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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
111

Molecular Mechanisms Governing Persistent Induction of Pro-Inflammatory Genes by Lipopolysaccharide

Glaros, Trevor Griffiths 17 August 2011 (has links)
Low dose endotoxemia is caused by several health conditions including smoking, alcohol abuse, high fat diets, and aging. Several studies have correlated low dose endotoxemia with increased risks of atherosclerosis, diabetes, and Parkinson's disease. Unlike high doses of endotoxin which induce a strong but transient induction of pro-inflammatory mediators, low doses of endotoxin result in a mild but chronic induction of pro-inflammatory genes. The central hypothesis of our study was that if low doses of endotoxin are capable of inducing mild prolonged inflammation, then a unique signaling circuit must be utilized. In the first study, the molecular mechanisms for the persistent induction of lipocalin 2 (LCN2) in response to 100 ng/mL of lipopolysaccharide (LPS) in kidney fibroblasts was examined. It appears that the intracellular signaling network responsible for the persistent induction of LCN2 requires both activator protein-1 (AP-1) and CCAAT/enhancer binding protein delta (C/ebpδ). Interleukin-1 receptor-associated kinase 1 (IRAK-1) is critical for LCN2 expression. In the second study, the molecular mechanisms governing the persistent induction of interleukin 6 (IL-6) upon a 50 pg/mL challenge of LPS in macrophages was examined. At this dose, only the persistent activation of cJun N-terminal kinase (JNK) and C/ebpδ was observed. IL-6 transcription requires the transient recruitment of activating transcription factor 2 (ATF2) and the persistent recruitment of C/ebpδ to the IL-6 promoter. In the third study, the molecular mechanisms that mediate LPS-induced priming was examined. The results demonstrate that macrophages are able to sense their prior history of exposure to LPS that result in either a priming or tolerance phenotype upon a secondary challenge of LPS. Results suggest that this sensing mechanism involves cross-talk between IRAK-1 and phosphoinositide-3-kinase (PI3K). Collectively, these studies indicate that JNK and C/ebpδ are the primary players responsible for the persistent expression of pro-inflammatory genes during low dose endotoxemia. IRAK-1 is a key intracellular signaling kinase that mediates signaling at low doses of LPS. IRAK-1 is not only critical for low dose induced expression, but also for LPS-induced priming. This research has revealed a novel signaling pathway that could provide new molecular targets for drug development against chronic inflammatory diseases. / Ph. D.
112

Role of irritation and mast cell mediators on thymic stromal lymphopoietin (TSLP) expression in the skin and its impact on severity of atopic dermatitis

Redhu, Davender 11 May 2020 (has links)
Die Haut ist das größte Organ des Menschen und stellt die primäre Barriere gegen Umwelteinflüsse und Pathogene dar. Eine Dysbalance der Hautbarriere birgt die Gefahr einer nachfolgenden Entzündungsreaktion. Bleibt diese bestehen, können sich Hautkrankheiten wie zum Beispiel die atopische Dermatitis (AD) entwickeln. Verschiedene Zytokine wie Thymic Stromal Lymphopoietin (TSLP) werden bei entzündlichen Hauterkrankungen eine bedeutende Rolle zugeschrieben. Die Bedeutung von TSLP wurde zunächst anhand mehrerer Knockout-Mausstämme untersucht. Hier zeigte sich, dass TSLPR-KO und TNF-TSLPR-DKO Mäuse im Gegensatz zu TNF-KO Mäusen keine bzw. weniger Zeichen einer Entzündungsreaktion in der Haut entwickeln. Die Rolle äußerer Einflüsse auf die TSLP-Produktion wurde anhand eines Irritationsmodells ebenfalls in Mäusen untersucht. Dabei führte die Hautirritation, ausgelöst durch Abtragen der oberen Hautschichten mittels eines Tesa-Abriss, zu einem signifikanten Anstieg von TSLP in der Haut?. Mit Hilfe von Agonisten und Inhibitoren konnte gezeigt werden, dass dieser Irritations-vermittelte TSLP-Anstieg über Interleukin-1 (IL-1) und Protease Activated Receptor 2 (PAR-2) vermittelt wird. In diesem Zusammenhang wurde auch gezeigt, dass die Aktivierung von IL-1- sowie PAR-2-abhängigen Signalwegen zu einer gesteigerten Aktivität des TSLP-Promotors führte. Die Untersuchung der Wirkung verschiedener Mastzellmediatoren auf die TSLP-Expression ergab, dass Tryptase, über die Aktivierung von PAR-2, der wichtigste Mediator für den Anstieg von TSLP nach der Degranulation von Mastzellen ist. Dieses Ergebnis wurde mittels verschiedener in vitro, in vivo und ex vivo Experimentalansätze belegt. So konnte in einem c48/80-abhängigen Degranulationsmodell in Mäusen gezeigt werden, dss PAR-2- sowie Mastzell-KO Mäuse im Vergleich zu Wildtypen nach Injektion von c48/80 signifikant weniger TSLP exprimierten. / The skin is the first line of defense against environmental or microbial pathogens. A deviation of the skin barrier homeostasis by any kind of insult can result in an inflammatory response. The inflammatory response in turn can promote the development of an eczemaincluding atopic eczema. Thymic stromal lymphopoietin (TSLP) due to its pleiotropic nature play an important role in inflammatory disorders. The major aim of this thesis was to better understand the underlying mechanisms of TSLP production in the context of skin irritation and mast cell (MC) mediators and their contribution in the development of atopic dermatitis (AD). The role of TSLP was studied using TSLPR-/- mice. The data show that TSLPR-/- and TNF-/-/TSLPR-/- mice were protected from AD development, by contrast TNF-/- mice exhibited severe AD. The role of exogenous triggers was studied using tape stripping mediated skin irritation mouse models. Skin irritation resulted in significant enhanced TSLP production. TSLP induction was identified to depend on interleukin (IL)-1 and protease activated receptor (PAR)-2 pathways proven by using exogenous activators or inhibitors of these pathways. Moreover, PAR-2 and IL-1 concomitantly promoted NF-κB binding to the human TSLP promoter which in turn resulted in an increased TSLP promoter activity. Additionally, the role of mast cell mediators in the context of TSLP induction was investigated. Tryptase turned out to be the trigger responsible for the enhanced TSLP response by activating the PAR-2 pathway. This finding was proven by employing in vitro, ex vivo and in vivo approaches. In detail PAR-2-/- and MC-/- mice were used in a compound 48/80 (C48/80) dependent MCs degranulation model. PAR-2-/- and MC-/- mice produced significantly less TSLP in comparison to control mice.
113

Pathways to Shortened Gestation among African American Women

Gillespie, Shannon L. January 2015 (has links)
No description available.
114

Développement de modulateurs allostériques peptidiques inhibiteurs de l’activité des récepteurs de l’interleukine 1 et de la vasopressine

Quiniou, Christiane 06 1900 (has links)
L’approche Module X a été créée dans le but de concevoir de petits peptides modulateurs ayant des propriétés allostériques. Module X reproduit de petites parties des portions extracellulaires flexibles des récepteurs. Ces petits peptides vont interagir en s’interposant entre deux sous unités ou entre deux régions de la même sous-unité qui interagissent par des liens hydrogènes, des ponts salins ou des liens disulfure. Ces régions sont spécialement choisies à l’extérieur du domaine de liaison du ligand orthostérique et sont situées dans les régions inter domaines, la portion juxta membranaire ou dans les boucles. Étant donné que les boucles sont exposées durant les changements de conformation, une séquence peptidique reproduisant certaines régions de ces boucles pourrait s’insérer à un endroit approprié dans la structure où se lier à son partenaire de signalisation dans le complexe protéique, ce qui aurait comme effet de déplacer l’équilibre de l’ensemble vers un état particulier et modulerait ainsi la signalisation. De cette façon, certaines voies de signalisation pourraient être partiellement inhibées tandis que d’autres voies ne seraient pas touchées puisque le ligand orthostérique pourrait toujours se lier au récepteur. Dans une première étude, nous avons conçu des peptides inhibiteurs du récepteur de l’interleukine 1 (IL-1R/IL-1RAcP) plus précisément en reproduisant des régions flexibles de la protéine accessoire, sous-unité signalisatrice du récepteur. IL-1 est un médiateur majeur de l’inflammation, mais le seul antagoniste disponible est l’analogue naturel de IL-1, IL-1Ra qui compétitionne avec IL-1 pour le site de liaison sur le récepteur. Nous avons conçu plusieurs peptides à partir des boucles de la protéine accessoire. Un de ces peptides, rytvela (101.10) a démontré des propriétés de non-compétitivité et de sélectivité fonctionnelle caractéristiques des modulateurs allostériques. 101.10 bloque la prolifération des thymocytes et la synthèse de PGE2 avec un IC50 de 1 nM mais une efficacité de 100 % et 45 % respectivement et ne déplace pas IL-1 radioactif dans des essais de radioliaisons. De plus, 101.10 n’a qu’un effet minime sur l’affinité de IL-1 pour son récepteur. 101.10 démontre, de plus, une activité inhibitrice in vivo dans des modèles d’inflammation de l’intestin chez le rat (efficacité supérieure aux corticostéroïdes et à IL-1Ra) et de dermatite chez la souris de même que dans un modèle d’hyperthermie induite par IL-1. La deuxième étude démontre que Module X peut être utilisé pour concevoir des inhibiteurs pour une autre grande famille de récepteurs : les récepteurs couplés aux protéines G. La vasopressine joue un rôle important dans l’équilibre hydro-osmotique et un moindre rôle dans la vasomotricité. Six peptides ont été conçus à partir de régions juxta membranaires du récepteur de la vasopressine V2R. Le peptide le plus actif, VRQ397 (IC50 = 0,69 nM dans un modèle de vasorelaxation du crémastère), a démontré de la sélectivité fonctionnelle en inhibant la synthèse de prostacycline mais sans inhiber l’activation de la protéine Gs et la génération d’ AMP cyclique. Le peptide VRQ397 ne pouvait déplacer le ligand naturel AVP marqué radioactivement; de même VRQ397 radioactif ne se liait que sur V2R et non pas sur d’autres récepteurs de la même famille tel que V1R (récepteur de la vasopressine de type I). Ces études décrivent la caractérisation de petits peptides modulateurs de la signalisation de IL-1R et V2R et présentant des propriétés de modulateurs allostériques. / The Module X approach was conceived to generate small allosteric peptides that do not (by definition) compete with the natural ligand to inhibit or modulate signalling. Orthosteric inhibition blocks the entire signalling pathways while allosteric modulators will bind to another site on the target and show functional selectivity. By reproducing parts of the flexible regions (loops) of two receptors, the IL-1 and vasopressin receptors, we generated small peptides that showed allosteric properties. To prove our concept we started with a pro-inflammatory target: IL-1 receptor. Interleukin (IL)-1 is a major pro-inflammatory cytokine which interacts with the IL-1 receptor I (IL-1RI) complex, composed of IL-1RI and IL-1R accessory protein (IL-1RacP) subunits. Presently, there are no small antagonists of the IL-1RI complex. Given this void, we derived 15 peptides from loops of IL-1RacP, which are putative interactive sites with the IL-1RI subunit. Here we substantiate the merits of one of these peptides, rytvela (we termed, 101.10), as an inhibitor of IL-1R and describe its properties consistent with those of an allosteric negative modulator. 101.10 (IC50  1 nM) blocked human thymocyte proliferation in vitro, and demonstrated robust in vivo effects in models of hyperthermia and inflammatory bowel disease as well as topically in contact dermatitis, superior to corticosteroids and IL-1ra; 101.10 did not bind to IL-1RI deficient cells and was ineffective in vivo in IL-1RI knockout mice. Importantly, characterization of 101.10, revealed non-competitive antagonist actions and functional selectivity by blocking certain IL-1R pathways while not affecting others. The second study involved a representative of the biggest family of membrane proteins: G-protein coupled receptors. Vasopressin type 2 receptor (V2R) exhibits mostly important properties for hydro-osmotic equilibrium and to a lesser extent on vasomotricity. Drugs currently acting on this receptor are analogs of the natural neuropeptide, vasopressin (AVP), and hence are competitive ligands. Six peptides reproducing juxtamembranous regions of V2R were designed and screened; the most effective peptide, CRAVKY (labelled VRQ397), was characterized. VRQ397 was potent (IC50 = 0.69 ± 0.25 nM) and fully effective in inhibiting V2R-dependent physiological function (specifically DDAVP-induced cremasteric vasorelaxation; this physiological functional assay was utilized to avoid overlooking interference of specific signaling events). Dose-response profile revealed non-competitive property of VRQ397; correspondingly, VRQ397 bound specifically to V2R-expressing cells, could not displace its natural ligand, AVP, but modulated AVP binding kinetics (dissociation rate). VRQ397 exhibited pharmacological permissiveness on V2R-induced signals as it inhibited DDAVP-induced PGI2 generation, but not that of cAMP or recruitment of — arrestin2. Consistent with in vitro and ex vivo effects as a V2R antagonist, VRQ397 displayed anticipated in vivo aquaretic efficacy. Findings describe the discovery of potent and specific small (peptide) antagonists of IL-1RI and V2R with properties in line with an allosteric negative modulator.
115

Neuroprotection in the Injured Spinal Cord : Novel Strategies using Immunomodulation, Stem cell Transplantation and Hyaluronic acid Hydrogel carriers

Schizas, Nikos January 2015 (has links)
The overall aim of this thesis was to establish strategies to minimize secondary damage to the injured spinal cord. Secondary damage that follows spinal cord injury (SCI) involves inflammatory and excitotoxic pathways. Regulation of these pathways using immunomodulatory and neuroprotective substances potentially protects the injured spinal cord from further damage. We also developed and studied resorbable biomaterials to be used as carriers for potential neuroprotectants to the injured spinal cord. We used transversal spinal cord slice cultures (SCSCs) derived from postnatal mice as a model. SCSCs were maintained on different biomaterials and were studied after treatment with immunomodulatory and/or neurotrophic factors. They were further excitotoxically injured and subsequently treated with interleukin-1 receptor antagonist (IL1RA) or by neural crest stem cell (NCSC)-transplantation. The results show that biocompatible and resorbable hydrogels based on hyaluronic acid (HA) preserved neurons in SCSCs to a much higher extent than a conventional collagen-based biomaterial or standard polyethylene terephthalate (PET) membrane inserts. Glial activation was limited in the cultures maintained on HA-based hydrogel. The anti-inflammatory factor IL1RA protected SCSCs from degenerative mechanisms that occur during in vitro incubation, and IL1RA also protected SCSCs from excitotoxic injury induced by N-Methyl-d-Aspartate (NMDA). IL1RA specifically protected neurons that resided in the ventral horn, while other neuronal populations such as dorsal horn neurons and Renshaw cells did not respond to treatment. Finally, transplantation of NCSCs onto excitotoxically injured SCSCs protected from neuronal loss, apoptosis and glial activation, while NCSCs remained undifferentiated. The results presented in this thesis indicate that carriers based on HA seem to be more suitable than conventional collagen-based biomaterials since they enhance neuronal survival per se. The observed neuroprotection is likely due to biomechanical properties of HA. IL1RA protects SCSCs from spontaneous degeneration and from NMDA-induced injury, suggesting that excitotoxic mechanisms can be modulated through anti-inflammatory pathways. Different neuronal populations are affected by IL1RA to various degrees, suggesting that a combination of different neuroprotectants should be used in treatment strategies after SCI. Finally, NCSCs seem to protect SCSCs from excitotoxic injury through paracrine actions, since they remain undifferentiated and do not migrate into the tissue during in vitro incubation. It seems that combinations of neuroprotectants and carrier substances should be considered rather than one single strategy when designing future treatments for SCI. Incorporation of neuroprotectants such as IL1RA combined with stem cells in injectable biocompatible carriers based on HA is the final goal of our group in the treatment of SCI.
116

Etude des mécanismes immunitaires dans un modèle d'inflammation pulmonaire allergique chez la souris : rôles de l'interleukine-22 / Roles of interleukin-22 in a mouse model of allergic airways inflammation

Besnard, Anne-Gaëlle 17 December 2010 (has links)
L’asthme est une maladie inflammatoire chronique des voies aériennes. Chez les individus sensibles, l’inhalation d’allergènes entraine une inflammation pulmonaire se traduisant par des épisodes récurrents de toux, de difficultés respiratoires et une sécrétion de mucus. Des études réalisées chez l’animal ont mis en évidence un rôle crucial des lymphocytes Th2 et des cytokines associées (IL-4, IL-5 et IL-13). Plus récemment, il a été montré que les lymphocytes Th17 participaient à la physiopathologie de l’asthme. La présente étude s’intéresse à une cytokine majoritairement produite par les Th17 : l’IL-22. Différents travaux indiquent que cette cytokine serait impliquée dans l’immunitémucosale où elle exercerait des effets protecteurs ou pro-inflammatoires en fonction du modèle expérimental étudié. En utilisant un modèle murin d’inflammation pulmonaire allergique induite par l’ovalbumine, nous avons montré que l’IL-22 jouait un rôle pro-inflammatoire au cours de l’induction de l’asthme allergique puisque les souris déficientes en IL-22 développent une forme atténuée de la maladie. A l’inverse, nous avons constaté que l’IL-22 avait un effet protecteur dans la phase effectrice, et que cet effet était dépendant de l’IL-17A. Nos travaux mettent donc en lumière une double fonction de l’IL-22 dans l’asthme allergique chez la souris. En parallèle de ce travail, nous nous sommes intéressés au rôle de l’IL-1 et de l’inflammasome NLRP3 dans ce même modèle d’inflammation pulmonaire. Enfin, une troisième étude a permis de mettre en lumière un rôle encore inconnu de l’interleukine-33 dans l’activation des cellules dendritiques au cours de la mise en place de la réponse asthmatique. / Asthma is a heterogenous inflammatory disorder of the airways characterized by chronic airway inflammation, airway hyper-reactivity and by symptoms of recurrent wheezing, coughing and shortness breath. Understanding of the role of allergy and Th2 cells in asthma has benefited from mouse model of allergic asthma. Recently, several studies highlighted Th17 involvement in asthma pathogenesis. In the present study, we investigate the role of IL-22, a Th17-related cytokine, in a mouse model of allergic lung inflammation induced by ovalbumin. First, using IL-22 deficient mice, we demonstrated a pro-inflammatory role of IL-22 during the sensitization phase. In contrast, we observed a protective function of IL-22 during the effective phase. This protective effect of IL-22 seems to be dependent of IL-17. In conclusion, we demonstrate here a dual role of IL-22 in asthma pathogenesis. Since interleukin-1_ is critical for Th17 polarization in human, we also investigated the role of IL-1 signalling and NLRP3 inflammasome in our model of allergic airway inflammation. We showed that NLRP3 inflammasome and IL-1R/IL-1 pathway are critical to induce allergic lung inflammation, even in the absence of adjuvant. Finally, we studied the effect of interleukin-33 on dendritic cells activation and Th2 priming during antigen sensitization and in established asthma.
117

Interleukin-1 Beta Mediated Regulation of Hyaluronan and Hyaluronan Synthase 2

Ducale, Ashley Elizabeth 01 January 2005 (has links)
Elevated levels of hyaluronan are associated with numerous inflammatory diseases including ulcerative colitis, Crohn's disease and wound healing. Various proinflammatory cytokines have shown to influence hyaluronan expression in cells originating from connective tissue. The overall purposes of this study included: 1. To determine the effects of IL-1β stimulation on HA and HAS2 steady state transcript levels and the signaling pathways involved in its effects. The signaling pathways utilized by proinflammatory mediators to modulate hyaluronan expression have only begun to be elucidated. In this aim, the effects of IL-1β on hyaluronan and HAS expressions in jejunum-derived mesenchymal cells were determined. Inhibition studies were utilized to determine the signaling pathways involved. The overall hypothesis of this aim was that stimulation of jejunum-derived mesenchymal cells with IL-1β activates the mitogen activated protein kinase pathways resulting in increased HAS2 steady state transcript and hyaluronan levels.Results: The results suggest that IL-1β induction of HAS2 expression involves, in part, the mitogen activated protein kinase signaling pathways that act in concert thus leading to an increase in expression of hyaluronan by jejunum-derived mesenchymal cells.2. To determine the effects of dexamethasone on IL-1β mediated increase in hyaluronan and HAS2 expressions and the mechanisms utilized by this glucocorticoid. Glucocorticoids are a mainstay treatment for the inflammatory component of inflammatory bowel disease. Given the recent evidence demonstrating increased hyaluronan in inflamed tissue from patients affected with inflammatory bowel disease, the objective of this aim was to determine the effect of dexamethasone on IL-1β-mediated induction of hyaluronan. The hypothesis of this aim was that pre-treatment with dexamethasone suppressed the ability of IL-1β to increase HAS2 transcript and hyaluronan levels via inhibition of the p38 MAP kinase pathway. Results: Pre-treatment with dexamethasone inhibited IL-1β-mediated hyaluronan and HAS2 induction by blocking the activation of the p38 MAP kinase pathways. 3. To identify the transcriptional and post-transcriptional mechanisms utilized by IL-1β to upregulate HAS2 steady state transcript levels. Very little is known about transcriptional and post-transcriptional regulation of the hyaluronan synthase 2 gene. In this aim, 5' and 3' mapping, luciferase analyses and actinomycin D studies were used to determine the transcriptional and post-transcriptional mechanisms utilized by IL-1β to regulate HAS2 steady state transcript levels. The hypothesis of this aim was that IL-1β used post-transcriptional mechanisms to regulate the HAS2 gene.Results: Dermal fibroblasts were used to find the 5'- and 3'-termini of the HAS2 message. Promoter constructs extending approximately 1 kb upstream from the transcription start site demonstrated no IL-1β response. Blocking protein synthesis prior to the addition of IL-1β dramatically increased HAS2 steady state transcript levels, while inhibition of transcription suppressed the effect of IL-1β on HAS2. Northern blot analysis revealed that cycloheximide and IL-1β exerted differential effects on the two HAS2 transcripts.
118

Novel Mechanisms Regulating Cytokine-induced Gene Expression in Astrocytes and Glioblastoma Cells

Bryan, Lauren 15 April 2009 (has links)
Chronic inflammation in the brain results in the development of several CNS diseases, including Alzheimer’s and Parkinson’s diseases, multiple sclerosis, and tumors. IL-1, a pro-inflammatory cytokine released by activated microglia and astrocytes, instigates the expression of factors promoting the progression of these CNS disorders, including cytokines, chemokines, and components of matrix remodeling systems, such as the plasminogen activator system. IL-1 also increases the mRNA expression and activity of SphK, the enzyme that phosphorylates Sph to form S1P, a bio-active sphingolipid. This thesis demonstrates that IL-1 and S1P enhance the mRNA and protein expression of PAI-1 and uPAR, two key components of the plasminogen activator system, in glioblastoma cells. The S1P-induced mRNA expression of PAI-1 and uPAR is mediated by the S1P2 receptor, and requires Rho-kinase and MEK1. However, IL-1 regulation of PAI-1 and uPAR mRNA expression is independent of SphK, and thus S1P. IL-1- and S1P-induced mRNA expression of PAI-1 and uPAR results in the increased in vitro invasion of glioblastoma cells. Since significant amounts of IL-1 are secreted from gliomas, and it increases the production of S1P via inciting the activity and mRNA expression of SphK, we propose a mechanism by which S1P and IL-1 influence the invasion of glioblastoma cells by increasing the mRNA and protein expression of uPAR and PAI-1. IL-1 and S1P also influence the mRNA expression of chemokines implicated in the development and progression of multiple sclerosis, namely IP-10 and RANTES, in primary human astrocytes. IP-10 and RANTES attract T cells, which are the major pathological cause of multiple sclerosis. This thesis demonstrates a novel mechanism by which S1P significantly inhibits the IL-1-induced mRNA expression of these chemokines. The mechanism by which S1P reduces IL-1-induced IP-10 and RANTES mRNA expression involves the prolonged hyperphosphorylation of TAK1, as well as the inhibition of IL-1-stimulated IFN beta production and the phosphorylation of STAT1 and STAT2. In summary, this dissertation describes the mechanisms by which S1P and IL-1 control the mRNA expression of two chemokines associated with multiple sclerosis, and the components of the plasminogen activator system, which are critical for the invasion of glioblastoma cells; thus, indicating future therapeutic targets for destructive CNS disorders.
119

Oligodendrocyte pathology following Traumatic Brain Injury : Experimental and clinical studies

Flygt, Johanna January 2017 (has links)
Traumatic brain injury (TBI) caused by traffic and fall accidents, sports-related injuries and violence commonly results in life-changing disabilities. Cognitive impairments following TBI may be due to disruption of axons, stretched by the acceleration/deceleration forces of the initial impact, and their surrounding myelin in neuronal networks. The primary injury, which also results in death to neuronal and glial cells, is followed by a cascade of secondary injury mechanisms including a complex inflammatory response that will exacerbate the white matter injury. Axons are supported and protected by the ensheathing myelin, ensuring fast conduction velocity. Myelin is produced by oligodendrocytes (OLs), a cell type vulnerable to many of the molecular processes, including several inflammatory mediators, elicited by TBI. Since one OL extends processes to several axons, the protection of OLs is an important therapeutic target post-TBI.  During development, OLs mature from oligodendrocyte progenitor cells (OPCs), also present in the adult brain. The aim of this thesis was to investigate white matter pathology, with a specific focus on the OL population, in experimental and clinical TBI. Since the inflammatory response may contribute to OL cell death and OPC proliferation, neutralization of interleukin-1β (IL-1β) was investigated. The lateral and central fluid percussion injury models were used in mice and rats where memory, learning and complex behaviors were investigated by two functional tests. Brain tissue, surgically resected due to life-threatening brain swelling or hemorrhage, from TBI patients was also investigated. Axonal injury, myelin damage, microglia alterations and OPCs and OL cell death were investigated by immunohistochemical techniques. In focal and diffuse experimental TBI, OL cell death was observed in important white matter tracts. OL cell death was accompanied by myelin damage, axonal injury and presence of microglia as well as an increased number of OPCs in both the experimental and human setting. OPCs were found to proliferate in diffuse TBI in mice where both complex behavioral changes and impaired memory were observed. Neutralization of IL-1β normalized and improved these behavioral alterations and also lead to a preserved number of mature OLs although without influencing OPC proliferation. The results provided in this thesis indicate that white matter pathology is a key component of the pathophysiology of TBI. The OPC proliferation may influence regeneration post-injury and might be an important future therapeutic targets for TBI. The present studies also suggest that treatment strategies targeting neuroinflammation may positively influence behavioral outcome and OL cell death in TBI. / <p>(Faculty of Medicine)</p>
120

Avaliação da associação entre o polimorfismo dos genes IL-1A (-889) e TNFA (-308) e a periodontite agressiva / Evaluation of IL-1A (-889) and TNFA (-308) gene polymorphisms in aggressive periodontitis

Freitas, Nívea Maria de 25 August 2004 (has links)
A periodontite agressiva (PAg) compreende um grupo de doenças periodontais raras caracterizadas por rápida destruição dos tecidos periodontais, em indivíduos jovens e que geralmente não apresentam doenças sistêmicas. Estudos em populações e em famílias indicaram que fatores genéticos possuem influência na susceptibilidade a periodontite agressiva. Os polimorfismos genéticos da interleucina-1 (IL-1) e do fator de necrose tumoral-? (TNF-?) foram associados com o aumento da severidade da periodontite crônica. O objetivo deste estudo foi avaliar a associação entre o polimorfismo dos genes IL-1A (-889) e TNFA (-308) e a periodontite agressiva. Foram selecionados 60 indivíduos não fumantes, sendo 30 portadores de periodontite agressiva e os outros 30 sem doença periodontal. O polimorfismo genético foi analisado utilizando-se a técnica da reação em cadeia da polimerase e análise do polimorfismo de comprimento dos fragmentos de restrição (PCR-RFLP). Foi observado que a freqüência do genótipo 1/1 para IL-1A foi de 63,3% no grupo controle e de 56,7% no grupo teste. A avaliação do genótipo 1/2 mostrou uma freqüência de 26,7% no grupo controle e de 40% no grupo teste. O genótipo 2/2 ocorreu com uma freqüência de 10% no grupo controle e de 3,3% no grupo teste. O genótipo 1/1 para TNFA estava presente em 73,3% do grupo controle e em 80% do grupo teste. O genótipo 1/2 ocorreu com freqüência de 20% em ambos os grupos. O genótipo 2/2 foi encontrado em 6,7% dos controles e não foi detectado no grupo teste. Em relação aos alelos, o alelo 1 apresentou freqüência de 76,7% e o alelo 2 de 23,3% para ambos os grupos, para o gene IL-1A (-889). E para o gene TNFA (- 308) o alelo 1 ocorreu com freqüência de 83,3% no grupo controle e de 90% no grupo teste e o alelo 2 de 16,7% no grupo controle e 10% no grupo teste. A análise estatística revelou que não houve diferença significativa na distribuição dos genótipos, para ambos os genes, entre os dois grupos estudados. Não foi encontrada associação entre a periodontite agressiva e o polimorfismo dos genes IL- 1A (-889) e TNFA (-308) na população estudada. / Agressive periodontitis (AgP) is a relatively uncommon form of periodontal disease characterized by a rapid destruction of the periodontal supporting tissues in young adults who are usually systemically well. The results of population and family studies indicate that genetic factors seem to have a strong influence on susceptibility to AP. Genetic polymorphism at the interleukin-1 (IL-1) and tumor necrosis factor alpha (TNFA) were associated with the increase on the severity of chronic periodontitis. The aim of this study was to explore a possible association between IL-1A and TNFA genotypes in Brazilian white Caucasian patients with aggressive periodontitis. Sixty nonsmoking subjects, 30 patients and 30 periodontal healthy controls were included in the study. All subjects were systemically healthy. Two polymorphisms, IL-1A (-889) and TNFA (-308), were analyzed by means of polymerase chain reaction-restriction fragment length polymorphism. The 1/1 genotype for IL-1A was present in 63.3% of the controls and in 56.7% of the aggressive periodontitis patients. The genotype 1/2 was present in 26.7% of the controls and in 40% of the patients. The 2/2 genotype was present in 10% of the controls and in 3.3% of the diseased subjects. The 1/1 genotype for the TNFA was present in 73.3% of the controls and in 80% of the patients. The genotype 1/2 was present in the 20% of both groups. The genotype 2/2 was present in 6.7% of the controls and was not detected in the patients group. With regard to the IL-1A (-889) genotype, 76.7% of controls and patients were positive for allele 1. Allele 1 of the TNFA (-308) polymorphism was carried by 83.3% of the controls and 90% of the patients and allele 2 was carried by 16.7% of the controls and 10% of the patients. Statistical analysis revealed no significant difference in the distribution of genotypes for both genes between the two groups. No association was found between AgP and the IL-1A (-889) and TNFA (-308) polymorphisms investigated in the population presented here.

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