatory function. Taken together with the novel detection of Egr3 in putative synapses, this thesis opens a new area for investigation that considers the role of phosphorylation in the marking and trafficking of Egr3 within neuronal processes. It is hoped that future studies into the mechanism that controls Egr3 synaptic presence will uncover new opportunities for therapeutic intervention and early detection of disease.
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Ghaffari, Emma Louise Marie. "Early growth response genes -2 and -3 are essential for optimal immune responses." Thesis, Brunel University, 2013. http://bura.brunel.ac.uk/handle/2438/8134.
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Early Growth Response Genes (EGR) is a family of four transcription factors containing a unique zinc finger domain. EGR-2 and EGR-3 are important for hindbrain development and myelination. These transcription factors are also necessary for lymphocyte function however, the mechanisms are still unclear. Previous findings have shown that EGR-2cKO mice develop lupus-like autoimmune disease with high levels of pro-inflammatory cytokines despite showing normal T and B cell proliferation after mitogenic stimulation. Therefore we established the CD2-EGR-2-/-EGR-3-/- mouse model to explore the phenotype, susceptibility to autoimmune disease and relevant lymphocyte function. We discovered that CD2-EGR-2-/-EGR-3-/- mice developed severe systemic autoimmune disease and expressed high levels of inflammatory cytokines. More importantly we discovered a novel finding that CD2-EGR-2-/-EGR-3-/- T and B cells had impaired cell proliferation after mitogenic stimulation. Further investigations revealed that the molecular mechanism defected in the T cell receptor signalling pathway is due to a dysfunction in Activator Protein-1 (AP-1). AP-1 is a heterodimeric protein composed of AP-1 family members including Jun, Atf and Fos. Our data shows that EGR-2 and EGR-3 directly bind with the Atf family member Batf, which prevents Batf’s inhibitory function on AP-1 activation. This research demonstrates that EGR-2 and EGR-3 intrinsically regulate chronic inflammation and also positively regulate antigen receptor activation. In conclusion EGR-2 and EGR-3 are essential for providing optimal immune responses, whilst limiting inflammatory immunopathology. We propose that this new model could be used for studying autoimmune disease.
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Yang, Dongsheng. "The response of two eucalypt subspecies to water stress and fertilizer at early seedling stage." Thesis, Canberra, ACT : The Australian National University, 1987. http://hdl.handle.net/1885/140223.
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Raymond, Meera V. "Early growth response gene-2 controls inflammatory responses of CD4+ T cells by negatively regulating Th17 differentiation." Thesis, Queen Mary, University of London, 2015. http://qmro.qmul.ac.uk/xmlui/handle/123456789/8953.
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CD4+ T cells play a central role in controlling the adaptive immune response by secreting cytokines to control the responses of different lymphocytes. Naïve CD4+ T cells differentiate into at least four subsets, Th1, Th2, Th17, and inducible regulatory T cells under antigen and corresponding cytokine microenvironment during an immune response. Therefore, each subset has unique functions for pathogen elimination. The differentiation of these subsets is induced in response to conditioned cytokine stimulation, which induces specific master regulator transcription factors. Multiple other transcription factors, both subset specific and shared, are also involved in promoting subset differentiation. Previously, our group has discovered that early growth response gene-2 (Egr-2) is important for the maintenance of T cell homeostasis and controls the development of autoimmune disease. However, the underlying mechanisms are unknown. In this study, using Egr-2 conditional knockout mice, a novel mechanism of Egr-2 in the control of Th17 differentiation has been discovered. Egr-2 is induced by TGFβ and IL-6 in naïve CD4+ T cells. The induced Egr-2 negatively regulates the expression of IL-17, the signature cytokine for Th17. In contrast, Egr-2 has less effect on the expression of IL-2 or IFN-γ in effector T cells. In the absence of Egr-2, CD4+ T cells produce high levels of Th17 cytokines. Deletion of Egr-2 in T cells renders mice susceptible to EAE induction; a model for Th17 mediated autoimmune diseases. T cells lacking Egr-2 show increased propensity for Th17, but not Th1 or Th2, differentiation in vitro. The key mechanism of Egr-2 in regulation of Th17 differentiation is to inhibit the function of Batf for transactivation of IL-17 expression and promotion of Th17 differentiation. Egr-2 interacts with Batf in CD4+ T cells and suppresses its interaction with DNA sequences derived from the IL-17 promoter, while the activation of STAT3 and expression of RORγt is unchanged in Th17 cells in the absence of Egr-2. Thus, Egr- 14 2 plays an important role to intrinsically control Th17 differentiation. We also found that CD4+ T cells from multiple sclerosis (MS) patients have reduced expression of Egr-2 and increased expression of IL-17 following stimulation with anti-CD3 in vitro. Collectively, our results demonstrate that Egr-2 is an intrinsic regulator that controls Th17 differentiation by inhibiting Batf activation which may be important for the control of inflammatory autoimmune diseases.
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White, Meredith Megan. "Growth and development of larval bay scallops (Argopecten irradians) in response to early exposure to high CO₂." Thesis, Massachusetts Institute of Technology, 2013. http://hdl.handle.net/1721.1/79190.
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Thesis (Ph. D.)--Joint Program in Oceanography/Applied Ocean Science and Engineering (Massachusetts Institute of Technology, Dept. of Biology; and the Woods Hole Oceanographic Institution), 2013.Cataloged from PDF version of thesis.
Includes bibliographical references.
Coastal and estuarine environments experience large variability and rapid shifts in pCO₂ levels. Elevated pCO², or ocean acidification, often negatively affects early life stages of calcifying marine invertebrates, including bivalves, but it is unclear which developmental stage is most sensitive. I hypothesized that initial calcification is a critical stage during which high pCO₂ exposure has severe effects on larval growth and development of bay scallop (Argopecten irradians). Using five experiments varying the timing of exposure of embryonic and larval bay scallops to high CO₂, this thesis identifies two distinct stages of development during which exposure to high CO₂/low pH causes different effects on bay scallop larvae. I show that any exposure to high CO₂ consistently reduces survival of bay scallop larvae. I also show that high CO₂ exposure during initial calcification (12-24 h post-fertilization) results in significantly smaller shells, relative to ambient conditions, and this size decrease persists through the first week of development. High CO₂ exposure at 2-12 h post-fertilization (pre-calcification), does not impact shell size, suggesting that the CO₂ impact on size is a consequence of water chemistry during calcification. However, high CO₂ exposure prior to shell formation (2-12 h post-fertilization) causes a high incidence of larval shell deformity, regardless of CO₂ conditions during initial calcification. This impact does not occur in response to high CO₂ exposure after the 2-12 h period. The observations of two critical stages in early development has implications for both field and hatchery populations. If field populations were able to time their spawning to occur during the night, larvae would undergo initial calcification during the daytime, when CO₂ conditions are more favorable, resulting in larger veliger larvae. Hatcheries could invest minimal resources to monitor and modify water chemistry only during the first day of development to ensure larva are exposed to favorable conditions during that critical period.
by Meredith Megan White.
Ph.D.
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Gaggioli, Cédric. "Etude de l'expression de la fibronectine dans les cellules de mélanome : rôle de la voie de signalisation des MAP kinases ERK et du facteur de transcription Egr-1." Paris 7, 2005. http://www.theses.fr/2005PA077021.
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Hosseini, Mohammad Khajeh. "The response of soybean seeds to the stresses of semi-arid environments during germination and early seedling growth." Thesis, University of Aberdeen, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.324912.
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Reduced water availability and salinity are two major environmental factors influencing crop establishment in semi-arid environments. Therefore the effect of reduced water availability using polyethylene glycol (PEG) 4000 solutions and of salinity (NaCl) on the germination of six soybean cultivars was examined. Cultivars differed in their response to reduced water availability and salinity and in their ability to recover from the stresses. A large increase in germination during a recovery period at 0 MPa following water stress suggested that PEG was not toxic whilst the failure of seeds to recover from high salinity revealed the toxic effects of NaCl. At the same water potential, germination in saline conditions was higher than that in PEG and the rate of water uptake by individual seeds was more rapid in NaCl solutions than in PEG. The most plausible explanation for the greater water uptake and germination in NaCl is that seeds accumulated salts which lowered their osmotic potential. The effects of NaCl on seedling growth were much greater when experiments were conducted in a hydroponic system compared with a paper towel method. However, analysis of the solutions soaking the paper towels revealed that 4.25 mMolal Ca2+ was available to the seeds in this system in saline conditions. This may have reduced Na+ uptake or provided a protective effect against Na+ toxicity. Germination (40%) was possible at a tissue Na+ concentration in the embryonic axis of 9.3mg g-1 FW whilst seedling growth was completely inhibited at a tissue Na+ concentration of 6.1 mg g-1 FW. Germination at higher tissue Na+ concentrations was associated with higher K++Ca2+ concentrations, suggesting that these ions may protect the seeds in the pregermination phase against salinity. A reduction in seed vigour due to ageing resulted in reduced germination under saline conditions compared to the germination of unaged seeds, but there was no significant interaction between salinity and seed ageing. However, unaged seeds showed a greater increase in germination after transfer to 0 MPa than did the aged seeds. Since both the site of ageing and the toxic effect of NaCl is the cell membrane, there may be additive effects of NaCl toxicity on cell membrane in aged seeds.
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Bhatia, Deepak. "Transcriptional and post-transcriptional regulation of Gadd45[alpha] in response to arsenic." Morgantown, W. Va. : [West Virginia University Libraries], 2007. https://eidr.wvu.edu/etd/documentdata.eTD?documentid=5311.
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Thesis (Ph. D.)--West Virginia University, 2007.Title from document title page. Document formatted into pages; contains xv, 156 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references (p. 112-153).
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Singh, Randeep. "Early growth response genes 2 and 3 are potent inhibitors of T-bet function for interferon gamma production in T-cells." Thesis, Brunel University, 2016. http://bura.brunel.ac.uk/handle/2438/14780.
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Early growth response (Egr) gene 2 and 3 are genes encoding transcription factors important for maintaining immune homeostasis. Here we define a fundamental role of Egr2 and 3 to control T cell proliferation and differentiation of effector T cells. Egr2 and Egr3 deficiency in T cells resulted in impaired T cell proliferation, but hyper-activation and excessive differentiation of T cells in response to viral infection, while, conversely, sustained Egr2 expression enhanced proliferation, but severely impaired effector differentiation in to T helper (Th) subsets, such as, Th1 and Th17 subtypes. T-bet is important for differentiation of effector T cells in response to pathogen and in particular it is a master regulator for modulating the T helper 1 lineage specific differentiation programme. Although T-bet has been extensively studied in T cells, the regulation of T-bet function is less well known. We have now discovered that Egr2 and 3 are potent inhibitors for Tbet function in CD4 and CD8 effector T cells. Together with Egr2 and 3, T-bet is induced in naïve T cells by antigen stimulation, but the expression was reciprocally regulated by IFNγ, which inhibited Egr2 and 3, but promoted Tbet expression. The expression of Egr2 and 3 in CD4 T cells under TH2 and TH17 condition was essential to suppress TH1 differentiation in vitro. In response to viral infection, sustained Egr2 expression in T cells profoundly inhibited differentiation of effector cells, while Egr2 and 3 deficient T cells produced excessive levels of IFNγ. We found that both Egr2 and 3 can directly interact with the Tbox domain of T-bet, block its DNA binding and inhibit T-bet mediated production of IFNγ. Thus, Egr2 and 3 are antagonists for T-bet function in effector T cells and essential for the control of T cell differentiation and immune pathology.
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Morimoto, Masafumi. "Lysophosphatidylcholine Induces Early Growth Response Factor-1 Expression and Activates the Core Promoter of PDGF-A Chain in Vascular Endothelial Cells." Kyoto University, 2002. http://hdl.handle.net/2433/149671.
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Pfaffenseller, B., Silva Magalhães P. V. da, Bastiani M. A. De, M. A. A. Castro, A. L. Gallitano, F. Kapczinski, and F. Klamt. "Differential expression of transcriptional regulatory units in the prefrontal cortex of patients with bipolar disorder: potential role of early growth response gene 3." NATURE PUBLISHING GROUP, 2016. http://hdl.handle.net/10150/616973.
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Bipolar disorder (BD) is a severe mental illness with a strong genetic component. Despite its high degree of heritability, current genetic studies have failed to reveal individual loci of large effect size. In lieu of focusing on individual genes, we investigated regulatory units (regulons) in BD to identify candidate transcription factors (TFs) that regulate large groups of differentially expressed genes. Network-based approaches should elucidate the molecular pathways governing the pathophysiology of BD and reveal targets for potential therapeutic intervention. The data from a large-scale microarray study was used to reconstruct the transcriptional associations in the human prefrontal cortex, and results from two independent microarray data sets to obtain BD gene signatures. The regulatory network was derived by mapping the significant interactions between known TFs and all potential targets. Five regulons were identified in both transcriptional network models: early growth response 3 (EGR3), TSC22 domain family, member 4 (TSC22D4), interleukin enhancer-binding factor 2 (ILF2), Y-box binding protein 1 (YBX1) and MAP-kinase-activating death domain (MADD). With a high stringency threshold, the consensus across tests was achieved only for the EGR3 regulon. We identified EGR3 in the prefrontal cortex as a potential key target, robustly repressed in both BD signatures. Considering that EGR3 translates environmental stimuli into long-term changes in the brain, disruption in biological pathways involving EGR3 may induce an impaired response to stress and influence on risk for psychiatric disorders, particularly BD.
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Ogbe, Ane Theodora. "Early Growth Response genes 2 and 3 play a role in chronic inflammation pathology and are essential for the differentiation of T follicular helper cells." Thesis, Brunel University, 2015. http://bura.brunel.ac.uk/handle/2438/11214.
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The Early Growth Response genes 2 and 3 (Egr2/3) are zinc finger transcription factors that play an important role in the immune system. These transcription factors have reported functions in T cell receptor signaling, differentiation of effector T cell subsets and the development of lupus-like autoimmune diseases. Using CD2-Egr2-/- Egr3-/- mouse model, I investigate the development of inflammation pathology, differentiation of T follicular helper (Tfh) cells and the formation of germinal centers (GC) following viral challenge within these mice. The onset of inflammation pathology in CD2-Egr2-/- Egr3-/- mice was discovered to correlate with high levels of pro-inflammatory cytokines in the serum and the development of autoimmune diseases as previously reported by Li et al, 2012. Most importantly, a novel role for the Egr2/3 genes in the differentiation of T follicular helper (Tfh) cells was identified. Tfh cells are responsible for T cell dependent antibody immune response in the GC. They support the differentiation of GC B cells into plasma cells producing long lived high-affinity isotype-switched antibodies and memory B cells. Tfh cell differentiation is regulated by Bcl6 however; the regulators of Bcl6 during Tfh differentiation remain largely unknown. We have now discovered that Egr2/3 genes are required for Bcl6 expression during Tfh cell differentiation. In the absence of the Egr2 and 3 genes, Tfh cell differentiation is severely impaired and GC formation and functions were defective in response to Vaccinia Virus Western Reserve strain (VVWR) infection. Further investigation revealed that Egr2 regulated Bcl6 expression in a Tfh-specific manner as adoptive transfer of WT CD4+ T cells into Egr2-/- Egr3-/- mice was able to rescue Bcl6 expression, Tfh differentiation and GC formation. When the molecular mechanism of how Egr2 regulated Bcl6 was investigated, it was uncovered that Egr2 directly bound to the promoter region of Bcl6 gene in CD4 T cells to regulated Bcl6 expression. Indeed constitutive expression of either Egr2 or Bcl6 in CD2-Egr2-/- Egr3-/- CD4+ T cells rescued Tfh cell differentiation and GC formation. Our results inferred that the Egr2/3 genes are essential for Tfh differentiation and GC formation by regulating Bcl6 expression in CD4 T cells under Tfh condition. Our studies thus suggest that the Egr2/3 genes are paramount for minimising immunopathology and are also critical for efficient antibody production by regulating Tfh cell differentiation.
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Dußmann, Philipp [Verfasser], and Elisabeth [Akademischer Betreuer] Deindl. "Characterization of a transgenic mouse expressing the reporter gene luciferase under the control of the murine early growth response-1 promoter / Philipp Dußmann. Betreuer: Elisabeth Deindl." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2016. http://d-nb.info/1096162571/34.
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Rauschkolb, Peter [Verfasser]. "Die Rolle von Early Growth Response 1 bei der Regulation von Timp1, Tenascin C und Elastin während des kompensatorischen Lungenwachstums und der postnatalen Alveolarisierung / Peter Rauschkolb." Gießen : Universitätsbibliothek, 2015. http://d-nb.info/1074101065/34.
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Kollert, Leonie [Verfasser], Jürgen [Gutachter] Deckert, Katharina [Gutachter] Domschke, and Charlotte [Gutachter] Förster. "Epigenetics of anxiety and depression – a differential role of TGFB-Inducible Early Growth Response Protein 2 gene promoter methylation / Leonie Kollert ; Gutachter: Jürgen Deckert, Katharina Domschke, Charlotte Förster." Würzburg : Universität Würzburg, 2021. http://d-nb.info/1240614721/34.
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Abdel, Malak Nelly. "Signalling and mediators of Angiopoietin-1 in endothelial cells." Thesis, McGill University, 2008. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=115914.
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Angiopoietin-1 (Ang-1), the main ligand for the endothelial cell (EC)-selective Tie-2 receptors, promotes survival, proliferation, migration and differentiation of these cells. Despite its importance in various aspects of vascular biology, the mechanisms of action of the Ang-1/Tie-2 receptor pathway have not been fully explored.To identify the downstream modulators of Ang-1, we evaluated changes in the transcriptome of human umbilical vein endothelial cells (HUVECs) treated with Ang-1 protein for four hours by employing the oligonucleotide rnicroarray technology. Eighty-six genes were significantly upregulated by this treatment and forty-nine genes were significantly downregulated. These genes are involved in the regulation of cell cycle, proliferation, apoptosis, transcription and differentiation. Furthermore, we found that the Erk1/2, PI3-Kinase and mTOR pathways are implicated in promoting gene expression in HUVECs in response to Ang-1. Analysis of the microarray data employing the Ingenuity Pathways analysis software to place the regulated genes in the context of biological networks revealed several highly connected nodes including the chemokine Interleukin-8 (IL-8) and the transcription factor Early growth response-1 (Egr-1). Due to the importance of these genes in promoting angiogenesis, we decided to evaluate their roles in Ang-1/Tie-2 receptor signaling and biological effects.
Ang-1 induced IL-8 expression in a time- and dose-dependent manner in ECs through both transcriptional and post-transcriptional mechanisms. To study the functional role of Ang-1-induced IL-8, we generated HUVECs that overexpress Ang-1. In these cells, neutralizing IL-8 significantly reduced EC proliferation and migration. IL-8 promoter activity experiments and gel shift assays revealed the involvement of the transcription factor AP-1 in Ang-1-induced IL-8. Ang-1 stimulated the phosphorylation of c-Jun through activation of Erk1/2, JNK and PI-3 kinase pathways. Similarly, Ang-1 provoked the expression and DNA binding of Egr-1 in HUVECs. Employing siRNA and DNAzyme to specifically knock-down Egr-1, we found that Ang-1-induced Egr-1 also promotes EC proliferation and migration.
We conclude that Ang-1 provokes a coordinated response intended to promote EC survival, proliferation, and angiogenesis and to inhibit EC apoptosis. Ang-1 induces EC proliferation and migration in part through the secretion of the soluble mediator Interleukin-8 and through induction of the transcription factor Egr-1.
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McGovern, Jacqui Anne. "Investigating epidermogenesis in a human skin equivalent model." Thesis, Queensland University of Technology, 2012. https://eprints.qut.edu.au/61036/1/Jacqui_McGovern_Thesis.pdf.
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Skin is the largest, and arguably, the most important organ of the body. It is a complex and multi-dimensional tissue, thus making it essentially impossible to fully model in vitro in conventional 2-dimensional culture systems. In view of this, rodents or pigs are utilised to study wound healing therapeutics or to investigate the biological effects of treatments on skin. However, there are many differences between the wound healing processes in rodents compared to humans (contraction vs. re-epithelialisation) and there are also ethical issues associated with animal testing for scientific research. Therefore, the development of skin equivalent (HSE) models from surgical discard human skin has become an important area of research. The studies in this thesis compare, for the first time, native human skin and the epidermogenesis process in a HSE model. The HSE was reported to be a comparable model for human skin in terms of expression and localisation of key epidermal cell markers. This validated HSE model was utilised to study the potential wound healing therapeutic, hyperbaric oxygen (HBO) therapy.
There is a significant body of evidence suggesting that lack of cutaneous oxygen results in and potentiates the chronic, non-healing wound environment. Although the evidence is anecdotal, HBO therapy has displayed positive effects on re-oxygenation of chronic wounds and the clinical outcomes suggest that HBO treatment may be beneficial. Therefore, the HSE was subjected to a daily clinical HBO regime and assessed in terms of keratinocyte migration, proliferation, differentiation and epidermal thickening. HBO treatment was observed to increase epidermal thickness, in particular stratum corneum thickening, but it did not alter the expression or localisation of standard epidermal cell markers. In order to elucidate the mechanistic changes occurring in response to HBO treatment in the HSE model, gene microarrays were performed, followed by qRT-PCR of select genes which were differentially regulated in response to HBO treatment.
The biological diversity of the HSEs created from individual skin donors, however, overrode the differences in gene expression between treatment groups. Network analysis of functional changes in the HSE model revealed general trends consistent with normal skin growth and maturation. As a more robust and longer term study of these molecular changes, protein localisation and expression was investigated in sections from the HSEs undergoing epidermogenesis in response to HBO treatment. These proteins were CDCP1, Metallothionein, Kallikrein (KLK) 1 and KLK7 and early growth response 1. While the protein expression within the HSE models exposed to HBO treatment were not consistent in all HSEs derived from all skin donors, this is the first study to detect and compare both KLK1 and CDCP1 protein expression in both a HSE model and native human skin. Furthermore, this is the first study to provide such an in depth analysis of the effect of HBO treatment on a HSE model. The data presented in this thesis, demonstrates high levels of variation between individuals and their response to HBO treatment, consistent with the clinical variation that is currently observed.
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Caviness, James A. "Stress biomarkers in a rat model of decompression sickness /." Download the thesis in PDF, 2005. http://www.lrc.usuhs.mil/dissertations/pdf/Caviness2005.pdf/.
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Ludajic, Katarina [Verfasser]. "Functional characterization of early growth response transcription factor 2 (EGR-2) / von Katarina Ludajic." 2005. http://d-nb.info/976438690/34.
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Chen, Yu-Te, and 陳宥德. "Induction of Early Growth Response (Egr)-1 by Epstein-Barr Virus Lytic Transactivator Zta." Thesis, 2005. http://ndltd.ncl.edu.tw/handle/00376230781659839890.
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碩士國立臺灣大學
微生物學研究所
93
Epstein-Barr virus (EBV) contains two phases in its life cycle: latent and lytic stages. According to previous studies, the progression of lytic cycle may affect many cellular events. To address this issue, we performed a microarray analysis on two groups of EBV-infected 293 cells that were distinguished into latent and lytic clones. We found that the expression of early growth response-1 (Egr-1), a zinc finger transcription factor, was increased in lytic clones, but not in latent clones. Immunoblot analysis confirmed that Egr-1 protein expression was associated with EBV lytic cycle. Zta is an immediate-early protein encoded by BZLF1 gene and plays a significant role to initiate viral lytic cascades. By using BZLF1-targetd siRNA to block EBV lytic progression, the expression of Egr-1 protein was reduced. Therefore, we suggested that the expression of Egr-1 protein was the downstream event of EBV lytic cycle. Furthermore, by using single gene transfection assay, we identified that Zta could induce Egr-1 protein expression in two EBV-negative cell lines, NPC-TW01 and NPC-TW04. In addition, in a Zta-inducible cell line (HONE-1-52), Egr-1 protein was also induced during Zta expression. As the regulator of EBV lytic cycle, Zta also affects the cellular gene expression at transcriptional level either by directly binding to a consensus DNA sequence or indirectly activating cellular signaling pathways. According to the reporter assays, Zta could activate Egr-1 promoter. By analysis of the deletion mutants of Egr-1 promoter, two regions relative to the transcriptional start site, -503bp~-438bp and –438bp~-395bp, were proven to critical for Zta-mediated activation. These two promoter regions contained putative ZREs (Zta response elements) and Elk-1/SRF binding site, respectively. The Elk-1/SRF binding site was crucial for Egr-1 gene expression upon Ras/Raf/Mek/Erk/Elk signaling pathway triggered by serum and many growth factors. Interestingly, Zta could dramatically increase the phosphorylattion status of Erk-1 protein in our study. In the presence of Erk phosphorylation inhibitos, PD98059 and U0126, Zta-induced Egr-1 protein expression was decreased significantly. Taken together, we demonstrate that the EBV lytic transactivator Zta can induce the expression of cellular Egr-1 gene, and the mechanism is dependent on direct DNA binding and indirect Erk signal activation. The biological meanings of Zta-induced Egr-1 protein remain be investigated in future study.
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Po-HsiuChien and 簡伯修. "Role of early growth response-1 (Egr-1) in insulin production and secretion in pancreatic islets." Thesis, 2012. http://ndltd.ncl.edu.tw/handle/19125109088987903937.
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碩士國立成功大學
生理學研究所
100
Early growth response-1 (Egr-1) is a zinc-finger transcription factor inducibly expressed in response to many stimuli. Egr-1 has been implicated in the regulation of cell differentiation, proliferation and apoptosis. The physiological role of Egr-1 is to response environmental challenges such as nutrient or insulin resistance. The expression of Egr-1 is highly enriched in the pancreatic islet. In addition, Egr-1 indirectly regulates the insulin promoter to converge on glucose-responsive enhancer sequences. Therefore, we hypothesized that lacking of Egr-1 results in glucose intolerance and islet dysfunction. First, we found that glucose levels were not different between regular chow (RC)-fed Egr-1 knockout (Egr1-/-) mice and wild-type (WT) mice. However, Egr1-/- mice cleared glucose less effectively than WT mice when both of them were fed a high-fat (HF) diet. Examination of the ability of pancreas to secret insulin after glucose stimulation found decreased insulin secretion in HF-Egr1-/- mice compared to HF-WT mice. Pancreatic islet morphometry showed that mean islet area, endocrine mass and number of islets were decreased in HF-Egr1-/- mice. Moreover, HF-Egr1-/- mice produced less insulin than HF-WT mice in the pancreatic islet. These data suggest that the deficiency of Egr-1 influences insulin production and secretion in pancreatic islets. The gene expression profiles involved in glucose sensing, pancreas development and islet differentiation were attenuated by Egr-1 deficiency in the condition of excess nutrient. We also detected reduced level of proliferation marker Ki67 in HF-Egr1-/- mice. These data suggest that the decreased proliferation protein level may be responsible for the reduced islet number, area and endocrine mass in HF-Egr1-/- mice. In conclusion, our data show that Egr-1 contributes to the glucose homeostasis and function of pancreatic islets especially in the condition with increased insulin demand.
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Youreva, Viktoria. "Early growth response protein 1 (Egr-1) expression by Insulin-like growth factor 1 (IGF-1) involves MAPKs and PKB pathways." Thèse, 2014. http://hdl.handle.net/1866/12771.
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Un remodelage vasculaire anormal est à la base de la pathogenèse des maladies
cardio-vasculaires (MCV) telles que l’athérosclérose et l’hypertension. Des
dysfonctionnements au niveau de la migration, l’hypertrophie et la prolifération des
cellules musculaires lisses vasculaires (CMLV) sont des évènements cellulaires qui
jouent un rôle primordial dans le remodelage vasculaire. L’insulin-like growth factor 1
(IGF-1), puissant facteur mitogène, contribue au développement des MCV, notamment
via l’activation des protéines MAPK et PI3-K/PKB, composantes clés impliquées dans
les voies de croissance cellulaire. Ces molécules sont également impliquées dans la
modulation de l’expression de nombreux facteurs de transcription, incluant le facteur
Egr-1. Egr-1 est régulé à la hausse dans différents types de maladies vasculaires
impliquant les voies de signalisation de croissance et de stress oxydant qui par ailleurs
peuvent être déclenchées par l’IGF-1. Cependant, la question d’une possible modulation
de l’expression d’Egr-1 dans les CMLV demeure inabordée; plus spécifiquement, la
caractérisation de la voie de signalisation reliant l’action d’IGF-1 à l’expression d’Egr-1
reste à établir. Dans cette optique, l’objectif de cette étude a été d’examiner l’implication
de MAPK, PKB et des dérivés réactifs de l’oxygène (DRO) dans l’expression d’Egr-1
induite par l’IGF-1 dans les CMLV. L’IGF-1 a induit une augmentation marquée du
niveau protéique de l’Egr-1 en fonction du temps et de la concentration utilisés. Cette
augmentation a été inhibée en fonction des doses d’agents pharmacologiques qui ciblent
les voies de signalisation de MAPK, PKB et DRO. De plus, l’expression du facteur de
transcription, Egr-1, en réponse de l’IGF-1, a été atténuée suite à un blocage
pharmacologique des processus cellulaires responsables de la synthèse d’ARN et de
synthèse protéique. Pour conclure, on a démontré que l’IGF-1 stimule l’expression
d’Egr-1 via les voies de signalisation, impliquant ERK1/2/JNK, PI3K/PKB. On a
également proposé que les DRO jouent un rôle important dans ce processus. Dans
l’ensemble, nous avons suggéré un nouveau mécanisme par lequel l’IGF-1 promeut la
prolifération et l’hypertrophie cellulaire, processus à la base des anomalies vasculaires.Aberrant vascular remodelling underlies the pathogenesis of major cardiovascular diseases (CVD), such as atherosclerosis and hypertension. Abnormal growth, migration and proliferation of vascular smooth muscle cells (VSMC) are believed to play a critical role in vascular remodelling. IGF-1, potent mitogen, is believed to contribute to the development of CVD through the hyperactivation of proliferative and growth promoting pathways including mitogen-activated protein kinase (MAPK) and protein kinase B (PKB) pathways. It has also been implicated in modulating the expression of multiple transcription factors, including the early growth response protein-1 (Egr-1). Egr-1 upregulation has been observed in different models of vascular diseases implicating growth and redox signalling such as observed in response to IGF-1. However, modulation of Egr-1 expression by IGF-1 in VSMC, more specifically the signaling pathways involved in this process remain poorly characterized. Therefore, in the present studies, we investigated the implication of MAPK, PKB and ROS in IGF-1-induce Egr-1 expression in VSMC. IGF-1 induced a marked increase in Egr-1 protein level in a time and dose-dependent fashion. This increase was dose dependently inhibited by different pharmacological inhibitors targeting MAPK, PKB and reactive oxygen species (ROS) generation. Furthermore, pharmacological inhibitors of RNA and protein synthesis also attenuated IGF-1-induce response on Egr-1 expression. In conclusion, we showed that IGF-1 stimulates the expression of Egr-1 through ERK1/2/JNK and PI3K/PKB. We also propose that ROS generation plays an important role in this response. Overall, we propose a novel mechanism through which IGF-1 may exert its deleterious responses in vascular abnormalities.
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Čermák, Vladimír. "Regulace transkripce proteiny rodin Early growth response a Myb." Doctoral thesis, 2013. http://www.nusl.cz/ntk/nusl-328727.
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The regulation of transcription of tens of thousands of genes in a vertebrate organism is an enormously complex phenomenon which entails the participation of thousands of various regulatory proteins. The largest functional category of these regulators is accounted for by sequence-specific DNA-binding proteins known as transcription factors. Proteins of the EGR and Myb families of transcription factors are long-studied regulators of a variety of physiological processes including cellular proliferation and differentiation. The structural and physical aspects of their function have been well characterized. Their cell-type specific participation in complex gene-regulatory networks, on the other hand, is still incompletely understood and represents a major challenge in the respective research areas. Preliminary analysis of gene expression data from metastasizing PR9692 and non- metastasizing PR9692-E9 chicken sarcoma cell lines revealed that the transcription factor EGR1 is expressed at a higher level in metastasizing cells and can thus take part in the regulatory processes that underlie the differences between the two cell lines. Further investigation demonstrated that the introduction of exogenous EGR1 into PR9692-E9 cells restored their metastatic potential to a level indistinguishable from PR9692...
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Simo, Cheyou Estelle Rolande. "Regulation of the Early Growth Response Protein-1 in vascular smooth muscle cells." Thèse, 2016. http://hdl.handle.net/1866/19027.
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Une hyperactivation de la prolifération des cellules musculaires lisses vasculaires (CMLV) contribue à la pathogenèse des maladies des vaisseaux. Des travaux antérieurs suggèrent que l’augmentation de l'adénosine monophosphate cyclique (AMPc) inhibe la prolifération des CMLV. Provoquer une augmentation d’AMPc préviendrait aussi certaines maladies vasculaires qui sont associées à des altérations dans sa signalisation impliquant l'activité de la protéine kinase A (PKA). Des études ont démontré la contribution du facteur de transcription « early growth response protein-1» (Egr-1) dans la pathogenèse des maladies vasculaires et une surexpression d’Egr-1 a été rapportée dans des modèles d'athérosclérose et d'hyperplasie intimale. Divers agents vasoactifs contrôlent l'expression d’Egr-1 suivant des mécanismes qui ont fait l’objet de plusieurs études mais demeurent incomplètement élucidés. L'angiotensine-II (Ang-II) est l'un des principaux peptides vasoactifs impliqués dans la pathogenèse des maladies vasculaires. Une des voies de signalisation induite par l’Ang-II implique l’augmentation du calcium (Ca2+) intracellulaire. Celle-ci se produit par l’activation de l'entrée de calcium opérée par la relâche des réserves (SOCE) de Ca2+ réticulaire suite à l’activation du récepteur à l’inositol-3-phosphate (IP3R) et le recrutement ultérieur du complexe conducteur formé par la molécule d'interaction stromale 1 (STIM-1) et le canal Orai-1. Bien qu’il ait déjà été démontré que l’expression de l'Egr-1 est régulée par la signalisation calcique en réponse à plusieurs stimuli, l'implication du complexe STIM-1/Orai-1 dans l'expression d'Egr-1 dans la CMLV n’a jamais été étudiée. De même, la question de savoir si la signalisation induite par l'Ang-II conduisant à l'expression d'Egr-1 est modulée par l'AMPc n’a jamais été explorée. Par conséquent, les travaux menés dans cette thèse ont consisté à examiner le rôle de la signalisation du Ca2+ dans l'expression d'Egr-1 induite par l’Ang-II dans la CMLV avec une attention particulière portée sur le rôle joué par STIM-1 et Orai-1. En outre, nous avons examiné l'effet de l’augmentation de l’AMPc sur l'expression d'Egr-1 induite par l’Ang-II et étudié les voies de signalisation associées. Nos données montrent que l’inhibition du récepteur IP3R et du SOCE par le 2-aminoéthoxydiphénylborate atténue la libération de Ca2+ induite par l’Ang-II et ceci s’accompagne d’une baisse des niveaux d’expression de protéine et d’ARN messager de l’Egr-1. La stimulation de l’expression de l'Egr-1 a également été supprimée à la suite du blocage de la calmoduline et de la protéine kinase CaMKII. De plus, le blocage par interférence d’ARN de l’expression de STIM-1 et Orai-1 a atténué l'expression d'Egr-1 induite par l’Ang-II ainsi que la phosphorylation des protéines ERK et CREB. Par ailleurs, l'isoproterenol (ISO) et la forskoline (FSK), deux activateurs de l'adénylate cyclase ont atténué de manière dose-dépendante l'expression d'Egr-1 induite par l’Ang-II. Des réponses similaires ont été observées en utilisant des analogues non spécifique (dibutyryl-cAMP) et PKA-spécifique (Benzoyl-cAMP) de l’AMPc, ainsi qu'un inhibiteur à large spectre de l'activité phosphodiesterase intracellualaire (isobutylméthylxanthine). L'inhibition de l'expression d'Egr-1 induite par l’Ang-II s’accompagne d'une augmentation de l’activité de la PKA mesurée par la phosphorylation de la « phosphoprotéine activée par les vasodilatateurs (VASP) », et d’une diminution concomitante de la phosphorylation de la protéine ERK. Le blocage pharmacologique de la PKA a réduit la phosphorylation de VASP et restauré la phosphorylation de la protéine ERK ainsi que l'expression d'Egr-1 en présence de l’Ang-II.
En résumé, nos données démontrent que la voie STIM-1/Orai-1 /Ca2+ médie l'expression de l'Egr-1 induite par l'Ang-II dans la CMLV et suggèrent que la suppression de la réponse à l’Ang-II menant à l’expression de l'Egr-1 peut expliquer les effets vasoprotecteurs de l’AMPc. En outre, ces travaux montrent que les mécanismes moléculaires de régulation de l’expression d’Egr-1 en réponse aux signaux externes culminent vers la modulation des cascades de signalisation en aval de la protéine ERK dans les CMLV.Aberrant vascular smooth muscle cell (VSMC) proliferative responses contribute to the development of neointimal lesions. Cyclic adenosine monophosphate (cAMP) is believed to inhibit VSMC proliferation, and vascular diseases are associated with impairments in cAMP-induced signalling responses involving protein kinase A (PKA) signaling. An enhanced expression of the early growth response protein-1 (Egr-1), a zinc finger transcription factor, has been reported in models of vascular diseases and, a crucial role of Egr-1 in regulating the expression of genes implicated in neointimal formation leading to atherogenesis has been suggested. Various vasoactive factors have been shown to modulate Egr-1 expression in VSMC via mechanisms which remain to be completely understood. Angiotensin-II (Ang-II) is one of the key vasoactive peptides implicated in the pathogenesis of vascular diseases. Ang-II elevates intracellular calcium (Ca2+) through activation of voltage-gated calcium channels as well as store-operated calcium channels. The store-operated calcium entry (SOCE) involves an inositol-3-phosphate receptor (IP3R)-coupled depletion of endoplasmic reticular Ca2+ and a subsequent activation of the stromal interaction molecule 1 (STIM-1) /Orai-1 complex. Although Egr-1 has been demonstrated to be upregulated in a Ca2+-dependent fashion in response to several stimuli, the involvement of STIM-1/Orai-1-dependent signaling in Egr-1 expression in VSMC has never been addressed. Besides, whether Ang-II-induced signaling leading to Egr-1 expression is modulated by cAMP-dependent signaling pathway remains unexplored. Therefore, in the present studies, we have examined the role of Ca2+ signaling in Ang-II-induced Egr-1 expression in VSMC and investigated the contribution of STIM-1 or Orai-1. Additionnaly, we have examined the effect of cAMP on Ang-II-induced expression of Egr-1 and have investigated the associated signalling pathways. Pharmacological blockade of IP3R and SOCE by 2-aminoethoxydiphenylborate (2-APB) decreased Ang-II-induced Ca2+ release and attenuated Ang-II-induced enhanced expression of Egr-1 protein and mRNA levels. Egr-1 upregulation was also suppressed following blockade of calmodulin and CaMKII. Furthermore, RNA interference-mediated depletion of STIM-1 or Orai-1 attenuated Ang-II-induced Egr-1 expression, as well as Ang-II-induced phosphorylation of ERK1/2 and CREB. Moreover, isoproterenol (ISO) and forskolin (FSK), two respective receptor and non-receptor activators of adenylate cyclase, attenuated Ang-II-induced Egr-1 expression in a dose-dependent fashion. Similar responses were observed using non-specific (dibutyryl-cAMP) and PKA-specific (Benzoyl-cAMP) analogs of cAMP, as well as a broad spectrum inhibitor of intracellular phosphodiesterase activity (isobutylmethylxanthine). The inhibition of Ang-II-induced Egr-1 expression was accompanied by an increase in serine 157 phosphorylation of the vasodilator-activated phosphoprotein (VASP), a marker of PKA activity, and this was associated with a concomitant decrease in ERK phosphorylation. Pharmacological blockade of PKA using H89 decreased VASP phosphorylation, restored Ang-II-induced ERK phosphorylation and abolished ISO- and FSK-mediated inhibition of Ang-II-induced Egr-1 expression. In summary, our data demonstrate that STIM-1/Orai-1/Ca2+-dependent signaling pathways mediate Ang-II-induced Egr-1 expression in A-10 VSMC and suggest that PKA-mediated suppression of Ang-II-induced Egr-1 expression and phosphorylation of ERK may be among the mechanisms by which cAMP exerts its vasoprotective effects. In addition, our data supports the notion that stimuli-induced regulation of Egr-1 expression involves the participation of signaling cascades downstream of ERK in VSMC.
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Hao-MinChen and 陳浩民. "The role of early growth response-1 (Egr-1) in the pathogenesis of dextran sulfate-induced inflammatory bowel disease." Thesis, 2013. http://ndltd.ncl.edu.tw/handle/47534643349600702284.
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碩士國立成功大學
生物化學暨分子生物學研究所
101
Inflammatory bowel disease (IBD) is a group of inflammatory conditions of the colon and small intestine. Two major types of the disease are Crohn's disease and ulcerative colitis. People who suffer from long-term IBD are at a high risk for colorectal cancer. Early growth response-1 (Egr-1) is a nuclear protein and functions as a transcriptional regulator. It has been known that Egr-1 regulates the expression of many genes and is involved in cell growth, proliferation, and differentiation. Previous studies have shown that IBD is associated with severe inflammation. However, its exact mechanisms of disease pathogenesis remain unclear. The aim of this study way to investigate the role of Egr-1 in the pathogenesis of IBD. First, using immunoblot analysis and immunohistochemical staining, we found high levels of Egr-1 expression in the dextran sulfate sodium (DSS)-induced colitis mouse model. After chronic treatment with DSS, Egr-1 knockout mice were resistant to the development of IBD. Furthermore, enzyme-linked immunosorbent assay (ELISA) and zymographic analysis revealed that the expression levels of pro-inflammatory cytokines IL-1β, IL-6 and TNF-α as well as matrix metalloproteinases (MMPs) decreased. Putative Egr-1 binding sites are present within the MMP12 promoter region. Through reporter assay and chromatin immunoprecipitation (ChIP) analysis, we demonstrated that Egr1 binds to MMP12 promoter and regulates the expression of MMP12. Based on the above data, I proposed that Egr-1 can participate in the process of inflammation and regulate other inflammation-related factors in IBD.
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"Regulation of the Serotonin 2a Receptor Encoding Gene Htr2a by Early Growth Response Gene 3 (Egr3)." Doctoral diss., 2017. http://hdl.handle.net/2286/R.I.45478.
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abstract: Schizophrenia is considered a multifactorial disorder with complex genetic variants in response to environmental stimuli. However, the specific genetic contribution to schizophrenia risk is largely unknown. The transcription factor early growth response gene 3 (EGR3) can be activated rapidly after stimuli and thus may translate environmental stimuli into gene changes that influence schizophrenia risk. However, the downstream genes that may be regulated by EGR3 are not clear. While the 5-Hydroxytryptamine receptor 2A (5HT2AR) - encoding gene Htr2a has been implicated in the etiology of schizophrenia, the mechanisms by which Htr2a influences susceptibility to this illness are poorly understood. We previously found that in addition to schizophrenia-like abnormalities, Egr3 -/- mice have approximately 70% deduction of 5HT2AR level in the prefrontal cortex, which underlines their resistant to the sedating effect of clozapine. These findings indicate that the two schizophrenia candidate genes are in the same biological pathway that integrates multiple components resulting in schizophrenia. This dissertation is aimed to identify the mechanisms by which Egr3 regulates the expression of Htr2a in response to environmental stimuli like stress.
To determine if Egr3 alters Htr2a transcription under stress, I examined messenger ribonucleic acid (mRNA) levels of these two genes in wildtype (WT) and Egr3 -/- mice after 6hrs of sleep deprivation (SD). I found both genes are increased in WT mice after SD compared with controls. In addition, Egr3 is required for Htr2a induction because SD fails to induce Htr2a expression in Egr3 -/- mice. Next, I performed chromatin immunoprecipitation (ChIP) to determine if EGR3 binds to Htr2a promoter in vivo. I found a significant increase of EGR3 binding to Htr2a distal promoter 2hrs after seizure. To determine the functionality of this binding, I co-transfected the CMV- EGR3 vector or CMV- vector alone with the Htr2a distal promoter reporter clone. I found overexpression of EGR3 activates the Htr2a distal promoter-driven luciferase gene. Although the ChIP assay shows no direct binding of EGR3 to Htr2a proximal promoter, I found EGR3 overexpression activates Htr2a proximal promoter-driven luciferase gene. These findings suggest that EGR3 regulates Htr2a probably through both direct and indirect ways.Dissertation/Thesis
Doctoral Dissertation Neuroscience 2017
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Nafez, Solmaz. "Early Growth Response 2 (Egr2) Induction by Neuronal Activity-dependent Nuclear Factor Kappa B (NF-κB) Activation." 2010. http://hdl.handle.net/1993/4191.
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Nuclear factor kappa B (NF-κB) mediated signalling is complex and plays a critical role in many biological processes. Investigators have reported that NF-κB is activated during the induction of long term potentiation (LTP), a proposed mechanism for memory encoding, and may be a requirement for synaptic plasticity and memory. In this study, mRNA extracted from hippocampal slices of NF-kB p50 knockout mice and its littermate before and after induction of LTP was analyzed using DNA microarray analysis (Affy-metrix GeneChip® Mouse Genome 430 2.0) to explore candidate target genes of NF-kB in LTP. The early growth response 2 (Egr-2) was identified as one putative NF-kB target gene.
Egr-2 mRNA and protein analysis of primary cortical neurons and HeLa cells chemically stimulated with Tumor Necrosis Factor α (TNFα) to activate the NF-kB sig-nalling pathway confirmed the microarray results. In addition, examination of the Egr-2 promoter sequence for NF-kB binding sites using chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift assays (EMSA) confirmed promoter occupancy and specificity of binding in vivo, respectively. These data suggest that Egr-2 expression level is controlled by direct transcriptional activity of the NF-kB transcription factor.
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"Environmental Stimuli Activates Early Growth Response 3 (EGR3), an Immediate Early Gene Residing at the Center of a Biological Pathway Associated with Risk for Schizophrenia." Doctoral diss., 2020. http://hdl.handle.net/2286/R.I.63032.
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abstract: Schizophrenia, a debilitating neuropsychiatric disorder, affects 1% of the population. This multifaceted disorder is comprised of positive (hallucinations/psychosis), negative (social withdrawal/anhedonia) and cognitive symptoms. While treatments for schizophrenia have advanced over the past few years, high economic burdens are still conferred to society, totaling more than $34 billion in direct annual costs to the United States of America. Thus, a critical need exists to identify the factors that contribute towards the etiology of schizophrenia. This research aimed to determine the interactions between environmental factors and genetics in the etiology of schizophrenia. Specifically, this research shows that the immediate early gene, early growth response 3 (EGR3), which is upregulated in response to neuronal activity, resides at the center of a biological pathway to confer risk for schizophrenia. While schizophrenia-risk proteins including neuregulin 1 (NRG1) and N-methyl-D-aspartate receptors (NMDAR’s) have been identified upstream of EGR3, the downstream targets of EGR3 remain relatively unknown. This research demonstrates that early growth response 3 regulates the expression of the serotonin 2A-receptor (5HT2AR) in the frontal cortex following the physiologic stimulus, sleep deprivation. This effect is translated to the level of protein as 8 hours of sleep-deprivation results in the upregulation of 5HT2ARs, a target of antipsychotic medications. Additional downstream targets were identified following maximal upregulation of EGR3 through electroconvulsive stimulation (ECS). Both brain-derived neurotrophic factor (BDNF) and its epigenetic regulator, growth arrest DNA-damage-inducible 45 beta (GADD45B) are upregulated one-hour following ECS in the hippocampus and require the presence of EGR3. These proteins play important roles in both cellular proliferation and dendritic structural changes. Next, the effects of ECS on downstream neurobiological processes, hippocampal cellular proliferation and dendritic structural changes were examined. Following ECS, hippocampal cellular proliferationwas increased, and dendritic structural changes were observed in both wild-type and early growth response 3 knock-out (Egr3-/-) mice. Effects in the number of dendritic spines and dendritic complexity following ECS were not found to require EGR3. Collectively, these results demonstrate that neuronal activity leads to the regulation of schizophrenia risk proteins by EGR3 and point to a possible molecular mechanism contributing risk for schizophrenia.Dissertation/Thesis
Doctoral Dissertation Neuroscience 2020
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Guerrero, Netro Hilda Morayma. "Differential regulation of early response genes by fibroblast growth factor (FGF) 8 and FGF18 in bovine granulosa cells in vitro." Thèse, 2013. http://hdl.handle.net/1866/10583.
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Les « Facteurs de croissance des fibroblastes» (FGF) agissent comme des régulateurs locaux sur la qualité des follicules et sont connus pour promouvoir la prolifération des cellules de granulosa, réduire l’apoptose et la stéroïdogenèse. Parmi la sous-famille FGF8, FGF18 est une exception puisqu’il semblerait avoir une fonction pro-apoptotique alors que FGF8 n’a pas été jusqu’à présent rapporté comme altérant la viabilité des cellules de la granulosa. Ces deux ligands ont un mode d’activation similaire et il pourrait être proposé que toute la sous-famille FGF8 ait la même réponse. L’objectif de cette étude était de déterminer si FGF8 et FGF18 activaient la même réponse précoce de gènes dans des cultures de granulosa bovine. Pour répondre à cette question, nous avons cultivé des cellules de la granulosa dans du milieu de culture sans sérum pendant 5 jours. Le jour 5, les cellules ont été traitées avec FGF8 ou FGF18. Nous avons eu recours à une approche de « puce à ADN » afin d’identifier la réponse précoce de gènes induite par FGF8 et FGF18, et les données ont été confirmées par des PCRs en temps réel lors d’une expérience in vitro où les cellules de granulosa ont été traitées avec FGF8 et FGF18 pendant différents temps. L’analyse du puce à ADN a identifié 12 gènes surexprimés par FGF8, incluant SPRY2, NR4A1, XIRP1, BAMBI, EGR1, FOS et FOSL1. A l’inverse, FGF18 n’a régulé aucun gène de manière significative. Les analyses de PCR ont confirmé l’augmentation d’ARNm codant pour EGR1, EGR3, FOS, XIRP1, FOSL1, SPRY2, NR4A1 et BAMBI après 2 h de traitement. FGF18 a entrainé seulement une augmentation de l’expression de EGR1 après 2 h de traitement parmi tous les gènes testés. Ces résultats démontrent donc que FGF8 et FGF18, malgré leur similarité dans le mode d’activation de leurs récepteurs, agissent sur les cellules de la granulosa via différentes voies de signalisation. FGF8 et FGF18, sont donc tous les deux capables de stimuler l’expression de EGR1, mais les voies de signalisation induites par la suite divergent.Fibroblast growth factors (FGF) act as local regulators of follicular health and are known to increase granulosa cell (GC) proliferation, reduce apoptosis and decrease steroidogenesis. One exception is FGF18, which appears to be a pro apoptotic member of the FGF8-subfamily while FGF8 has not been reported to alter GC health. These two ligands have similar activation patterns and it could be proposed that all FGF8-subfamilies would have the same response. The objective of this study was to determine if FGF8 and FGF18 activate the same early response genes in cultured bovine GC. To address this we cultured GC in serum free medium for five days. On day 5, cells were challenged with FGF8 or FGF18. We used a microarray approach to identify early response genes altered by FGF8 and FGF18, and data were confirmed by real-time PCR in an independent time-course experiment. Microarray identified 12 genes up-regulated by FGF8, including SPRY2, NR4A1, XIRP1, BAMBI, EGR1, FOS and FOSL1. In contrast FGF18 did not result in significant regulation of any gene. PCR analysis confirmed the stimulation of abundance of mRNA encoding EGR1, EGR3, FOS, XIRP1, FOSL1, SPRY2, NR4A1 and BAMBI after 2 hours of challenge. FGF18 resulted in an increase of EGR1 mRNA abundance at 2 h, but not of the other genes tested. These results demonstrate that FGF8 and FGF18, despite reportedly similar receptor activation patterns, act on granulosa cells through different intracellular pathways. Both FGF8 and FGF18 stimulate EGR1 expression, but thereafter their signaling pathways diverge.
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Vollmann, Henning [Verfasser]. "Differentielle Expression des early growth response gene Egr1 und frühe Aktivierung der Mikroglia nach ionisierender Bestrahlung im zentralen Nervensystem der Ratte / vorgelegt von Henning Vollmann." 2007. http://d-nb.info/985141379/34.
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Wölfel, Sarah [Verfasser]. "Frühe transkriptionelle Veränderungen der mRNA-Varianten des Early-growth-response-Genes egr1 sowie des endothelialen Monozytenaktivierungspeptids emap nach ionisierender Bestrahlung im zentralen Nervensystem der Ratte / vorgelegt von Sarah Wölfel." 2007. http://d-nb.info/985421290/34.
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Kapakos, Georgia. "Modulation of Endothelin-1 and Insulin-like Growth Factor Type 1-induced Signaling by Curcumin in A-10 Vascular Smooth Muscle Cells." Thèse, 2011. http://hdl.handle.net/1866/6223.
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Les maladies cardio-vasculaires (MCV), telles que l’hypertension et l’athérosclérose, s’accompagnent de modifications structurales et fonctionnelles au niveau vasculaire. Un fonctionnement aberrant de la migration, l’hypertrophie et la prolifération des cellules musculaires lisses vasculaires (CMLV) sont des évènements cellulaires à l’origine de ces changements. L’endothéline-1 (ET-1) contribue à la pathogénèse des anomalies vasculaires, notamment via l’activation des protéines MAPK et PI3-K/PKB, des composantes clés impliquées dans les voies prolifératives et de croissance cellulaires. Il a été suggéré que le stress oxydant jouerait un rôle intermédiaire dans les effets pathophysiologiques vasculaires de l’ET-1. En conséquence, une modulation de la signalisation induite par l’ET-1 peut servir comme éventuelle stratégie thérapeutique contre le développement des MCV. Il apparaît de nos jours un regain d’intérêt dans l’utilisation des agents phyto-chimiques pour traiter plusieurs maladies. La curcumine, constituant essentiel de l’épice curcuma, est dotée de plusieurs propriétés biologiques parmi lesquelles des propriétés anti-oxydantes, anti-prolifératrices et cardio-protectrices. Cependant, les mécanismes moléculaires de son effet cardio-protecteur demeurent obscurs. Dans cette optique, l’objectif de cette étude a été d’examiner l’efficacité de la curcumine à inhiber la signalisation induite par l’ET-1 dans les CMLV. La curcumine a inhibé la phosphorylation des protéines IGF-1R, PKB, c-Raf et ERK1/2, induite par l’ET-1 et l’IGF-1. De plus, la curcumine a inhibé l’expression du facteur de transcription Egr-1 induite par l’ET-1 et l’IGF-1, dans les CMLV. Ces résultats suggèrent que la capacité de la curcumine à atténuer ces voies de signalisation serait un mécanisme d’action potentiel de ses effets protecteurs au niveau cardiovasculaire.Cardiovascular diseases (CVDs), including hypertension and atherosclerosis, are associated with vascular functional and structural changes. Some of the cellular events underlying these processes include aberrant vascular smooth muscle cell (VSMC) proliferation, hypertrophy and migration. Endothelin-1 (ET-1) has been implicated in the pathogenesis of vascular abnormalities through the hyperactivation of key components of growth promoting and proliferative signaling pathways, including MAPKs and PI3-K/PKB. Vascular oxidative stress has also been suggested to play an intermediary role in mediating ET-1-induced pathophysiological effects. Interference with ET-1-induced signaling may therefore serve as a potential therapeutic strategy against the progression of cardiovascular disorders. There is presently a surge of interest in the use of plant-derived phytochemicals for the treatment of various diseases. Curcumin, the main constituent of the spice turmeric, exhibits multiple biological properties, amongst them, antioxidant, anti-proliferative and cardioprotective properties. However, the molecular mechanisms of its cardiovascular protective action remain obscure. Therefore, in the present studies, we investigated the effectiveness of curcumin to inhibit ET-1-induced signaling events in VSMC. Curcumin inhibited ET-1-induced as well as IGF-1-induced phosphorylation of IGF-1R, PKB, c-Raf and ERK1/2, in VSMC. Furthermore, curcumin inhibited the expression of transcription factor early growth response-1 (Egr-1) induced by ET-1 and IGF-1, in VSMC. In summary, these results demonstrate that curcumin is a potent inhibitor of ET-1 and IGF-1-induced mitogenic and proliferative signaling events in VSMC, suggesting that the ability of curcumin to attenuate these effects may contribute as potential mechanism for its cardiovascular protective response.
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Mun-WaiCheong and 張文維. "Early growth response-1 protects pancreatic beta-cells from free fatty acid-induced apoptosis." Thesis, 2013. http://ndltd.ncl.edu.tw/handle/348fjf.
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碩士國立成功大學
生理學研究所
101
Early growth response-1 (Egr1), a zinc-finger DNA binding transcription factor, is induced by many environmental signals and is highly associated with cell differentiation, proliferation and apoptosis. In the pancreatic islet, Egr1 mediates responses of pancreatic beta cells to sustained glucose stimulation and regulates insulin production. Pancreatic beta cell plays a crucial role in glucose homeostasis and its failure is related to diabetes mellitus. Previously, our lab revealed that mean islet area and number decreased in high-fat-fed Egr1 knockout mice. Thus, we hypothesized that Egr1 is increased in response to FFA to attenuate FFA-induced apoptosis in pancreatic beta cells. In this study, we used MIN6 insulinoma cells and treated with palmitic acid (PA), the most abundant FFA in circulation. Our data revealed that Egr1 was induced within 2 hours by PA in MIN6 cells. Treatment of EGTA (calcium chelator) or nifepidine (L-type calcium channel inhibitor) blocked PA-induced Egr1 upregulation. Moreover, we found increased phosphorylation of ERK1/2 after treatment of PA, and PA-induced Egr1 upregulation was attenuated by ERK1/2 inhibitor. These results suggest that PA induces Egr1 expression through Ca2+ influx and ERK1/2 activation. Next, we found that Egr1-knockdown cells were more susceptible to PA-induced caspase 3 activation and increased the level of pro-apoptotic ER stress marker, CHOP. Furthermore, Akt phosphorylation in Egr1 knockdown cells was decreased, suggesting that the absence of Egr1 downregulates the PI3K/Akt survival pathway. Meanwhile, we found that Egr1 knockdown cells decreased insulin mRNA but did not affect insulin secretion under PA treatment. Finally, Egr1 knockdown impaired insulin signal transduction, and insulin supplementation rescued PA-induce apoptosis in Egr1 knockdown cells. In conclusion, our data showed that Egr1 is induced by PA and further attempts to rescue beta cells from PA-induced apoptosis through improving insulin signaling pathway. This study demonstrates other functions of Egr1 in pancreatic beta cells and provides a candidate to protect from beta cell failure.
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Jensen, Penny J. "Early growth response family of transcription factor members regulate the expression of synaptic genes." 1997. http://catalog.hathitrust.org/api/volumes/oclc/37841967.html.
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Mohtar, Omar. "Early growth response protein 1 mediates the effect of insulin on leptin transcription in adipocytes." Thesis, 2019. https://hdl.handle.net/2144/38533.
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All cells and organisms consume energy for survival. A robust system has evolved in vertebrates to serve as an energy reservoir. In particular, specialized cells, adipocytes, are responsible for the dynamic storage of energy by accumulating and releasing fatty acids. Fluctuating energy demands require adipose tissue to adjust in size, however complications can arise in both extremes giving rise to systemic diseases, such as obesity and diabetes mellitus (T2D).
In mammals, leptin production in adipocytes is up-regulated by feeding and insulin to provide long-term post-prandial satiety. Although this regulatory connection is central to all physiological effects of leptin, the molecular mechanism remains unknown for leptin production. Here, we show that the transcription factor Egr1 is rapidly but transiently induced by insulin in adipose cells both in vitro and in vivo in a mTORC1-dependent fashion. Induction of Egr1 was immediately followed by an increase in leptin transcription. Chromatin immunoprecipitation and luciferase assays demonstrate that Egr1 directly binds to and activates the leptin promoter. Interestingly, the lipid droplet protein Fat specific protein 27 (FSP27) may work as a co-factor for Egr1 in regulating leptin expression. By using siRNA-mediated knock out of Egr1 along with its over-expression in adipocytes, we demonstrate that Egr1 is both necessary and sufficient for the stimulatory effect of insulin on leptin transcription. Knockout of the mTORC1-regulated translation repressor 4EBP1/2 increases leptin transcription both in vitro and in vivo. Adipose specific doxycycline-inducible constitutively active Rheb transgenic mouse lines contained higher circulating leptin and transcription of leptin following doxycycline treatment and were able to maintain elevated leptin levels following a 16 hour fast. Thus, insulin and nutrients, such as amino acids and glucose, activate leptin expression via the mTORC1-Egr1 regulatory axis.
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Rondeau, Vincent. "Expression de l’early growth response protein-1 (Egr-1) par le peroxyde d’hydrogène (H2O2) nécessite l’activation de l’IGF-1R, de c-Src et de PKC dans les CMLV." Thèse, 2016. http://hdl.handle.net/1866/18882.
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Une augmentation de la génération des dérivés réactifs de l’oxygène (DRO), tels que le peroxyde d’hydrogène (H2O2), joue un rôle clé dans la pathophysiologie des maladies cardiovasculaires (MCV). La croissance et la prolifération excessives des cellules musculaires lisses vasculaires (CMLV) ont été suggérées comme étant les mécanismes à la base de la dysfonction vasculaire. Une implication potentielle du facteur de transcription Early growth response protein-1 (Egr-1) dans le développement des dommages vasculaires a été proposée. Des études ont démontré que le H2O2 augmente l’expression de l’Egr-1 dans les CMLV. Cependant, les voies de signalisation intracellulaire menant à l’expression de l’Egr-1 en réponse au H2O2 restent à établir. L’objectif de cette étude vise à examiner les différentes voies de signalisation impliquées dans l’expression de l’Egr-1 induite par le H2O2 dans les CMLV. Le H2O2 augmente l’expression de l’Egr-1 en fonction du temps et de la dose dans les CMLV A10. Le blocage pharmacologique des tyrosines kinases insulin-like growth factor-1 receptor (IGF-1R) et c-Src, par AG1024 et PP2 respectivement, atténue l’expression de l’Egr-1 induite par le H2O2, alors que l’AG1478, un inhibiteur de l’epidermal growth factor receptor (EGFR), et le PP3, l’analogue inactif du PP2, n’ont aucun effet sur l’expression de l’Egr-1. Le blocage pharmacologique de l’extracellular signal-regulated kinase 1/2 (ERK1/2), par UO126, et de la protéine kinase C (PKC), par rottlerin et rö-31-8220, diminue l’expression de l’Egr-1 induite par le H2O2. En résumé, nos résultats suggèrent que le H2O2 déclenche l’expression de l’Egr-1 via l’IGF-1R, la kinase c-Src, l’ERK1/2 et la PKC dans les CMLV.Increased generation of reactive oxygen species (ROS), such as hydrogen peroxide (H2O2), plays a key role in the pathophysiology of cardiovascular diseases (CVD). Excessive growth and proliferation of vascular smooth muscle cells (VSMCs) has been suggested as an important contributor of vascular dysfunction. A potential involvement of early growth response protein-1 (Egr-1), a zinc-finger transcription factor, in the development of vascular injury has been proposed. Recent studies have shown that H2O2 increases Egr-1 expression in VSMCs. However, signaling events leading to H2O2-induced Egr-1 expression are not fully understood. Therefore, this study aims to examine the signaling pathways implicated in H2O2-induced Egr-1 expression in VSMC. H2O2 increased Egr-1 expression in a time and dose-dependent fashion in A10 VSMC. Pharmacological blockade of tyrosine kinases insulin-like growth factor-1 receptor (IGF-1R) and c-Src, by AG1024 and PP2 respectively, attenuated H2O2-induced Egr-1 expression, while AG1478, an epidermal growth factor receptor (EGFR) inhibitor, and PP3, the inactive analogue of PP2, have no effect on Egr-1 expression. Pharmacological blockade of extracellular signal-regulated kinase 1/2 (ERK1/2), by UO126, and proteine kinase C (PKC), by rottlerin and rö-31-8220, decreased H2O2-induced Egr-1 expression. In summary, our results suggest that H2O2 triggers Egr-1 expression through IGF-1R, c-Src, ERK1/2 and PKC in VSMC.
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Li-ChunHo and 何立鈞. "Study for the roles of early growth response-1 and secondary hyperparathyroidism in chronic kidney disease." Thesis, 2017. http://ndltd.ncl.edu.tw/handle/dj96ma.
Full textAbstract:
博士國立成功大學
臨床醫學研究所
105
Chronic kidney disease (CKD) consisting of renal inflammation and fibrosis is associated with many cardiovascular risk factors, and secondary hyperparathyroidism (SHPT) is one of them. Early growth response-1 (Egr-1) protein is a zinc-finger transcription factor participating in tissue inflammation and fibrosis, but its role in CKD is not fully understood. My PhD research aimed to investigate the potential of Egr-1 and SHPT as therapeutic targets for the treatment of CKD and associated mortality risk. The kidney tissues from animals with tubulointerstitial nephritis and from humans with renal failure both showed increased expression and activation of Egr-1 in renal tubules. Egr-1 deficiency in mice attenuated renal failure via interfering with NF-κB-mediated renal inflammation and transforming growth factor-β-mediated renal fibrosis, but the effect of Egr-1 deficiency on inflammasome was minor. The ex vivo studies using primary cultures of proximal tubular epithelial cells (PTECs) also showed that Egr-1 deficiency suppressed NF-κB pathway and attenuated the responses of PTECs to pro-inflammatory and pro-fibrotic stimulations. These findings suggested the causative role of Egr-1 in renal failure. As for targeting SHPT for the treatment of CKD patients, I studied the association between parathyroidectomy (PTx) and long-term mortality risk in dialysis patients. Histories of receiving radionuclide parathyroid scan were used, for the first time, as a selection criterion to ensure the presence of SHPT in all enrolled cases of a nationwide cohort of dialysis patients. The patients undergoing PTx after scanning had a lower crude mortality rate than the matched patients not undergoing PTx. The analysis of multivariable Cox proportional hazard model showed that PTx was independently associated with a 20% to 25% reduction of all-cause mortality rate. These findings provide minimally biased evidence to support current guidelines that PTx should be recommended for CKD patients with unremitting SHPT. To sum up, my thesis suggested that Egr-1 may serve as a potential therapeutic target for CKD and showed that targeting SHPT with PTx is effective in reducing mortality risk of CKD patients. The study results added to the understanding of pathological relevance of Egr-1 and suggest implications for clinical therapy.
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Wong-Goodrich, Sarah Jeanne Evens. "Mechanisms by Which Early Nutrition Influences Spatial Memory, Adult Neurogenesis, and Response to Hippocampal Injury." Diss., 2010. http://hdl.handle.net/10161/2469.
Full textAbstract:
Altered dietary availability of the vital nutrient choline during early development leads to persistent changes in brain and behavior throughout adulthood. Prenatal choline supplementation during embryonic days (ED) 12-17 of the rodent gestation period enhances memory capacity and precision and hippocampal plasticity in adulthood, and protects against spatial learning and memory deficits shortly after excitotoxic seizures, whereas prenatal choline deficiency can compromise hippocampal memory and plasticity in adulthood. Recent evidence from our laboratory has determined that lifelong proliferation of newborn neurons in the adult hippocampus, a feature of adult hippocampal plasticity that has been implicated in some aspects of learning and memory, is modulated by early choline availability. Prenatal choline's effects on adult neurogenesis may be one mechanism for diet-induced cognitive changes throughout life and in response to injury, although little is known about the mechanisms underlying how prenatal choline alters adult neurogenesis or the neural mechanisms underlying prenatal choline supplementation's protection against cognitive deficits after seizures. To address these issues, the present set of experiments investigated how prenatal choline availability modulates specific properties of neurogenesis in the adult brain (in the intact brain and in response to injury), as well as hippocampal markers known to change in response to excitotoxin-induced seizures, and sought to relate changes in neurogenesis and in neuropathological markers following injury to changes in performance on spatial learning and memory tasks. Subjects in each experiment were adult offspring from rat dams that received either a control diet or diet supplemented with choline chloride or deficient of choline on ED 12-17. To measure neurogenesis, rats were given injections of the mitotic marker bromodeoxyurdine to label dividing cells in the hippocampus. Prenatal choline supplementation enhanced several properties of basal adult hippocampal neurogenesis (cell division and survival, neural stem/progenitor cell phenotype and proliferative capacity, trophic support), and this increase was associated with improvements in spatial working memory retention in a delayed-matching-to-place water maze task. In contrast, prenatal choline deficiency had little effect on basal adult hippocampal neurogenesis, and no effect on spatial memory performance. Prenatal choline supplementation also enhanced olfactory bulb neurogenesis without altering cell proliferation in the subventricular zone, while prenatal choline deficiency had no effect on either measure, showing for the first time that prenatal choline's effects on adult neurogenesis is similarly expressed in another distinct neurogenic region of the adult brain. Altered prenatal choline availability also modulated the hippocampal response to kainic acid-induced seizures where supplementation attenuated while deficiency had no effect on the injury-induced proliferative response of the dentate gyrus shortly after injury. Prenatal choline supplementation also attenuated other markers of hippocampal neuropathology shortly after seizures and promoted the long-term hippocampal recovery from seizures months after injury, including rescuing declines in adult hippocampal neurogenesis and in spatial memory performance in a standard water maze task. Taken together, these findings demonstrate a robust neuroprotective effect of prenatal choline supplementation that may be driven by enhanced adult hippocampal plasticity and trophic support prior to injury, and shed light on the mechanisms underlying how prenatal choline availability alters adult hippocampal neurogenesis, which may contribute to changes in memory capacity and precision both throughout life and following neural assault.
Dissertation