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Castro, Cruz Monica del Carmen. "The impact of the syndecan-PDZ interactome on endosomal trafficking and extracellular vesicle composition." Thesis, Aix-Marseille, 2018. http://www.theses.fr/2018AIXM0302.
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Les syndécans forment une famille de quatre protéines transmembranaires qui sont substituées par l'héparane sulfate. Grâce à ces chaînes glucidiques extracellulaires, les syndécans contrôlent la signalisation d'une pléthore de facteurs de croissance et de molécules d'adhésion. Une autre caractéristique remarquable des syndécans est la conservation de leur domaine intracellulaire au cours de l'évolution. Ce domaine contient un motif C-terminal qui peut induire une interaction avec les protéines dites «PDZ». Les interactions PDZ sont promiscues et les protéines PDZ contrôlent divers aspects de la signalisation cellulaire et de la communication cellule-cellule. Quatre interactions syndecan-PDZ ont été décrites à ce jour et toutes ces interactions ont des effets drastiques sur le comportement des cellules. En particulier, il a été documenté que l'interaction syndécan-synténine a un impact sur le trafic intracellulaire de molécules de signalisation liant l’héparan sulfate. De plus, les syndécans et la synténine coopèrent dans le contrôle la biogenèse des exosomes, organites extracellulaires fonctionnant comme des médiateurs importants de la communication cellule-cellule (y compris dans différentes maladies systémiques comme le cancer). Le protéome humain compte 150 protéines PDZ qui contiennent 266 domaines PDZ. Dans ce travail, nous avons mis à jour la complexité de l'interactome syndecan-PDZ et testé son impact sur le trafic membranaire et sur la composition des vésicules extracellulaires. Notre travail ouvre la voie à une meilleure compréhension des réseaux moléculaires contrôlant la communication cellule-cellule en physio-pathologieSyndecans form a family of four transmembrane proteins that are substituted with heparan sulfate. By virtue of these extracellular carbohydrate chains, syndecans control the signaling of a plethora of growth factors and adhesion molecules. Another remarkable feature of syndecans is the conservation of their intracellular domain through evolution. This domain contains a C-terminal motif that can mediate interaction with PDZ proteins. PDZ interactions are promiscuous and PDZ proteins control various aspects of cell signaling and cell-cell communication. Four syndecan-PDZ interactions have been described so far and all these interactions have broad effects on cell behavior. In particular, it was documented that syndecan-syntenin interaction has impact on the intracellular trafficking of heparan sulfate cargo. Moreover syndecan-syntenin controls the biogenesis of exosomes, extracellular organelles emerging as important mediators of cell-cell communication in health and diseases. The human proteome contains 150 PDZ proteins and 266 PDZ domains. Here we started addressing the complexity of the syndecan-PDZ interactome and tested for its impact on membrane trafficking and on the composition of extracellular vesicles. Our work paves the way for a better understanding of the molecular mechanisms and networks controlling cell-cell communication in health and disease
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Alexopoulou, Annika. "The role of syndecans in murine embryonic stem cells and their differentiation into mesodermal cell types." Thesis, Imperial College London, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.438968.
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Zong, Fang. "Studies on syndecan-1 in mesenchymal tumors." Stockholm : Department of Laboratory Medicine, Karolinska Institutet, 2010. http://diss.kib.ki.se/2010/978-91-7409-749-8/.
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Rossi, Piva Maria Bethania [Verfasser]. "The impact and underlying molecular mechanisms of cell adhesion molecules integrins and syndecans in the cisplatin chemoresistance of melanoma cells / Maria Bethania Rossi Piva." Bonn : Universitäts- und Landesbibliothek Bonn, 2019. http://d-nb.info/1204479763/34.
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Eustace, Andrew David. "Syndecan 3 and inflammation." Thesis, University of Bristol, 2016. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.720843.
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Carulli, Sonia. "Molecular basis of syndecan-1 mediated cell adhesion to laminin 332." Thesis, Lyon 1, 2011. http://www.theses.fr/2011LYO10134.
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L’interaction du récepteur syndecan-1 de la famille des héparanes sulfates protéoglycanes avec le fragment carboxy-terminal alpha3LG4/5 de la protéine d’adhérence matricielle, la laminine 332, induit une réorganisation du cytosquelette de la cellule conduisant à la formation de filopodes et de microspicules, caractéristiques de la migration cellulaire. Notre laboratoire a mis en évidence que l’adhésion cellulaire syndecan-1 dépendante implique les chaînes d’héparanes sulfates et chondroïtine sulfate. Afin d’identifier le (les) zone(s) impliquée(s) dans l’interaction domaine LG4/5-syndécan-1, une approche de mutagenèse dirigée a été mise en place sur le fragment LG4/5 recombinant. Les résidus conservés parmi les laminines, identifiés dans la littérature comme liant l’héparine, aussi bien que des résidus basiques spécifiques à la chaine α3 identifiés par des approches prédictives, ont été remplacés par le résidu neutre glutamine. Toutes les protéines couplées avec l’étiquette 6-Histidine ont été produites dans des cellules de mammifère, purifiées par chromatographie d'affinité et caractérisées biochimiquement et par dichroïsme circulaire. L’évaluation de l’affinité des protéines produites pour l’héparine nous a permis d’identifier un site d’interaction majeur avec les glycosaminoglycanes dans le domaine LG4/5, entouré par des résidus à mineur affinité. La technique de résonance plasmonique de surface et des tests d’adhérence cellulaire nous ont permis de confirmer ce résultat puisque l’absence du site d’interaction majeur avec l’héparine a produit une inhibition totale de l’adhérence. Des expériences de pull-down nous ont montré que ce site est aussi impliqué dans l’interaction avec le syndecan-4, indiquant que cette séquence pourrait ainsi jouer un rôle dans différents processus cellulaires. Une collaboration avec des bio-informaticiens nous a permis de proposer un modèle structural du domaine LG4/5 et de montrer que la zone identifiée est localisée dans une boucle exposée à l’extérieure du module LG4, entourée par des résidus à plus faible affinitéThe HSPG receptor syndecan-1 interacts with the carboxy-terminal LG4/5 domain in laminin 332 to participate in keratinocyte migration by inducing formation of cytoskeleton related protrusive structures. We have shown that syndecan-1 mediated cell adhesion occurs in heparan sulphate and chondroitin sulphate dependent manner and that these two glycosaminoglycan (GAG) chains bind independently to LG4/5 with different affinities. To identify residues involved in the interaction of the LG4/5 domain with syndecan-1 and to apprehend the molecular basis of the GAGs interaction specificity, we have used a site-directed mutagenesis approach of the recombinant LG4/5 fragment. The residues identified as conserved heparin binding residues throughout laminins, as well as “candidate” basic residues identified through predictive approaches, have been replaced by the neutral residue glutamine. All LG4/5 proteins carrying a hexa-histidine tag at their C-terminal end were expressed in mammalian cells. The produced proteins were purified and characterized biochemically. Circular dichroism studies performed on all mutagenised proteins showed that the overall structure of each mutant is comparable to that of the wild type protein. Heparin affinity chromatography analysis allowed us to identify a major heparin binding site in the LG4/5 domain surrounded by several minor GAG binding sites. Surface plasmon resonance analysis of mutated LG4/5 proteins-heparan sulphate interaction confirmed these results. These findings were well correlated with our in cellulo syndecan-1 mediated cell adhesion as the lack of this major heparin binding site totally abrogated cell adhesion. Pull down experiments allowed us to show that this heparin binding site sequence is responsible not only for the interaction of the receptors syndecan-1 but also for syndecan-4 suggesting that additional cellular functions may be carried by this sequence. Our structural predictions suggest that the LG4/5 in laminin 332 encompasses a major GAG binding site surrounded by a track of converging positively charged residues
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Hidding, Heriburg [Verfasser], and Michael J. [Akademischer Betreuer] Raschke. "Die Bedeutung der Proteoglykane Syndecan-1 und Syndecan-4 während der Frakturheilung / Heriburg Hidding ; Betreuer: Michael J. Raschke." Münster : Universitäts- und Landesbibliothek Münster, 2013. http://d-nb.info/1138280402/34.
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Habes, Chahrazed. "Stimulation du signal calcique et de la migration des cellules cancéreuses mammaires par le peptide LL-37 : un mécanisme d’attachement membranaire impliquant les glycosaminoglycanes et les syndécanes." Thesis, Tours, 2019. http://www.theses.fr/2019TOUR3807.
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Le peptide LL-37, peptide antimicrobien de l’immunité innée, est associé au développement tumoral. Sur des lignées cancéreuses mammaires. Il augmente le calcium intracellulaire et la migration. via l’activation de la voie PI3K/AKT et de canaux calciques. L’énantiomère (D)-LL-37 induit des effets similaires, excluant une interaction classique ligand-récepteur. Avec sa structure en hélice α amphipathique et sa charge nette +6, l’hypothèse était que le peptide utilise les charges négatives de glycanes sulfatés ou sialylés pour sa fixation membranaire avant d’induire ses activités. Des lectines végétales reconnaissant des structures glycaniques sialylées ou sulfatées inhibent la migration et le signal calcique induits par LL-37 mais l’implication de sialyltransférases n’a pas été démontrée. Des glycoaminoglycanes (GAGs) tels que les chondroïtine et héparine sulfatées, utilisés en tant que compétiteurs, ou une digestion enzymatique des GAGs (Chondroïtinase et héparinase) conduisent à une inhibition de 50 à 100% des activités migratoire et calcique induites par LL-37. L’inhibition de synthèse des GAGs par le Methylumbelliferyl β-D-xyloside ainsi qu’une diminution de la sulfatation par le chlorate de sodium confirment l’implication de ces glycanes sulfatés. Dans la perceptive d’identifier la ou les protéines glycosylées membranaires susceptibles de transduire les effets de LL-37, nous avons utilisé une approche ciblée en invalidant par siRNA la synthèse des protéines arborant des GAGs. Le syndécane 4 est impliqué dans les activités de LL-37. En conclusion, ces résultats soulignent l’implication de GAGs sulfatés portés par le syndécane 4 pour orienter la fixation de LL-37 à la membrane des cellules cancéreuses et médier ses activités pro-tumoralesInitially characterized by its antimicrobial activities, LL-37 has also been shown to significantly contribute to tumor development. On breast cancer cell lines, LL-37 increases intracellular calcium and their migration via the activation of PI3K/AKT signaling. Its all-D enantiomer (D)-LL-37 induces similar effects, which excludes an protein-protein interaction of LL-37 in a classic ligand-receptor manner. Its structure of an amphipathic a-helix with a net charge of +6 gave rise to the hypothesis that the peptide uses the negative charges of sulfoglycans or sialic acids to facilitate its attachment to the cell membrane and to induce its activities. Whereas several lectins, specifically attaching to sialylated or sulfated structures, blocked the activities of LL-37 on both calcium increase and cell migration, the suppression of several sialyltransferases had no effect. However, the competitive use of glycoaminoglycans (GAG) and chrondroitin and sulfated heparin, or treatment of the cell surface with chondroitinase and heparinase resulted in an activity loss of 50-100%. Similar results were obtained by confirmed by blocking the synthesis of GAGs with Methylumbelliferyl β-D-xyloside, and by suppression of glycan sulfurylation by sodium chlorate. Using a candidate approach by suppressing proteoglycan synthesis by RNA interference, syndecan 4 was shown to be involved in the activities of LL-37. This leads to the conclusion that sulfated GAGs linked to syndecans 4 guides the association of LL-37 to the membrane of cancer cells, thus being a mediator of its activities
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Sadot, Lebouvier Sophie Campone Mario. "Expression du syndecan-1 dans les carcinomes." [S.l.] : [s.n.], 2008. http://castore.univ-nantes.fr/castore/GetOAIRef?idDoc=48311.
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Tkachenko, Eugene. "Syndecan-4 in cell signaling and membrane trafficking." [Maastricht : Maastricht : Universiteit Maastricht] ; University Library, Maastricht University [Host], 2005. http://arno.unimaas.nl/show.cgi?fid=6428.
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Eriksson, Anna S. "Syndecan - Regulation and Function of its Glycosaminoglycan Chains." Doctoral thesis, Uppsala universitet, Institutionen för medicinsk biokemi och mikrobiologi, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-197691.
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The cell surface is an active area where extracellular molecules meet their receptors and affect the cellular fate by inducing for example cell proliferation and adhesion. Syndecans and integrins are two transmembrane molecules that have been suggested to fine-tune these activities, possibly in cooperation. Syndecans are proteoglycans, i.e. proteins with specific types of carbohydrate chains attached. These chains are glycosaminoglycans and either heparan sulfate (HS) or chondroitin sulfate (CS). Syndecans are known to influence cell adhesion and signaling. Integrins in turn, are important adhesion molecules that connect the extracellular matrix with the cytoskeleton, and hence can regulate cell motility. In an attempt to study how the two types of glycosaminoglycans attached to syndecan-1 can interact with integrins, a cell based model system was used and functional motility assays were performed. The results showed that HS, but not CS, on the cell surface was capable of regulating integrin-mediated cell motility. Regulation of intracellular signaling is crucial to prevent abnormal cellular behavior. In the second part of this thesis, the aim was to see how the presentation of glycosaminoglycan chains to the FGF signaling complex could affect the cellular response. When attached to the plasma membrane via syndecan-1, CS chains could support the intracellular signaling, although not promoting as strong signals as HS. When glycosaminoglycans were attached to free ectodomains of syndecan-1, both types of chains sequestered FGF2 from the receptors to the same extent, pointing towards functional overlap between CS and HS. To further study the interplay between HS and CS, their roles in the formation of pharyngeal cartilage in zebrafish were established. HS was important during chondrocyte intercalation and CS in the formation of the surrounding extracellular matrix. Further, the balance between the biosynthetic enzymes determined the ratio of HS and CS, and HS biosynthesis was prioritized over CS biosynthesis. The results presented in this thesis provide further insight into the regulation of HS biosynthesis, as well as the roles of both HS and CS on the cell surface. It is evident, that in certain situations there is a strict requirement for a certain HS structure, albeit in other situations there is a functional overlap between HS and CS.
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Jones, F. K. "Syndecan-3-mediated signalling in the regulation of myogenesis." Thesis, University of Liverpool, 2017. http://livrepository.liverpool.ac.uk/3018336/.
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Jones, Tiffany Celeste. "Syndecan-4 binds insulin-like growth factor binding protein-4." Birmingham, Ala. : University of Alabama at Birmingham, 2009. https://www.mhsl.uab.edu/dt/2010r/jones.pdf.
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Grönkvist, Pamela. "Effects of overexpression of syndecan-1 in mesenchymal tumor cells." Thesis, Södertörns högskola, Institutionen för livsvetenskaper, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:sh:diva-8665.
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BackgroundAll cells carry a transmembrane proteoglycan calledsyndecan. Syndecans influence many functions like cell migration, cell adhesionand cell proliferation and it is involved in cellular signaling andtumourigenesis. The common features of differentiation in twomesenchymal tumor cell types, malignant mesothelioma cells and fibrosarcoma cells,are connected to the synthesis of syndecans. By studying the overexpression ofsyndecan-1 we hope to discover new features of the syndecan-1 molecule that wecan add to the puzzle of mesenchymal tumors. Methods and findingsMalignant mesothelioma cells and fibrosarcoma cellswere cultured and transfected with full-length- and truncated syndecan-1 constructs.To detect the expression of syndecan-1 on RNA level Rt-Q-PCR was conductedfollowed by immunocytochemical analysis to establish the syndecan-1 expressionon protein level. The result showed a 2-7 fold increase of syndecan-1 in thetransfectants comparing to the control. The proliferation of transfectants was analyzedby cell proliferation assay and cell cycle analysis. All transfectants showed alower proliferation rate comparing to the controls and a slight increase inG0/G1 phase. Because of the high structural similarities ofsyndecan family members, I studied how overexpression of syndecan-1 affected theother syndecans using Rt-Q-PCR. Syndecan-2 and -4 were downregulated in thetransfectants carrying syndecan-1 ectodomain, whereas the truncated versionshad the opposite effect. The expression of syndecan-bound heparan sulfate wasstudied by FACS and indicated an upregulation for heparan sulfate whenmeasuring internal- and membrane bound syndecans simultanesly. ConclusionsIn this study I haveshown that overexpression of full-length syndecan-1 and the different truncatedvariants, had similar profound effects on mesenchymal cell proliferation. Syndecan-1also influences the other members of the syndecan family suggesting a complexregulation.
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Mahoney, Claire. "Therapeutic ultrasound bypasses canonical syndecan-4 signaling to activate Rac1." Thesis, University of Manchester, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.495747.
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Song, Yan. "THE ROLE OF SYNDECAN-4 IN MUSCLE GROWTH AND DEVELOPMENT." The Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1305732018.
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Michopoulou, Anna. "Receptor syndecan-1 controls MMP-9 expression during keratinocyte migration." Thesis, Lyon, 2016. http://www.theses.fr/2016LYSE1130.
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La phase de l'épithélialisation de la réparation cutanée se déroule en impliquant plusieurs processus dynamiques et interactifs pendant lesquels les kératinocytes migrent, prolifèrent et se différentient afin de reconstruire la fonction de la barrière. La migration des kératinocytes est l'événement qui détermine l'efficacité du processus entier. Le comportement migratoire est contrôlé au même temps au niveau extracellulaire et intracellulaire et dépend d'interactions dynamiques entre les cellules et leur environnement extracellulaire, des facteurs de croissance et des cytokines. Parmi les protéines de la matrice extracellulaire, la laminine 332 est un substrat d'adhésion majeur des kératinocytes qui joue un rôle important au cours de la migration des kératinocytes, travers son domaine LG4/5 localisé à l'extrémité carboxy-terminale de sa chaine a. Des études récentes ont rapporté que l'induction de la migration des kératinocytes par LG4/5 est dépendante des Métalloprotéinases Matricielles pro-migratoires (MMP)-9 et -1 qui jouent des rôles essentiels au cours de la cicatrisation et surtout pendant la ré-épithélialisation. Etant donné que des travaux antérieurs du laboratoire ont montré que le domaine LG4/5 participe à la dynamique du cytosquelette et à la motilité cellulaire au travers de liaisons avec les récepteurs de type de protéoglycanes à heparane sulfate, syndécan-1 et -4 on a regardé l'implication potentielle de ces récepteurs au processus. Afin d'analyser la participation possible des syndecans dans ce processus, nous avons développé une approche de mutagénèse dirigée dans la protéine LG4/5 recombinante pour altérer les sites de liaison aux syndécan-1 ou -4. Notre analyse PCR et nos résultats de zymographie ont révélé une différence du profile d'activation des MMPs en fonction de la mutation produite et donc de la capacité de la protéine à recruter le syndécan-1 ou le syndécan-4, ainsi que le syndécan-1, et pas la syndécan-4, est impliqué dans l'activation de la production de la MMP-9 par LG4/5. Nous avons ensuite confirmé ces résultats en réduisant l'expression du syndécan-1 dans des kératinocytes et on a pu aussi montrer que le traitement avec des cytokines telles que TNFalpha et IL-1beta, connues pour leur capacité d'induire l'activation de la MMP-9, a produit le même résultat dans ce systéme. L'addition de l'héparine dans nos experiences a inhibé l'activation de l'expression de MMP-9 suggerant que les heparanes sulfates dans syndecan-1 sont impliqué au mécanisme. Pour confirmer ces résultats des experiences avec des séries de syndecan-1 mutés sont en cours. Pour conclure, nos résultats montrent pour la première fois un rôle important de syndecan-1 à l'expression de MMP-9 suggérant que sa re-distribution au front des kératinocytes migratoires puisse éventuellement être liée au clivage ou à la dégradation des protéines de la matrice extracellulaire. En plus, nos résultats proposent que le domain LG4/5 de la laminin 332 libéré soit capable d'affecter la balance de l'expression de la MMP-9 lors de la migration des kératinocytes en leur permettant de traverser le caillot de fibrineDuring skin repair, the epithelialization phase occurs by an orderly series of events whereby keratinocytes migrate, proliferate, and differentiate to restore the barrier function. Keratinocyte migration determines the efficiency of the overall wound repair process. The migratory behaviour is governed at both the extracellular and intracellular levels and depends on the carefully balanced dynamic interactions of the cells with ECM components, growth factors and cytokines. Among extracellular matrix proteins, laminin 332, known as a major adhesion substrate for keratinocytes was shown to contribute to skin reepithelialization through its a3 chain C-terminal domains LG45. Recent studies have reported that LG45 induces keratinocyte migration, an event that relies on the involvement of the pro-migratory matrix metalloproteinases-1 and -9, two MMPs known to play a role in the reepithelialization phase of wound healing. As findings from our laboratory have reported that LG45 domains participate in cytoskeleton dynamic and cell movement through binding of the heparan sulphate proteoglycans syndecan-1 and -4, we analyzed the potential involvement of these receptors in this process. To that end, we have developed a site-directed mutagenesis approach within a recombinant LG45 protein to alter either the syndecan-1 or syndecan-4 binding site. Our PCR analysis and zymography results revealed that depending on the mutants, syndecan-1 or syndecan-4 recruitment induced different MMP activation profile and suggested that syndecan-1 plays a role in LG45 induced MMP-9 expression and activation. We confirmed these results by down regulating syndecans expression in keratinocytes and revealed that this phenomenon also occurred when cells were treated with TNFalpha or IL1beta, two cytokines known to up-regulate MMP-9 expression. Addition of heparin in these experiments abolished MMP-9 expression activation suggesting that syndecan-1 heparan sulfate moieties are involved in this mechanism. Confirming experiments using a series of mutated syndecan-1 in their ectodomain (lacking glycosaminoglycan chains) or in their cytoplasmic tail are ongoing in the lab. Taken together, our data demonstrate for the first time that syndecan-1 plays a pivotal role in MMP-9 expression, suggesting that its re-distribution at the front edge of migrating keratinocyte may have a role to play in the cleavage or degradation of extracellular matrix proteins. Our results further suggest that the released laminin 332 LG45 domain has the ability to impact the MMP9 expression balance during keratinocyte migration therefore facilitating their path through the fibrin clot
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Ussat, Sascha [Verfasser]. "Die Funktion von Syndecan-1 und Syndecan-4 bei der epithelial-mesenchymalen Transformation und Migration von Kolonkarzinomzellen und ihre Modulation durch MAP-Kinasen / Sascha Ussat." Magdeburg : Universitätsbibliothek, 2016. http://d-nb.info/1129779890/34.
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Pasqualon, Tobias [Verfasser], Andreas [Akademischer Betreuer] Ludwig, and Lothar [Akademischer Betreuer] Elling. "In vivo and in vitro analysis of syndecan-1 and syndecan-4 cleavage fragments as regulators of cell migration / Tobias Pasqualon ; Andreas Ludwig, Lothar Elling." Aachen : Universitätsbibliothek der RWTH Aachen, 2016. http://d-nb.info/1129261662/34.
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Dovas, Athanassios. "Regulation of RhoA by PKCa during syndecan-4-mediated cell adhesion." Thesis, Imperial College London, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.434916.
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Wu, Lap-kei, and 胡立基. "Control of syndecan-1 shedding to limit smoking-related neutrophilic inflammation." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2015. http://hdl.handle.net/10722/211108.
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Férrer, Natalia Monte Benevides. "Syndecan-1 urinário e lesão renal aguda após cirurgia cardíaca pediátrica." Universidade de Fortaleza, 2018. http://dspace.unifor.br/handle/tede/108649.
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Previous issue date: 2018-07-16ABSTRACTIntroduction: Acute kidney injury (AKI) is a common occurrence after pediatric cardiac surgery. Plasma syndecan-1 is a biomarker of endothelial glycocalyx damage and it is associated with AKI. Syndecan-1 is also expressed in renal tubular cells but there is no study evaluating urinary sundecan-1 in predicting AKI. Methods: Prospective cohort study with 86 patients under 18 years old submitted to cardiac surgery at one reference institution. Postoperative urinary and plasma syndecan-1 was collected within the first 2 hours after cardiac surgery. Severe AKI - defined according KDIGO stage 2 or 3 - doubling of serum creatinine from the preoperative value or need for dialysis during hospitalization was the main outcome. Analyses were adjusted for clinical cofounders. Results: Postoperative urinary syndecan-1 levels were higher in patients with severe AKI and even after adjustment for several clinical variables and adding plasma syndecan-1 levels, the fourth quartile was significantly associated with severe AKI. The AUC-ROC for postoperative urinary syndecan-1 presented a good discriminatory capacity (AUC-ROC 0.793). The addition of urinary syndecan-1 improved the discrimination capacity of a clinical model (0.78 to 0.84) and of a clinical model + plasma syndecan-1 (0.82 to 0.89, p<0.05 for both). It also improved risk prediction, as measured by net reclassification improvement (NRI). Conclusion: Urinary syndecan-1 predicts severe AKI after pediatric cardiac surgery. Moreover, its capacity to predict severe AKI appears to be independent of plasma syndecan-1 levels. Keywords: Acute Kidney Injury. Pediatric. Cardiac Surgery. Biomarkers.
Introdução: A lesão renal aguda (LRA) é uma ocorrência comum após a cirurgia cardíaca pediátrica. Syndecan-1 plasmático é um biomarcador de lesão do glicocálix endotelial e está associado a LRA. Syndecan-1 também é expresso em células tubulares renais, mas não há estudo avaliando o syndecan-1 urinário na predição da LRA. Metodologia: estudo de coorte prospectivo com 86 pacientes menores de 18 anos submetidos à cirurgia cardíaca em uma instituição de referência. O sangue e a urina foram coletados nas primeiras 2 horas após a cirurgia cardíaca. LRA grave - definida de acordo com o estágio do Kidney Disease Improvement Global Outcome (KDIGO) 2 ou 3 - a duplicação da creatinina sérica a partir do valor pré-operatório ou a necessidade de diálise durante a hospitalização foi o principal desfecho. As análises foram ajustadas para confundidores clínicos. Resultados: os níveis de syndecan-1 urinário no pós-operatório foram maiores em pacientes com LRA grave e, mesmo após ajuste para variáveis clínicas e adição de níveis plasmáticos de syndecan-1, o quartil mais elevado foi significativamente associado a LRA grave. A curva ROC para syndecan-1 urinário pós-operatório apresentou boa capacidade discriminatória (AUC 0,793). A adição de syndecan-1 urinário melhorou a capacidade de discriminação de um modelo clínico (de 0,78 para 0,84) e de um modelo clínico + syndecan-1 plasmático (de 0,82 para 0,89, p <0,05 para ambos). Também melhorou a previsão de risco, conforme medido pela melhoria da Net Reclassification Improvement (NRI). Conclusão: o syndecan-1 urinário prediz a LRA grave após a cirurgia cardíaca pediátrica. Além disso, sua capacidade de prever a LRA grave parece ser independente dos níveis plasmáticos de syndecan-1. Palavras-chave: Lesão Renal Aguda. Cirurgia Cardíaca. Pediatria. Biomarcadores.
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Zhang, Zheng. "Function of Frizzled-7/Syndecan-4 Signaling in Foregut Organ Development." University of Cincinnati / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1428653451.
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Sulka, Béatrice. "Étude des mécanismes de contrôle de l'interaction syntenine-1 / syndecan-1." Lyon 1, 2008. http://www.theses.fr/2008LYO10327.
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La synténine-1 est une protéine intracellulaire comportant des domaines PDZ. Par ces domaines, elle établit des liaisons multiples avec des partenaires transmembranaires et cytoplasmiques qu’elle relie aux cascades de signalisation ou au cytosquelette. Notamment, elle interagit avec la séquence EFYA du récepteur syndécan-1, la tyrosine (Y309) de ce motif étant indispensable pour l’interaction. Notre objectif a été d’analyser le rôle potentiel de l’état de phosphorylation de ce résidu dans la régulation de la liaison synténine1-syndécan1. Nous avons montré, en utilisant une série de mutants du domaine cytoplasmique du syndécan-1, que l’interaction synténine1-syndécan1 dépend de l’état de phosphorylation d’Y309. Nos expériences menées avec la synténine-1 entière ou avec ses domaines PDZ, isolés ou en tandem, produits sous forme recombinante, ont permit de montrer que la phosphorylation de l’Y309 inhibe l’interaction. Ces résultats ont été confirmés par l’utilisation de peptides EFYA comportant une tyrosine phosphorylée. Nos résultats corrèlent avec les travaux du laboratoire montrant que l’adhésion cellulaire au domaine C-terminal de laminine-332 induit la déphosphorylation des tyrosines du syndécan-1. De plus, la colocalisation du syndécan-1 avec la synténine-1 dans les prolongements cytoplasmiques de ces cellules indique que cette dernière est recrutée dans ce processus. Nos expériences de siRNA confortent ces résultats puisque les cellules n’exprimant plus de synténine-1 sont incapables de s’étaler. La phosphorylation du motif EFYA joue donc probablement un rôle dans la régulation du recrutement de la synténine-1 influant ainsi sur les cascades de signalisation associéesThe intracellular PDZ domain-containing protein syntenin-1 functions as a scaffold protein that recruits multiple transmembrane and cytoplasmic partners to the signalling and cytoskeletal machineries. Particularly, syntenin-1 interacts with the EFYA sequence of the syndecan-1 receptor and the tyrosine residue (Y309) within this motif is essential for the interaction. The aim of our work was to analyze the potential role of this residue in the regulation of syntenin-1 binding to syndecan-1. By using a panel of syndecan-1 cytoplasmic mutants, we showed that this interaction depends on the phosphorylation level of the Y309. Further experiments with the full-length syntenin-1 or with its isolated or tandem PDZ domains demonstrated that the phosphorylation of the Y309 inhibits the PDZ binding. These results were confirmed by using EFYA peptides comprising a phosphorylated tyrosine residue. These data confirm the findings of our group, demonstrating that cell adhesion to the C-terminal domain of the laminin-332 triggers tyrosine-dephosphorylation of the syndecan-1. Moreover, syndecan-1 colocalize with syntenin-1 within cytoplasmic extensions of these cells suggesting a link between syntenin-1 and the syndecan-1 dependent membrane cytoskeleton organization. Indeed, these results were corroborated since cell spreading was prevented by siRNA assays abolishing syntenin-1 expression. Thus, phosphorylation of the EFYA sequence seems to play a role in the regulation of syntenin-1 recruitment affecting by this way the related signalling pathways
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Hamidi, Hellyeh. "The role of differential phosphorylation of syndecan-4 in cell migration." Thesis, University of Manchester, 2010. https://www.research.manchester.ac.uk/portal/en/theses/the-role-of-differential-phosphorylation-of-syndecan4-in-cell-migration(7bdf4634-5421-4ddf-a160-e60765a1ff77).html.
Full textAbstract:
Syndecans are transmembrane proteoglycans that act as receptors for extracellular matrix molecules and co-receptors for growth factors, cytokines and morphogens. Syndecan-4 is a ubiquitously expressed member of the syndecan family and encompasses a unique PKCα-binding motif within its variable region. Engagement of syndecan-4 by fibronectin regulates Rho family guanosine triphosphatase (Rho GTPase) activity to promote focal adhesion formation and reorganisation of the actin cytoskeleton that is dependent on syndecan-4-mediated PKCα activity. Recent work in our laboratory has demonstrated a role for syndecan-4 in the dynamic recycling of other fibronectin receptors, α5β1 and αVβ3 integrins. Here, it is demonstrated that phosphorylation of syndecan-4 mediated by another PKC isoform, PKCδ, and a non-receptor tyrosine kinase, Src, regulates syndecan-4-dependent GTPase activity, heterodimer-specific integrin recycling and focal adhesion formation, providing a mechanism for spatiotemporal control of cell migration.Src is associated with processes regulating adhesion disassembly and cell migration, and aberrant activation of Src contributes to neoplastic progression. Using in vitro kinase assays, syndecan-4 was identified as a target for Src-mediated phosphorylation. Mutagenesis studies coupled with mass spectrometric analysis of phosphorylation indicated the existence of two novel Src phosphorylation sites within the syndecan-4 cytoplasmic domain, tyrosine180 (Y180) and tyrosine197 (Y197). Importantly, modulation of the phospho-competence of the PKCδ-phosphorylation site (Serine179 (S179)) within syndecan-4 cytoplasmic domain increased Src-mediated syndecan-4 phosphorylation by promoting preferential phosphorylation of Y180 over Y197. Thus, PKCδ primes syndecan-4 for Src-mediated phosphorylation, functioning as a molecular switch to regulate phosphorylation of alternative tyrosine residues. In cells, Src-mediated phosphorylation of Syn4Y180 suppressed activity of the small GTPase Arf6. Similarly, phosphomimetic mutation of the PKCδ-phosphorylation site within syndecan-4 inhibited Arf6 activation in response to fibronectin engagement. These results suggested that PKCδ-dependent phosphorylation of syndecan-4 regulated Arf6 activation by controlling Src-dependent Y180 phosphorylation. Furthermore, suppression of Arf6 activity or perturbation of the S179 residue promoted membrane delivery of internalised αVβ3 integrin but not α5β1. Thus, syndecan-4-dependent Arf6 activity regulates differential recycling of α5β1 and αVβ3 integrins and is controlled by phosphorylation by PKCδ and Src. As, the other identified Src kinase target, Y197, is located within the PDZ-binding motif of syndecan-4, it was hypothesised that phosphorylation of this residue may regulate the interaction of syndecan-4 with PDZ-domain-containing proteins. Protein binding to GST-syndecan-4 constructs was assessed in pull-down assays. Interestingly, binding of syntenin, a PDZ-domain containing syndecan-4 binding partner, was inhibited in the presence of a phosphomimetic Y197 residue. By contrast, syntenin binding was enhanced in PKCδ-phosphorylation site mutants of syndecan-4 that decrease Src-dependent Y197 phosphorylation. Therefore, the phosphorylation state of Y197 is a critical determinant of syndecan-4-PDZ-binding motif interactions. Intriguingly, cells expressing a syndecan-4 receptor defective for PDZ interactions exhibited constitutive activation of Arf6 and a severe defect in syndecan-4 and integrin receptor internalisation. These data suggest that syndecan-4 endocytic pathways may be intimately associated with integrin internalisation and that interactions at the PDZ-binding motif of syndecan-4 may be critical for regulating syndecan-4 internalisation.Finally, it was demonstrated that ECM engagement of syndecan-4 induces a transient wave of PKCα activity and that this is dependent on the integrity of the PKCδ-phosphorylation site. Furthermore, perturbation of S179 or siRNA-mediated knockdown of PKCδ resulted in suppressed Rac1 activity and enhanced focal adhesion formation. Thus, PKCδ-mediated phosphorylation of syndecan-4 appears to regulate several key processes involved in cell migration including cell-surface expression of integrin heterodimers, GTPase activity and focal adhesion formation. Consequently, cells expressing a syndecan-4 receptor with mutations in the PKCδ-phosphorylation site exhibited defects in migration speed and persistence on cell-derived matrices. Together, these data suggest that in migrating cells PKCδ activity is essential to coordinate differential phosphorylation of syndecan-4 by Src on two separate residues, to spatially and temporally restrict GTPase activity, heterodimer-specific integrin recycling and focal adhesion formation.
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Berndt, Christine Charlotte. "Characterization of human syndecan-3 and its influence on the actin cytoskeleton." [S.l.] : [s.n.], 2002. http://deposit.ddb.de/cgi-bin/dokserv?idn=966003055.
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Angsana, Julianty. "The role of syndecan-1 in the resolution of chronic inflammatory responses." Diss., Georgia Institute of Technology, 2013. http://hdl.handle.net/1853/52947.
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Inflammation is an integral part of the body defense mechanism that occurs in vascularized tissue in response to harmful stimuli that is perceived as being a threat to tissue homeostasis. It is a complex physiological host response that is designed to neutralize and eliminate harmful agents, initiate tissue healing, and orchestrate a return to tissue homeostasis. While inflammation is designed to be an acute event that resolves following the elimination of harmful stimuli and tissue healing, there are instances where inflammation fails to resolve and instead evolves into chronic inflammation. It is now well understood that ongoing inflammation can serve as the underlying cause of many chronic inflammatory diseases, including atherosclerosis. In fact, one of the most pressing issues that is currently faced in the field of inflammation research, one that has also become the focus of numerous ongoing investigations, is how to turn this excessive, unwarranted and undesirable inflammation response off. Once thought to be a passive and simple process, resolution is now understood to be an active and complex process that is orchestrated by various inflammatory mediators, signaling pathways and biophysical processes. The discovery of novel biosynthetic pathways that turn on the pro-resolution signals has lead to a surge in research aimed at taking a closer look at processes that can stimulate the resolution of inflammation. While major advances in the field have resulted in a better understanding of the proactive nature of resolution, many of the mechanisms involved are still unknown. To date, the repertoire of chemokine receptors that participate in macrophage clearance during resolution, for the most part, remain unidentified. Overall, there is a growing appreciation that the discovery of mechanisms involved in the resolution responses can lead to the development of novel therapeutic approaches to resolve many chronic inflammatory diseases. Syndecan-1 (Sdc-1), a member of a family of cell surface proteoglycans, has been previously shown to regulate events relevant to tissue repair and chronic injury responses. Macrophage Sdc-1 expression during inflammation has been reported to be protective in various inflammatory models. Given these observations, we hypothesize that Sdc-1 expression on macrophages is a critical component of an anti-inflammatory, pro resolution program necessary for the successful resolution of inflammatory response. In this dissertation, we report the presence of a unique population of macrophages expressing Sdc-1 that are present within the vascular wall of mice undergoing atherosclerosis. Consistent with previous publications, the presence of Sdc-1 expressing macrophages was found to limit atherosclerosis progression. In addition, Sdc-1 expression on macrophages was associated with anti-inflammatory M2 polarization state and high intrinsic motility. Macrophage Sdc-1 expression was also linked with efferocytosis and enhanced macrophage egress from the site of inflammation to the draining lymphatic network. Moreover, we discovered that the chemokine receptor CXCR4, which was found on Sdc-1 expressing macrophages, was also involved in macrophage egress during inflammation resolution. In summary, while the overall mechanism regulating resolution processes is still unknown, our work has managed to identify two components that are involved in the process: macrophage Sdc-1 and CXCR4. Collectively, these results reinforce the physiological significance of macrophage efferocytosis and macrophage motility as endogenous modulators of the inflammatory response.
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Scarpellini, A. "Syndecan-4 regulates cell-surface trafficking and biological activity of transglutaminase-2." Thesis, Nottingham Trent University, 2009. http://irep.ntu.ac.uk/id/eprint/296/.
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Transglutaminase-2 (TG2) is a Ca2+-dependent crosslinking enzyme involved in the post-translational modification of proteins via the formation of Nε(γ-glutamyl)lysine isodipeptides. TG2 is externalised in the extracellular matrix (ECM) through an unconventional and not fully understood pathway. Under normal conditions, TG2 modulates cell adhesion, proliferation and tissue repair. Under continuous cell insult higher expression and elevated extracellular trafficking of TG2 contribute to the pathogenesis of tissue scarring. TG2 is known to have affinity for heparin, and in a previous study cell-surface heparan sulphate (HS) has been implicated in extracellular TG2 mediated RGD-independent cell adhesion, a non-enzymatic process independent from the α5β1 integrin-binding to the RGD domain on FN (Verderio et al., 2003). Hence HS proteoglycan (HSPG) could act as cell surface co-receptor for FNbound TG2 or contribute to the regulation of extracellular TG2 activity in cell adhesion and tissue repair. The aims of this study were: 1) to study the role of externalised TG2 in cell adhesion in primary fibroblasts. 2) to investigate the role of HSPG syndecan-4 (Sdc-4), a crucial component of focal adhesions in TG2-mediated cell-adhesion. 3) to characterise the interaction between TG2 and HSPG, in particular Sdc-4, and to investigate how this interaction can influence TG2 biological functions in vitro. 4) to examine the role of Sdc-4 as a regulator of pro-fibrotic TG2 activity in experimental model of kidney fibrosis (UUO). The results obtained have shown that: 1) externalised TG2 plays an important role in mediating early events of cell adhesion in primary fibroblasts. 2) FN-bound TG2 relies on the presence of Sdc-4 for its role in RGD-independent cell adhesion. 3) TG2 has a high affinity for HS (Kd ~ 20 nM) and it is associated with Sdc-4 at the cell surface in primary fibroblasts. 4) TG2 crosslinking activity at the cell surface relies on the presence of the HS chains of Sdc- 4 and other HS proteoglycans. HS-binding does not have a direct role in TG2 activity regulation, but the presence of intact Sdc-4 is essential for TG2 localisation at the cell surface. 5) Sdc-4 is protective against the development of UUO and it regulates the release and activity of the pro-fibrotic factor TG2 in UUO, suggesting a possible co-operative role of TG2 and Sdc-4 in the development of kidney fibrosis. In conclusion, HSPG, and in particular Sdc-4 emerged to have a crucial role in the cellsurface trafficking and regulation of TG2 biological activities both in vitro and in vivo.
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Bezerra, Candice Torres de Melo. "Syndecan-1: preditor de lesÃo renal aguda grave apÃs cirurgia cardÃaca pediÃtrica." Universidade Federal do CearÃ, 2016. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=17748.
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Background: Acute kidney injury (AKI) is common after pediatric cardiac surgery and is associated with adverse patient outcomes. Syndecan-1 is a biomarker of endothelial glycocalyx damage and its early increment after surgery can be associated with AKI. Objectives: evaluate Syndecan-1 and others biomarkers as predictors of severe AKI after pediatric cardiac surgery. Methods: Prospective cohort study with 289 patients less than 18 years old submitted to cardiac surgery at one reference institution. Postoperative plasma syndecan-1, intercellular adhesion molecule -1 (ICAM-1), e-selectine and neutrophil gelatinase-associated lipocalin (NGAL) were measured within the first 2 hours after cardiac surgery. Severe AKI âdefined according Kidney Disease Improvement Global Outcome (KDIGO) stage 2 or 3- doubling of serum creatinine from the preoperative value or need for dialysis during hospitalization- was the main outcome. Analyses were adjusted for clinical variables for AKI risk stratification, including age, sex, preoperative estimated glomerular filtration rate, type of surgery, use of and cardiopulmonary bypass time longer than 120 minutes and ârenal angina indexâ components - early decrease in estimated creatinine clearance from baseline and increase in % ICU fluid overload in the first day postoperative. Results: Plasma syndecan-1 measured early postoperative was independently associated with severe AKI. The accuracy of postoperative syndecan-1 for diagnosis of severe AKI was moderate (AUC-ROC of 0.77, 95% CI 0.68 â 0.85). The addition of syndecan-1 improved the discrimination capacity of a clinical model from 0.80 to 0.86 (p=0.004) and it also improved risk prediction as measured by net reclassification improvement (NRI) and integrated discrimination improvement (IDI). Postoperative sundecan-1 was also independently associated with longer length of ICU and hospital stay. N-GAL, e-selectine and I-CAM -1 were not associated with AKI and other outcomes. Conclusions: Postoperative plasma syndecan-1 is associated with subsequent severe AKI and poor outcomes among children undergoing cardiac surgery. It may be useful to identify patients who are at increased risk for AKI after cardiac surgery.IntroduÃÃo: A lesÃo renal aguda (LRA) à uma complicaÃÃo comum apÃs cirurgia cardÃaca pediÃtrica e està associada com resultados desfavorÃveis. Syndecan-1 à um biomarcador do dano ao glicocÃlix endotelial e seu aumento precoce apÃs cirurgia pode estar associado à LRA. Objetivos: avaliar o Syndecan-1 e outros biomarcadores como preditores precoces de LRA grave apÃs cirurgia cardÃaca. Metodologia: Estudo de coorte prospectivo com 289 pacientes menores de 18 anos submetidos à cirurgia cardÃaca em uma instituiÃÃo de referÃncia. Nas primeiras duas horas de cirurgia, foram realizadas as dosagens dos biomarcadores: Syndecan-1, Intercellular adhesion molecule-1 (ICAM-1), e-Selectina e Neutrophil gelatinase-associated lipocalin (NGAL). O diagnÃstico de LRA grave foi definido de acordo com a classsificaÃÃo da Kidney Disease Improving Global Outcome (KDIGO) estÃgio 2 ou 3 (duplicaÃÃo dos valores de creatinina sÃrica em relaÃÃo aos valores prÃ-operatÃrios ou necessidade de diÃlise durante internamento). As anÃlises foram ajustadas de acordo um modelo clÃnico de estratificaÃÃo de risco para LRA, com inclusÃo das seguintes variÃveis: idade, sexo, pressÃo arterial sistÃlica na admissÃo na unidade de terapia intensiva (UTI), taxa de filtraÃÃo glomerular prÃ-operatÃria, tipo de cirurgia, uso e tempo de circulaÃÃo extracorpÃrea maior que 120 minutos e componentes do Ãndice de Angina Renal (diminuiÃÃo precoce do clearance de creatinina estimado em relaÃÃo à linha de base e aumento, em porcentagem, do acÃmulo de lÃquido no primeiro dia de pÃs-operatÃrio - PO). Resultados: Syndecan-1 plasmÃtico dosado nas primeiras 2 horas de PO foi independentemente associado com LRA grave. A acurÃcia do Syndecan-1 PO para diagnÃstico de LRA grave foi moderada (Ãrea sob curva ROC de 0,77, IC 95% 0,68 â 0,85). A adiÃÃo do Syndecan-1 melhorou a capacidade discriminatÃria do modelo clÃnico de 0,80 para 0,86 (p=0,004) e tambÃm aumentou a prediÃÃo de risco para LRA, utilizando o Net reclassification improvement (NRI) e o Integrated discrimination improvement (NDI). O Syndecan-1 PO apresentou associaÃÃo direta com os tempos de permanÃncia em unidade de terapia intensiva (UTI) e hospitalar. Os outros marcadores de ativaÃÃo endotelial e o NGAL nÃo apresentam associaÃÃo LRA e nem com outros desfechos clÃnicos. ConclusÃo: Syndecan-1 plasmÃtico està associado com LRA grave subseqÃente e piores desfechos clÃnicos em crianÃas submetidas a cirurgias cÃrdicas. Pode ser um biomarcador precoce Ãtil para identificaÃÃo de pacientes com risco elevado de LRA apÃs cirurgias cardÃacas.
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Kaksonen, Marko. "Syndecan-3 in neural plasticity : from cell surface interactions to cytoskeletal regulation." Helsinki : University of Helsinki, 2002. http://ethesis.helsinki.fi/julkaisut/mat/bioti/vk/kaksonen/.
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Manakil, Jane Francis. "Syndecan-1 expression in human lymphocytes and its relationship with periodontal disease /." [St. Lucia, Qld.], 2003. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe16891.pdf.
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Cavalcante, Candice Torres de Melo Bezerra. "Syndecan-1: preditor de lesão renal aguda grave após cirurgia cardíaca pediátrica." reponame:Repositório Institucional da UFC, 2016. http://www.repositorio.ufc.br/handle/riufc/19651.
Full textAbstract:
BEZERRA, C. T. M. Syndecan-1: preditor de lesão renal aguda grave após cirurgia cardíaca pediátrica. 2016. 109 f. Tese (Doutorado em Ciências Médicas) - Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, 2016.Submitted by Erika Fernandes (erikaleitefernandes@gmail.com) on 2016-09-20T15:51:23Z No. of bitstreams: 1 2016_tese_ctmbcavalcante.pdf: 2595518 bytes, checksum: d7921e3b2c1c75e2484ddae2ca74c000 (MD5)
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Background: Acute kidney injury (AKI) is common after pediatric cardiac surgery and is associated with adverse patient outcomes. Syndecan-1 is a biomarker of endothelial glycocalyx damage and its early increment after surgery can be associated with AKI. Objectives: evaluate Syndecan-1 and others biomarkers as predictors of severe AKI after pediatric cardiac surgery. Methods: Prospective cohort study with 289 patients less than 18 years old submitted to cardiac surgery at one reference institution. Postoperative plasma syndecan-1, intercellular adhesion molecule -1 (ICAM-1), e-selectine and neutrophil gelatinase-associated lipocalin (NGAL) were measured within the first 2 hours after cardiac surgery. Severe AKI –defined according Kidney Disease Improvement Global Outcome (KDIGO) stage 2 or 3- doubling of serum creatinine from the preoperative value or need for dialysis during hospitalization- was the main outcome. Analyses were adjusted for clinical variables for AKI risk stratification, including age, sex, preoperative estimated glomerular filtration rate, type of surgery, use of and cardiopulmonary bypass time longer than 120 minutes and “renal angina index” components - early decrease in estimated creatinine clearance from baseline and increase in % ICU fluid overload in the first day postoperative. Results: Plasma syndecan-1 measured early postoperative was independently associated with severe AKI. The accuracy of postoperative syndecan-1 for diagnosis of severe AKI was moderate (AUC-ROC of 0.77, 95% CI 0.68 – 0.85). The addition of syndecan-1 improved the discrimination capacity of a clinical model from 0.80 to 0.86 (p=0.004) and it also improved risk prediction as measured by net reclassification improvement (NRI) and integrated discrimination improvement (IDI). Postoperative sundecan-1 was also independently associated with longer length of ICU and hospital stay. N-GAL, e-selectine and I-CAM -1 were not associated with AKI and other outcomes. Conclusions: Postoperative plasma syndecan-1 is associated with subsequent severe AKI and poor outcomes among children undergoing cardiac surgery. It may be useful to identify patients who are at increased risk for AKI after cardiac surgery.
Introdução: A lesão renal aguda (LRA) é uma complicação comum após cirurgia cardíaca pediátrica e está associada com resultados desfavoráveis. Syndecan-1 é um biomarcador do dano ao glicocálix endotelial e seu aumento precoce após cirurgia pode estar associado à LRA. Objetivos: avaliar o Syndecan-1 e outros biomarcadores como preditores precoces de LRA grave após cirurgia cardíaca. Metodologia: Estudo de coorte prospectivo com 289 pacientes menores de 18 anos submetidos à cirurgia cardíaca em uma instituição de referência. Nas primeiras duas horas de cirurgia, foram realizadas as dosagens dos biomarcadores: Syndecan-1, Intercellular adhesion molecule-1 (ICAM-1), e-Selectina e Neutrophil gelatinase-associated lipocalin (NGAL). O diagnóstico de LRA grave foi definido de acordo com a classsificação da Kidney Disease Improving Global Outcome (KDIGO) estágio 2 ou 3 (duplicação dos valores de creatinina sérica em relação aos valores pré-operatórios ou necessidade de diálise durante internamento). As análises foram ajustadas de acordo um modelo clínico de estratificação de risco para LRA, com inclusão das seguintes variáveis: idade, sexo, pressão arterial sistólica na admissão na unidade de terapia intensiva (UTI), taxa de filtração glomerular pré-operatória, tipo de cirurgia, uso e tempo de circulação extracorpórea maior que 120 minutos e componentes do Índice de Angina Renal (diminuição precoce do clearance de creatinina estimado em relação à linha de base e aumento, em porcentagem, do acúmulo de líquido no primeiro dia de pós-operatório - PO). Resultados: Syndecan-1 plasmático dosado nas primeiras 2 horas de PO foi independentemente associado com LRA grave. A acurácia do Syndecan-1 PO para diagnóstico de LRA grave foi moderada (área sob curva ROC de 0,77, IC 95% 0,68 – 0,85). A adição do Syndecan-1 melhorou a capacidade discriminatória do modelo clínico de 0,80 para 0,86 (p=0,004) e também aumentou a predição de risco para LRA, utilizando o Net reclassification improvement (NRI) e o Integrated discrimination improvement (NDI). O Syndecan-1 PO apresentou associação direta com os tempos de permanência em unidade de terapia intensiva (UTI) e hospitalar. Os outros marcadores de ativação endotelial e o NGAL não apresentam associação LRA e nem com outros desfechos clínicos. Conclusão: Syndecan-1 plasmático está associado com LRA grave subseqüente e piores desfechos clínicos em crianças submetidas a cirurgias cárdicas. Pode ser um biomarcador precoce útil para identificação de pacientes com risco elevado de LRA após cirurgias cardíacas.
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Leblanc, Raphaël. "Rôle de l'autotaxine dans la dissémination métastatique à l'os : implication des plaquettes sanguines, de l'intégrine Alpha V/Beta3 et du protéoglycane syndecan-4." Thesis, Lyon 1, 2014. http://www.theses.fr/2014LYO10354/document.
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L'autotaxine (ATX) est une glycoprotéine sécrétée qui grâce à son activité lysophospholipase D est à l'origine d'un lipide biologiquement actif, l'acide lysophosphatidique (LPA), dans la circulation sanguine. L'expression de l'ATX par les cellules tumorales contrôle la dissémination métastatique spontanée des cellules de cancer du sein et la formation des métastases osseuses. Au cours de cette thèse, nous avons observé que le ciblage thérapeutique précoce de l'ATX dans un modèle animal préclinique bloque de façon remarquable la dissémination métastatique des cellules de cancer du sein. Cependant les mécanismes moléculaires à l'origine de l'action du LPA sur les cellules tumorales sont mal caractérisés. Nous avons ici montré, via des expériences in vitro et in vivo, que l'ATX circulante d'origine non tumorale libérée par les plaquettes sanguines sous l'action des cellules tumorales, contrôle les évènements précoces de la dissémination métastatique. Cependant, le LPA est un lipide extrêmement sensible à l'action des phosphatases, présentes en grande quantité dans les milieux extracellulaires : l'activité du LPA serait dépendante de sa production locale, au voisinage de ses récepteurs présents à la surface des cellules. Ces travaux ont ainsi mis en évidence que le pouvoir pro-métastatique de l'ATX dépend à la fois de son interaction avec l'intégrine Alpha V/Beta3exprimée par les cellules tumorales, mais également d'un protéoglycane, Syndecan-4 présent en surface cellulaire. En conclusion, le ciblage de l’ATX via son activité ou via ses interactions présente un haut potentiel thérapeutique chez des patientes atteintes d'un cancer du sein à fort risque métastatiqueBone metastases are a frequent complication of cancer, occurring in up to 70 percent of patients with advanced breast or prostate cancer. Despite the improvement of current therapies, the survival of bone metastasis patients is only 24 months. This study aims to find new mechanisms involved in bone metastasis formation. Autotaxin (ATX/NPP2) is a secreted glycoprotein that generates lysophosphatidic acid (LPA) through its lysophospholipase D activity. Our lab previously demonstrated that ATX is overexpressed in multiple types of cancers and together with LPA generated during platelet activation promotes skeletal metastasis of breast cancer. However, the pathophysiological sequelae of regulated interactions between circulating LPA, ATX and platelets remain undefined in cancer. In this work we show that ATX is stored in a- granules of resting human platelets and released upon tumor cell-induced platelet aggregation, leading to the production of LPA. Our in vitro and in vivo experiments using human breast cancers cells that do not express ATX demonstrate that non-tumoral ATX controls the early stage of bone colonization by tumor cells. However, LPA is extremely sensitive to phosphatases, which are highly expressed in extracellular environment and at cell membranes. The molecular mechanisms involved in the local production of LPA at the bone metastatic site are still not well characterized. The present results establish that binding of ATX to alphaV/Beta3 integrin and/or the proteoglycan syndecan-4 allow LPA delivery to its receptors present at the surface of tumor cells. These results may have important implications in the development of new therapies for patients with bone metastases
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Shepherd, Tyson Robert. "Structural and thermodynamic origins of distinct ligand specificity of two homologous PDZ domains." Diss., University of Iowa, 2011. https://ir.uiowa.edu/etd/3381.
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Guanine nucleotide exchange factor proteins of the Tiam family are activators of the Rho GTPase Rac1 and critical for cell morphology, adhesion, migration, and polarity. These proteins are modular and contain a variety of interaction domains, including a previously uncharacterized post-synaptic density-95/discs large/zonula occludens-1 (PDZ) domain. Here we report on the structure, specificity, and function of the Tiam1 and Tiam2 PDZ domains.
A consensus PDZ-binding motif for Tiam1 was used to predict that two cell adhesion proteins, Syndecan 1 (Sdc1) and Caspr4, are potential Tiam1 PDZ domain binding proteins. Binding interactions were confirmed using fluorescence- and NMR- based binding experiments. The Tiam1 PDZ domain in complex with the C-terminal tails of Sdc1 and phosphorylated Sdc1 were solved using X-ray crystallography. Results showed four residues in two binding pockets in the PDZ domain are important for specificity. Cell biological analysis confirmed the Tiam1/Sdc1 interaction and showed that the PDZ domain has a function in cell-matrix adhesion and cell migration.
The four residues deemed important determinants of Tiam1 PDZ domain specificity are not conserved in Tiam2. A combinatorial peptide screen, in combination with biophysical studies, identified a consensus binding sequence for both PDZ domains. Analysis of these consensus sequences and binding assays with peptides derived from native proteins indicated that these two PDZ domains have overlapping but distinct specificities - the Tiam2 PDZ domain was found to bind Caspr4 and neurexin1 but not Sdc1. Additionally, the Tiam2 PDZ domain exhibits significant flexibility in two different regions, a feature not seen in Tiam1.
Double-mutant cycle analysis of the four important residues revealed ligand- dependent energetic couplings. Mutating all four residues switched the ligand specificity to that of Tiam2. Analysis of Tiam-family PDZ domain sequences indicated that the PDZ domains segregate into four distinct families based on the residues studied here. A set of "evolved peptides" was used to show the PDZ domain interactions are cooperative throughout the binding pocket in a ligand-specific manner. Collectively, our data suggest that Tiam family proteins have highly evolved PDZ domain/ligand interfaces with distinct specificities and that they have disparate PDZ domain-dependent biological functions.
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Neves, Fernanda Macedo de Oliveira. "Syndecan-1 na insuficiÃncia cardÃaca descompensada: associaÃÃo com a funÃÃo renal e mortalidade." Universidade Federal do CearÃ, 2014. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=14153.
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nÃo hÃIntroduÃÃo: Nas Ãltimas dÃcadas, a insuficiÃncia cardÃaca (IC) emergiu como um problema de saÃde pÃblica mundial. Dados do MinistÃrio da SaÃde de 2006 sugerem prevalÃncia de dois milhÃes de portadores de IC, sendo esta uma das principais causas de hospitalizaÃÃo entre as doenÃas cardiovasculares no Sistema Ãnico de SaÃde. LesÃo renal aguda (LRA) à uma complicaÃÃo comum em pacientes admitidos por IC. Portanto, sabe-se que a diminuiÃÃo da funÃÃo renal està associada com o aumento do risco de Ãbito, hospitalizaÃÃes e eventos cardiovasculares com importantes implicaÃÃes socioeconÃmicas. Apesar da terapia avanÃada para IC, o prognÃstico de pacientes com IC continua reservado. Objetivo: Avaliar o biomarcador syndecan-1 na admissÃo hospitalar em pacientes internados por IC descompensada e a sua associaÃÃo com lesÃo renal aguda/crÃnica. Metodologia: Trata-se de um estudo prospectivo observacional com 201 pacientes apresentando IC descompensada no departamento de emergÃncia. O estudo foi realizado em um hospital pÃblico, na cidade de Fortaleza/CE entre abril e setembro de 2013. Foi aprovado pelo Comità de Ãtica em Pesquisa do Hospital de Messejana Doutor Carlos Alberto Studart Gomes. Os pacientes foram comparados com um grupo controle composto por 15 indivÃduos sadios. A anÃlise foi realizada em amostras de soro por meio da tÃcnica de imunoensaio ligado à enzima (ELISA) e pelos ensaios bioquÃmicos. A anÃlise estatÃstica foi realizada atravÃs do programa SPSS 19.0 para Windows. Resultados: A idade mÃdia foi 64,2  13,5 anos e a fraÃÃo de ejeÃÃo (FE) calculada foi de 41.5  14.4 no momento da admissÃo. Considerando todos os pacientes, 80 (39,8 %) tinham doenÃa renal crÃnica (DRC) e 62 pacientes (37,8 %) desenvolveram ou pioraram da LRA durante a internaÃÃo. Dos pacientes com DRC, 43 pacientes mantiveram funÃÃo renal estÃvel durante a internaÃÃo hospitalar. A mÃdia de internaÃÃo hospitalar foi de 8,7  4,9 dias e mortalidade intra-hospitalar foi de 5,5%. Os pacientes IC descompensada tinham syndecan-1 sÃrico aumentado na admissÃo hospitalar (133,7  95,0 vs. 18,3  9,2, p<0,001) em comparaÃÃo ao grupo controle. O aumento do nÃvel de syndecan-1 foi observada em pacientes com LRA (mÃdia de 248,7  165.6ng/mL). Pacientes com estÃgio 2/3 de LRA (n =13) apresentaram maior nÃvel syndecan-1 em comparaÃÃo aos pacientes com estÃgio 1 de LRA (n = 63) - 443,2  281,1 vs. 178,9  100,8 ng/mL, p <0,001). A curva ROC para a previsÃo LRA foi 0,741 (IC 95% 0,669-0,812, p <0,001). Os resultados foram ainda melhores quando considerados apenas os graus mais elevados de severidade da LRA (estÃgio2/3) â curva ROC 0,840 (IC 95% 0,733-0,948, p <0,001) Na anÃlise uni variada, a concentraÃÃo de syndecan-1 como variÃvel contÃnua se correlacionou de forma significativa com a mortalidade hospitalar (OR = 1,046 com 95% CI 1,025-1,067, p<0,001 para cada 10ng/mL). AlÃm disso, nÃvel de syndecan-1 na admissÃo da emergÃncia teve boa capacidade discriminativa para prever a mortalidade hospitalar (AUC 0,788 IC 95% 0,673-0,903, p<0,001). ConclusÃo: Em pacientes com IC descompensada, syndecan-1 mensurada na prÃ-admissÃo hospitalar pode ser considerado como um biomarcador efetivo para predizer a LRA e mortalidade.
Introduction: In recent decades, heart failure (HF) has emerged as a global public health problem. Data from the Ministry of Health, 2006, suggest prevalence of two million patients with HF, thus representing one of the major causes of hospitalization among cardiovascular diseases in the Unified Health System (SUS). Acute kidney injury (AKI) is a common complication in patients admitted for HF. Therefore, it is known that the decrease of renal function is associated with increased risk of death, hospitalization, and cardiovascular events with significant socioeconomic implications. Despite the advanced therapy for HF, the prognosis of patients with HF remains guarded. Objective: To evaluate the biomarker syndecan-1 at admission in patients hospitalized for decompensated HF and its association with acute/chronic renal injury. Methods: This is a prospective observational study conducted with 201 patients with decompensated HF at the emergency department. The study took place in a public hospital in the city of Fortaleza-CE, Brazil, between April and September 2013. The Research Ethics Committee of the Hospital de Messejana Doutor Carlos Alberto Studart Gomes approved the study. We compared the patients with a control group of 15 healthy individuals. The analysis happened through serum samples applying the enzyme-linked immunosorbent assay (ELISA) technique and through biochemical assays. For statistical analysis, we used the SPSS 19.0 for Windows. Results: The mean age was 64.2 Â 13.5 years and the ejection fraction (EF) calculated was 41.5 Â 14.4 at the time of admission. Considering all the patients, 80 (39.8%) had chronic kidney disease (CKD) and 62 (37.8%) developed or worsening AKI during hospitalization. Of the patients with CKD, 43 maintained stable renal function during hospitalization. The average length of hospital stay was 8.7 Â 4.9 days and the in-hospital mortality was 5.5%. The patients with decompensated HF had increased serum syndecan-1 at admission (133.7 Â 95.0 vs. 18.3 Â 9.2, p<0.001) compared with the control group. We observed an increased level of syndecan-1 in patients with AKI (mean of 248.7 Â 165.6ng/mL). Patients with AKI stage 2/3 (n=13) had higher level of syndecan-1 compared with patients with AKI stage 1 (n=63) (443.2 Â 281.1 vs. 178.9 Â 100.8 ng/mL, p <0.001). The ROC curve for AKI prediction was 0.741 (95% CI 0.669-0.812, p<0.001). The results were even better when considering only the highest levels of AKI severity (stage 2/3) â ROC curve 0.840 (95% CI 0.733-0.948, p<0.001). In the univariate analysis, the concentration of syndecan-1 as a continuous variable was significantly correlated with hospital mortality (OR=1.046 95% CI 1.025-1.067, p<0.001 for each 10ng/mL). Additionally, the level of syndecan-1 at admission on emergency had good discriminative ability to predict hospital mortality (AUC 0.788 95% CI 0.673-0.903, p<0.001). Conclusion: In patients with decompensated HF, syndecan-1 measured in the pre-hospital admission can be considered as an effective biomarker to predict AKI and mortality.
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Bret, Caroline. "Biologie de syndecan-1 au cours du myélome multiple : synthèse, modifications et inhibition." Thesis, Montpellier 1, 2010. http://www.theses.fr/2010MON1T012.
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Ce travail de thèse a eu pour thème principal le protéoglycane syndecan-1 au cours du myélome multiple, une hémopathie maligne caractérisée par la présence d'un clone de plasmocytes tumoraux au sein de la moelle osseuse. Syndecan-1 est un élément majeur de la physiopathologie du myélome multiple, ce protéoglycane étant au coeur d'un réseau complexe d'interactions moléculaires conditionnant le devenir des cellules plasmocytaires tumorales.Les chaînes de glycosaminoglycanes présentes sur le core protéique de syndecan-1sont responsables d'une grande partie de son activité. Nous avons ainsi caractérisé, par une approche transcriptomique, 100 gènes codant les protéines impliquées dans la synthèse et la modification de ces chaînes. Nous avons de cette manière identifié des cibles moléculairesen vue de moduler, voire d'inhiber leur activité.Dans le but d'identifier les métalloprotéinases des familles ADAM et ADAMTS susceptibles d'interagir avec syndecan-1, nous avons réalisé l'étude du profil d'expression des gènes codant ces reprolysines et leurs inhibiteurs dans les cellules de la différentiation lymphocytaire B, les cellules plasmocytaires normales et tumorales ainsi que dans l'environnement médullaire.Dans une dernière partie, nous avons évalué l'efficacité d'une approche d'inhibitiondes chaînes héparanes sulfates via l'utilisation de l'héparine. Nous observons que certaines lignées myélomateuses sont inhibées par l'héparine et ses dérivés et que ces mêmes lignées sont stimulées par l'antidote de l'héparine, le sulfate de protamine. Les mécanismes mis enjeu sont en relation avec la modulation de la biodisponibilité des facteurs permettant la croissance des cellulesMultiple myeloma is a hematological malignancy characterized by the expansion of aclone of malignant plasma cells in the bone marrow compartment. Syndecan-1 is a majorproteoglycan involved in a complex network of molecular interactions in multiple myelomaphysiopathology. As heparan sulfate and chondroitin sulfate chains are the bioactive components ofsyndecan-1, we first analysed the signature of genes encoding 100 proteins involved in thesynthesis of these chains, from precursor uptake to post-translational modifications, usingAffymetrix microarrays.In order to identify the metalloproteinases belonging to ADAM and ADAMTS familiespotentially implicated in the interactions with syndecan-1, we performed a gene expressionprofile focused on the genes encoding these reprolysines and their inhibitors.In a last part, we evaluated the efficacy of an inhibitory approach based on theutilization of heparin in human myeloma cell lines in vitro, inhibitory effects being in relationwith a modulation of the biodisponibility of heparin-binding factors.This work led us to identify targets of interest in relation with syndecan-1 biology inmultiple myeloma. They could be used to design new therapeutic strategies
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Olszewska, Ewa Hanna [Verfasser], and Peter [Akademischer Betreuer] Bruckner. "Rolle von Syndecan-4 bei der Chondrozytendifferenzierung / Ewa Hanna Olszewska. Betreuer: Peter Bruckner." Münster : Universitäts- und Landesbibliothek der Westfälischen Wilhelms-Universität, 2011. http://d-nb.info/1027018270/34.
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Neves, Fernanda Macedo de Oliveira. "Syndecan-1 na insuficiência cardíaca descompensada : associação com a função renal e mortalidade." reponame:Repositório Institucional da UFC, 2014. http://www.repositorio.ufc.br/handle/riufc/12229.
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NEVES, Fernanda Macedo de Oliveira. Syndecan-1 na insuficiência cardíaca descompensada : associação com a função renal e mortalidade. 2014. 71 f. Dissertação (Mestrado em Ciências Médicas) – Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, 2014.Submitted by denise santos (denise.santos@ufc.br) on 2015-05-18T11:25:42Z No. of bitstreams: 1 2014_dis_fmoneves.pdf: 1538148 bytes, checksum: 0839f637c9fb390c68a802ea67650486 (MD5)
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Introduction: In recent decades, heart failure (HF) has emerged as a global public health problem. Data from the Ministry of Health, 2006, suggest prevalence of two million patients with HF, thus representing one of the major causes of hospitalization among cardiovascular diseases in the Unified Health System (SUS). Acute kidney injury (AKI) is a common complication in patients admitted for HF. Therefore, it is known that the decrease of renal function is associated with increased risk of death, hospitalization, and cardiovascular events with significant socioeconomic implications. Despite the advanced therapy for HF, the prognosis of patients with HF remains guarded. Objective: To evaluate the biomarker syndecan-1 at admission in patients hospitalized for decompensated HF and its association with acute/chronic renal injury. Methods: This is a prospective observational study conducted with 201 patients with decompensated HF at the emergency department. The study took place in a public hospital in the city of Fortaleza-CE, Brazil, between April and September 2013. The Research Ethics Committee of the Hospital de Messejana Doutor Carlos Alberto Studart Gomes approved the study. We compared the patients with a control group of 15 healthy individuals. The analysis happened through serum samples applying the enzyme-linked immunosorbent assay (ELISA) technique and through biochemical assays. For statistical analysis, we used the SPSS 19.0 for Windows. Results: The mean age was 64.2 ± 13.5 years and the ejection fraction (EF) calculated was 41.5 ± 14.4 at the time of admission. Considering all the patients, 80 (39.8%) had chronic kidney disease (CKD) and 62 (37.8%) developed or worsening AKI during hospitalization. Of the patients with CKD, 43 maintained stable renal function during hospitalization. The average length of hospital stay was 8.7 ± 4.9 days and the in-hospital mortality was 5.5%. The patients with decompensated HF had increased serum syndecan-1 at admission (133.7 ± 95.0 vs. 18.3 ± 9.2, p<0.001) compared with the control group. We observed an increased level of syndecan-1 in patients with AKI (mean of 248.7 ± 165.6ng/mL). Patients with AKI stage 2/3 (n=13) had higher level of syndecan-1 compared with patients with AKI stage 1 (n=63) (443.2 ± 281.1 vs. 178.9 ± 100.8 ng/mL, p <0.001). The ROC curve for AKI prediction was 0.741 (95% CI 0.669-0.812, p<0.001). The results were even better when considering only the highest levels of AKI severity (stage 2/3) – ROC curve 0.840 (95% CI 0.733-0.948, p<0.001). In the univariate analysis, the concentration of syndecan-1 as a continuous variable was significantly correlated with hospital mortality (OR=1.046 95% CI 1.025-1.067, p<0.001 for each 10ng/mL). Additionally, the level of syndecan-1 at admission on emergency had good discriminative ability to predict hospital mortality (AUC 0.788 95% CI 0.673-0.903, p<0.001). Conclusion: In patients with decompensated HF, syndecan-1 measured in the pre-hospital admission can be considered as an effective biomarker to predict AKI and mortality.
Introdução: Nas últimas décadas, a insuficiência cardíaca (IC) emergiu como um problema de saúde pública mundial. Dados do Ministério da Saúde de 2006 sugerem prevalência de dois milhões de portadores de IC, sendo esta uma das principais causas de hospitalização entre as doenças cardiovasculares no Sistema Único de Saúde. Lesão renal aguda (LRA) é uma complicação comum em pacientes admitidos por IC. Portanto, sabe-se que a diminuição da função renal está associada com o aumento do risco de óbito, hospitalizações e eventos cardiovasculares com importantes implicações socioeconômicas. Apesar da terapia avançada para IC, o prognóstico de pacientes com IC continua reservado. Objetivo: Avaliar o biomarcador syndecan-1 na admissão hospitalar em pacientes internados por IC descompensada e a sua associação com lesão renal aguda/crônica. Metodologia: Trata-se de um estudo prospectivo observacional com 201 pacientes apresentando IC descompensada no departamento de emergência. O estudo foi realizado em um hospital público, na cidade de Fortaleza/CE entre abril e setembro de 2013. Foi aprovado pelo Comitê de Ética em Pesquisa do Hospital de Messejana Doutor Carlos Alberto Studart Gomes. Os pacientes foram comparados com um grupo controle composto por 15 indivíduos sadios. A análise foi realizada em amostras de soro por meio da técnica de imunoensaio ligado à enzima (ELISA) e pelos ensaios bioquímicos. A análise estatística foi realizada através do programa SPSS 19.0 para Windows. Resultados: A idade média foi 64,2 ± 13,5 anos e a fração de ejeção (FE) calculada foi de 41.5 ± 14.4 no momento da admissão. Considerando todos os pacientes, 80 (39,8 %) tinham doença renal crônica (DRC) e 62 pacientes (37,8 %) desenvolveram ou pioraram da LRA durante a internação. Dos pacientes com DRC, 43 pacientes mantiveram função renal estável durante a internação hospitalar. A média de internação hospitalar foi de 8,7 ± 4,9 dias e mortalidade intra-hospitalar foi de 5,5%. Os pacientes IC descompensada tinham syndecan-1 sérico aumentado na admissão hospitalar (133,7 ± 95,0 vs. 18,3 ± 9,2, p<0,001) em comparação ao grupo controle. O aumento do nível de syndecan-1 foi observada em pacientes com LRA (média de 248,7 ± 165.6ng/mL). Pacientes com estágio 2/3 de LRA (n =13) apresentaram maior nível syndecan-1 em comparação aos pacientes com estágio 1 de LRA (n = 63) - 443,2 ± 281,1 vs. 178,9 ± 100,8 ng/mL, p <0,001). A curva ROC para a previsão LRA foi 0,741 (IC 95% 0,669-0,812, p <0,001). Os resultados foram ainda melhores quando considerados apenas os graus mais elevados de severidade da LRA (estágio2/3) – curva ROC 0,840 (IC 95% 0,733-0,948, p <0,001) Na análise uni variada, a concentração de syndecan-1 como variável contínua se correlacionou de forma significativa com a mortalidade hospitalar (OR = 1,046 com 95% CI 1,025-1,067, p<0,001 para cada 10ng/mL). Além disso, nível de syndecan-1 na admissão da emergência teve boa capacidade discriminativa para prever a mortalidade hospitalar (AUC 0,788 IC 95% 0,673-0,903, p<0,001). Conclusão: Em pacientes com IC descompensada, syndecan-1 mensurada na pré-admissão hospitalar pode ser considerado como um biomarcador efetivo para predizer a LRA e mortalidade.
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Sayyad, Megan R. "The role of Syndecan-1 and extracellular vesicles in breast cancer brain metastasis." VCU Scholars Compass, 2019. https://scholarscompass.vcu.edu/etd/5874.
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Breast cancer metastasizes to the brain in 15-30% of all breast cancer cases, and metastasis is the predominant cause of breast cancer-related deaths. Patients with HER2-enriched and triple-negative breast cancers (TNBCs) are more likely to develop brain metastases. While targeted therapies exist for HER2-enriched breast cancers, there are no effective treatments for TNBCs. Thus, a greater understanding of how these cancers spread to the brain is critical. In order to spread to the brain, disseminated breast cancer cells must overcome 2 major steps—crossing the blood-brain barrier (BBB) and survival and successful colonization of the distinctive and mostly cellular brain environment. Here, we report a novel role for breast cancer cell surface receptor, Syndecan-1 (Sdc1), a heparan sulfate proteoglycan, in promoting breast cancer cell transmigration across the BBB. We found that when we silenced Sdc1 expression in a highly metastatic TNBC cell line, MDA-MB-231, these cells exhibited reduced migration across an in vitro BBB model system. Further, in an in vivo experimental model of metastasis, mice injected with MDA-MB-231 Sdc1 KD (knock-down) cells developed less brain metastases than mice injected with control non-silencing (NS1) cells. Conversely, we found that overexpression of Sdc1 in a metastatic triple-negative mouse mammary carcinoma cell line, 4T1, led to an increase in brain metastases compared to empty vector control-treated mice. We predicted that a secreted factor(s) facilitated BBB disruption that allowed for Sdc1-mediated BBB transmigration, and found that silencing Sdc1 led to decreases in the production and/or release of various cytokines and chemokines implicated in BBB permeability and transmigration. In addition to supporting BBB transmigration, through an in vitro tissue section adhesion assay, we found that Sdc1 also facilitates adhesion of breast cancer cells to the brain, and not to the liver or lungs, revealing specificity for the brain. Further, we report that Sdc1 is expressed in 81% of breast cancer patient brain metastases in our tissue microarray study and that patients with TNBC and high Sdc1 expression have shorter disease-free survival based on a study performed using data from The Cancer Genome Atlas. Taken together, we predict that breast cancer cell Sdc1-regulated cytokines and chemokines promote BBB permeability and/or support transmigration to facilitate breast cancer metastasis to the brain.
We also provide evidence for breast cancer-secreted extracellular vesicles, namely exosomes, in supporting the formation of a pro-metastatic brain environment. We compared exosomes derived from the metastatic 4T1 mouse mammary carcinoma cell line to a non-metastatic counterpart, the 67NR cell line, to assess their microRNA and protein composition and their effect(s) on recipient astrocytes, known mediators of brain metastasis. We found that there are inherent differences in both the microRNA and protein cargo from the metastatic 4T1 cells compared to the non-metastatic 67NR cells, whereby the metastatic 4T1 cells contained various tumor-promoting microRNAs and proteins, and also contained 4.5-fold more protein than the non-metastatic 67NR cells. Mouse astrocytes treated with the metastatic 4T1 exosomes exhibited a shift towards a pro-metastatic phenotype, characterized by upregulation of pro-inflammatory genes, and genes associated with astrocyte reactivity and cancer, whereby 67NR exosome-treated astrocytes exhibited a response profile that overlapped with untreated controls. Overall, these findings reveal an important role for exosomes in driving changes in the brain microenvironment to create a site conducive for cancer growth. Together, both studies help to elucidate how breast cancer cells can invade and colonize the unique brain environment.
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Haddad, Oualid. "Etude des effets pro-angiogéniques du fucoïdane de bas poids moléculaire : implication des syndécannes et des enzymes impliquées dans la biosynthése et la dégradation des héparanes sulfates." Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCD078.
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L’ischémie se définit par la réduction de la lumière d’un vaisseau, ce qui provoque dans les tissus une baisse du flux sanguin, et une hypoxie locale. Pour lutter contre l’ischémie, différentes thérapies pro-angiogéniques ont été développées afin de stimuler la formation de nouveaux vaisseaux à partir des vaisseaux préexistants. Durant ma thèse j’ai étudié l’effet pro-angiogénique du fucoïdane, un polysaccharide sulfaté provenant de l’algue brune, qui est un mimétique de glycosaminoglycanes (GAGs). Nous avons choisi le fucoïdane de bas poids moléculaire (LMWF), qui a une bonne affinité pour des facteurs pro-angiogéniques(VEGF, SDF-1/CXCL12). Puis, nous avons analysé son effet dans les cellules endothéliales humaines (HUVEC). Nos résultats montrent que LMWF est internalisé par les HUVEC en 2h par la voie d’endocytose clatherine-dépendante. De plus, LMWF stimule la viabilité, la migration des HUVEC et la formation de réseaux vasculaires. Nous avons démontré par la suite qu’en absence de GAGs sur les HUVEC, le LMWF garde toujours son potentiel pro-angiogénique. Nous avons mis en évidence que l’exostosine-2(EXT-2), l’héparanase (HPSE) et le syndécane-4 (SDC-4), sont impliqués dans l’effet pro-angiogénique du LMWF, puisque quand nous inhibons leurs expressions par ARN interférence, le pouvoir pro-angiogénique du LMWF est diminué. Nous avons démontré,dans le modèle d’hyperplasie intimale chez le rat, que le LMWF a un effet opposé sur l’expression des SDC. En effet, le LMWF induit l’expression du SDC-1 et diminue celle duSDC-4 dans la néo-intima. Nos données indiquent que l'EXT2, l'HPSE et le SDC-4 sont impliqués dans les effets pro-angiogéniques du LMWF, suggérant que les changements du métabolisme des HS liés à l'angiogenèse induite par le LMWF offrent la possibilité d'une nouvelle approche thérapeutique pour le traitement des maladies ischémiquesInduction of angiogenesis is a potential treatment for chronic ischemia. In this study we propose the analysis of pro-angiogenic treatment with fucoidan, sulfated polysaccharide from brown seaweeds, which act as glycosaminoglycans mimetics. Herein we used the low molecular weight fucoidan (LMWF), which presents a good affinity for pro-angiogenic factors(VEGF, SDF-1/CXCL12). The LMWF was mainly internalized through human vascular endothelial cell (HUVEC) clathrin-dependent endocytosis (in 2h) in which GAGs were partially involved. Our results showed that LMWF induced migration and angiogenesis in HUVEC. Interestingly, in a GAG-free HUVECs model, LMWF still kept a pro-angiogenic potential. In addition, we reported the implication of two heparan sulfate (HS) metabolism enzymes, exostosin-2 (EXT2) and heparanase (HPSE), and syndecan-4 (SDC-4) in LMWF induced angiogenesis. LMWF-treated and EXT2- or HPSE-siRNA-transfected cells shows that EXT2 or HPSE expression significantly affects the LMWF pro-angiogenic potential. In addition, LMWF increased SDC-1, but decreased SDC-4 expression. We studied the LMWF implication in SDC-1 and SDC-4 expression in rat model of intimal hyperplasia after balloon injury. Our results showed that LMWF treatment of injured artery increased SDC-1 expression, but decreased SDC-4 expression in the neointima layer. Our data indicate that EXT2, HPSE, and SDC-4 are involved in the pro-angiogenic effects of LMWF, suggesting that the HS metabolism changes linked to LMWF-induced angiogenesis offer the opportunity for new therapeutic approach for ischemic diseases treatment
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Croce, Daniel. "Investigation of Syndecan-1 Ectodomain Isolated from Chinese Hamster Ovary (CHO) Cell Culture Medium." Thesis, Uppsala universitet, Institutionen för medicinsk biokemi och mikrobiologi, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-256771.
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Syndecan-1 is a cell surface proteoglycan which participates in cell adhesion, differentiation, motility, morphogenesis and intracellular signaling. The two glycosaminoglycans heparan sulfate and chondroitin sulfate are covalently attached to the ectodomain of syndecan-1 via a tetra saccharide linkage sequence. However, the ectodomain can be modified having only one or neither of the glycosaminglycans attached. The glycosaminoglycans are capable of binding ligands such as fibroblast growth factors (FGFs) and support activation of receptors. The ectodomain is proteolytically cleaved from the cell surface by metalloproteinases in a process known as shedding. Shedding turns the ectodomain into a soluble effector which can stimulate other cells in the surroundings by delivering growth factors and also translocate into cells through endocytosis. In this study the aim was to find out if a modified ectodomain, which only contains chondroitin sulfate, could support intracellular signaling in the absence of heparan sulfate. The aim was also to find out whether a modified ectodomain could translocate into the cell. The methods used were cell culturing, isolation and purification of syndecan-1 ectodomain, cell signaling and immunohistochemistry. It was found that modified shed syndecan-1 ectodomain was able to support intracellular signaling almost to the same degree as wild type syndecan-1 ectodomain. This may suggest that heparan sulfate does not have to be present on the ectodomain to support intracellular signaling, although the signal is slightly higher when present. When trying to detect translocation of the ectodomain the results were too uncertain and further research is required.
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Ntounia-Fousara, Sofia. "The role of adamalysins in the shedding of syndecan-1 from breast cancer cells." Thesis, University of East Anglia, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.426573.
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Altergot-Ahmad, Olga [Verfasser]. "Der Chemokin-regulierende Einfluss von Syndecan-1 auf die embryonale Implantation / Olga Altergot-Ahmad." Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2015. http://d-nb.info/1073969932/34.
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Münch, Phillip. "Syndecan-1 und Heparansulfat als Biomarker der endothelialen Glykokalyx im Infarkt-assoziierten kardiogenen Schock." Doctoral thesis, Universitätsbibliothek Leipzig, 2017. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-218142.
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Trotz enormer Fortschritte in der Therapie, bleibt der kardiogene Schock die führende Todesursache im akuten Myokardinfarkt. Die pathophysiologischen Veränderungen umfassen dabei unter anderem Störungen der Mikrozirkulation, endotheliale Dysfunktion mit vaskulärer Leckage, sowie vermehrte Thrombozyten- und Leukozytenadhäsion an die Gefäßwand. Die endotheliale Glykokalyx wurde als zentraler Regulator dieser Prozesse identifiziert. Das Glykosaminoglykan Heparansulfat repräsentiert dabei den Hauptbestandteil der Endothelzelloberfläche und Syndecan-1 das am weitesten verbreitete Proteoglykan. Diesbezüglich konnte in Studien eine Assoziation zwischen Schädigung der endothelialen Glykokalyx und den zirkulierenden Membranbestandteilen im Patientenblut beobachtet werden.
Ziel der Arbeit war die Analyse der Glykokalyxmarker bei 184 Patienten mit Infarkt-assoziiertem kardiogenen Schock. In den Serumproben zum Zeitpunkt der Aufnahme und nach einem Tag wurde mittels ELISA die Konzentration von Heparansulfat und Syndecan-1 bestimmt.
Dabei zeigte sich ein signifikanter Konzentrationsabfall von Syndecan-1 innerhalb des Analysezeitraums. Des Weiteren hatten die Überlebenden an beiden Tagen signifikant niedrigere Syndecan-1-Serumwerte. Durch eine schrittweise Multiregressionsanalyse wurde Syndecan-1 bei Patienten mit akutem Myokardinfarkt und assoziiertem kardiogenen Schock als unabhängiger Prädiktor der 30-Tage- Mortalität identifiziert.
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Rousseau, Caroline. "Cancer du sein triple négatif : ciblage du Syndecan-1 pour la radioimmunothérapie et l'immunoTEP." Nantes, 2012. https://archive.bu.univ-nantes.fr/pollux/show/show?id=7eec5118-11ae-4e7f-a439-7d8f081c406f.
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La première partie de ce travail avait pour objectif d'évaluer la toxicité et l'efficacité de la radioimmunothérapie (RIT) avec l'anticorps monoclonal humain B-B4 (anti-CD138) marqué à l'iode 131 dans un modèle de souris nude greffée avec une lignée humaine de cancer du sein triple négatif MDA-MB-468. Malgré l'expression relativement faible du nombre de sites antigéniques CD138 par cellule (Bmax=1,19. 104±9,27. 102), la fixation tumorale du 125I-B-B4 a atteint un maximum de 14% de l'activité injectée par gramme, 24h après l'injection. La toxicité avec le 131I-B-B4 a été hématologique. A la dose maximale tolérée déterminée à 22,2 MBq, 3 réponses partielles et 5 réponses complètes ont été obtenues chez les 8 souris traitées, avec une absence de reprise évolutive à 95 jours pour 3 d'entre elles. La RIT avec le 131I-B-B4 apparaît donc une alternative thérapeutique du cancer du sein triple négatif métastatique. La deuxième partie de ce travail avait pour objectif de comparer l'immuno-TEP (iTEP) avec le 124I-B-B4 à l'imagerie FDG et FLT et aux données de pharmacocinétique et de biodistribution obtenues avec le 124I-B-B4, afin de valider l'iTEP ciblant le CD138 dans le même modèle de cancer du sein triple négatif. Les données de pharmacocinétique obtenues à partir de l'imagerie ou de la biodistribution au 124I-B-B4 ont été concordantes. Les rapports Tumeur/Muscle en TEP FDG et TEP FLT ont été respectivement de 1,67±0,24 et 5,28±0,49, inférieurs à celui calculé pour l'iTEP (12,17±0,62 à 96h). Ce travail confirme la faisabilité de l'approche d'iTEP avec le 124I-B-B4 pour les carcinomes mammaires triples négatifs, avec des intérêts potentiels diagnostiques et pré-thérapeutiquesThe objective of the first part of this research was to evaluate the toxicity and the efficiency of radioimmunotherapy (RIT) with a monoclonal human anti-body B-B4 (anti-CD138) labelled with iodine 131 in a nude mouse model grafted with a human line of triple-negative breast cancer MDA-MB-468. Despite the relatively low expression of the number of CD138 antigen sites per cell (Bmax=1,19. 104±9,27. 102), the tumoral attachment of 125I-B-B4 reached a maximum of 14% of activity injected per gram, 24 hours after the injection. Toxicity with 131I-B-B4 was haematological. With the maximum tolerated dose determined to be 22. 2 MBq, three partial and five complete responses were obtained on eight treated mice, with an absence of relapse at 95 days for three of them. RIT with 131I-B-B4 would therefore appear to be an alternative therapy for triple-negative metastatic breast cancer. The objective of the second part of this research was to compare the iPET with 124I-B-B4 with FDG and FLT imaging and with pharmacokinetic and biodistribution data obtained with 124I-B-B4, in order to validate iPET targeting CD138 in the same model of triple-negative breast cancer. The pharmacokinetic data obtained from imaging or biodistribution with 124l-B-B4 was concordant. Tumor/Muscle ratios in FDG PET and FLT PET were respectively 1. 67±0. 24 and 5. 28±0. 49, lower than that calculated for iPET (12. 17±0. 62 at 96 hours). This research confirms the feasibility of the iPET approach with 124I-B-B4 for triple-negative mammary carcinomas with potential diagnostic and pre-therapeutic interests
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Julien, Mathéau A. "Mechanical Strain-Mediated Syndecan Regulation and Its Effects on Adhesion of Vascular Smooth Muscle Cells." Diss., Georgia Institute of Technology, 2005. http://hdl.handle.net/1853/7007.
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An injured vascular system has a substantial impact on an individuals overall health, and an understanding of the mechanisms that underlie blood vessel pathophysiology is required for the development of rational and effective treatment strategies. The phenotypic modulation of smooth muscle cells (SMC) during vascular injury, characterized by altered adhesion, migration and synthetic behavior, plays an important role in the eventual outcome. Specifically, the ability of SMCs to adhere to and remodel their extracellular environment via regulation of the syndecan class of cell adhesion molecules dictates the response of the vascular wall to local injury. The effect of in vitro syndecan-4 regulation on SMC adhesion was investigated through the use of a glass microsphere centrifugation assay, and an antisense-mediated reduction in gene expression was found to correlate with decreased adhesive strength. Regulation of syndecan-1, syndecan-2, and syndecan-4 gene expression was observed experimentally by mechanical strain of SMCs. Using real-time polymerase chain reaction (PCR), the kinetics of both static and cyclic mechanical strain were found to modify the gene expression in a time and strain magnitude-dependent manner unique to each syndecan. In particular, the responses of syndecan-4 were acute, but transient, while the evolution of syndecan-1 and syndecan-2 regulation was delayed by comparison. Mechanical strain also modulated syndecan-4 protein expression and ectodomain shedding, as measured by Western immunoblotting, and this effect was found, through selective inhibition, to be at least in part dependent on mitogen-activated protein (MAP) kinase signaling. In particular, intact extracellular signal-regulated MAP kinase (ERK) 1/2 and c-Jun NH2-terminal kinase / stress-activated protein kinase (JNK/SAPK) signaling pathways were found to be required for the observed strain-induced shedding. These findings offer a better understanding of syndecan function in response to mechanical strain and suggest potential new mechanisms by which physical forces may modulate vascular SMC behavior and regulation during normal physiology, pathologic conditions, and engineered arterial substitute development.
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Mundhenke, Heidi [Verfasser]. "Bedeutung der Syndecan-1 Expression beim Ductalen Carcinoma in situ der Mamma (DCIS) / Heidi Mundhenke." Kiel : Universitätsbibliothek Kiel, 2014. http://d-nb.info/1059391023/34.
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Mahtouk, Karène. "Syndecan-1 : un partenaire indispensable des membres de la famille EGF dans le myélome multiple." Montpellier 2, 2005. http://www.theses.fr/2005MON20107.
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Markiewicz, Anna Maria. "Impact of syndecan-4 on T cell-antigen presenting cell recognition and the immunological synapse." Thesis, Imperial College London, 2011. http://hdl.handle.net/10044/1/6987.
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Syndecan-4 (SDC-4), a transmembrane heparan sulphate proteoglycan and a co-receptor of integrins for fibronectin, has been reported to modulate the adhesion of cells to a range of extracellular matrix ligands. In addition to the modulation of integrins, SDC-4 has been recently reported to modify the interaction of some growth factors with their receptors. T cells are essential effectors of the adaptive immune response. When conjugating with antigen-presenting cells (APCs), T cells transform their shape to enable formation of a specialised morphological structure, called the immunological synapse (IS). The IS formation is associated with the polarisation of signalling and adhesive molecules towards the APC. The IS is formed and stabilized by similar adhesive forces and structures as in the motile fibroblasts - an extensively studied model of syndecan function. In this thesis I have investigated the role of SDC-4 in T cell - APC recognition and the IS. First, I confirmed the tight regulation of SDC-4 expression in T cells during the process of activation. Flow cytometry and PCR data demonstrate increased presence of SDC-4 in stimulated human T cells compared to their resting counterparts, indicating involvement of SDC-4 in the processes of T cell activation. Transient transfection of exogenous SDC-4 into Jurkat T cells with low endogenous SDC-4 expression was used as a model to study the effect of increased SDC-4 expression on T cell function. Using live cell imaging and advanced data image analysis I have quantitatively demonstrated that SDC-4 transfected Jurkat T cells are less likely to modify their shape during IS formation when compared to mock transfected Jurkat T cells. I also observed a delay in T cell antigenic response caused by SDC-4 over-expression. Moreover, I was able to visualise the exogenous SDC-4 in the IS using confocal microscopy and demonstrate the independence of this phenomenon on T cell receptor. In summary, my observations indicate a regulatory role for SDC-4 in T cell adhesion causing delays in the IS formation and reduced transformation of T cell shape during conjugate formation.
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Lefevre, Mathieu. "Rôle de l'apoliprotéine E dans le cycle du virus de l'hépatite C." Thesis, Strasbourg, 2014. http://www.theses.fr/2014STRAJ003.
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L’infection par le virus de l’hépatite C (HCV) est une cause majeure de maladies hépatites sévères et constitue un problème majeur de santé public. Le HCV est associé aux lipopoprotéines formant une lipoviroparticule (LVP) qui est la forme infectieuse du virus. L’apolipoprotéine E (apoE), associée aux lipoprotéines, est impliquée dans les étapes précoces et tardives de l’infection. Elle interagit avec de récepteurs impliqués dans le métabolisme lipidique tels les héparanes sulfates protéoglycanes (HSPG). Durant ma thèse, j’ai démontré que les acides aminés chargés positivement du domaine de liaison aux HSPG d’apoE sont impliqués dans l’entrée du HCV dans l’hépatocyte. J’ai également démontré que la production et/ou l’infectiosité des particules virales est corrélée au taux d’expression d’apoE dans les cellules sans avoir d’impact sur la traduction ou la réplication virales. Enfin, j’ai identifié syndecan-4, un membre de la famille des HSPG, comme l’HSPG principal impliqué dans l’entrée du HCV dans les lignées Huh7.5.1. L’ensemble de ces résultats démontre qu’HCV utilise l’interaction apoE-SDC4 pour établir une infection virale efficaceHepatitis C virus (HCV) infection is a major cause of liver disease worldwide and represents a major health problem. HCV associates with host lipoproteins forming host/viral hybrid complexes termed lipoviral particles. Apolipoprotein E (apoE) is a lipoprotein component that interacts with heparan sulfate proteoglycans (HSPG) to mediate hepatic lipoprotein uptake, and may likewise mediate HCV entry. I sought to define the functional regions of apoE with an aim to identify critical apoE binding partners involved in HCV infection. I demonstrated a direct correlation of apoE expression and HCV infectivity, whereas no correlation exists with viral protein translation or replication. Mutating the HSPG binding domain (HSPG-BD) of apoE revealed key residues that are critical for mediating HCV infection. Finally, I identified Syndecan-4 (SDC4), an HSPG family member, as the principal HSPG mediating HCV entry. Our data demonstrate that HCV uses apoE-SDC4 interactions to enter hepatocytes and establish efficient viral infection