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Duval, Stéphanie. "Imagerie du microenvironnement matriciel tumoral : les héparanes mimétiques". Thesis, Tours, 2014. http://www.theses.fr/2014TOUR3802.
Pełny tekst źródłaHeparan sulfate proteoglycans (HSPG), like all proteoglycans (PG), consisting of a protein portion and a glycosaminoglycan (GAG), heparan sulphate (HS) for HSPG. They are part of the extracellular matrix (ECM). PG are able, through their GAG, to bind a number of partners such as growth factors, chemokines, cytokines or enzymes. They regulate the bioavailability of many soluble mediators and thus their biological activity. They are thus involved in the regulation of many processes such as proliferation, differentiation, tissue remodeling, angiogenesis... In addition, it was shown that the binding of proteins having a heparan binding site (HB) with HS of HSPG protect them from enzymatic degradation. However, HSPG are among the first components of the ECM to be digested by heparanase during cellular tissue damage. This digestion makes HB sites available and proteins are sensitive to proteolytic degradation. It is in order to protect the HSBP (heparan sulfate binding protein) that was developed technology heparan mimetics (HM) that will replace the degraded HS on available HB sites and protect proteins of middle injured. These HM, already used as a therapeutic agent of the ECM, are identified in this use under the symbol RGTA for regenerating agent because they increase the speed and quality of the tissue repair, potentially leading to a true tissue regeneration. During tumor development and metastasis, it has been shown that the enzymatic activity of heparanase is multiplied, leading to an increased degradation of HS. In this context, the HM will be able to fix this matrix injured hence the idea of their diagnostic use in oncology. Using labeled HM (HM*) with a radioisotope such as fluorine-18 (18F) and followed by molecular imaging PETScan (positon emission tomography with scanner associated) should allow a particularly efficient marking of the matrix surrounding metastatic and tumor cells. HM* could indeed target ECM involved, through its early degradation in the processes of tumor growth and tumor spread and become a new marker oncology in molecular imaging. To date, among the various studied cancer markers, none address the matrix compartment. The use of HM* should allow the detection of peri-tumor and find a place in the early diagnosis of cancer and the therapeutic monitoring
Alavi, Naini Seydeh Maryam. "Etude de la physiopathologie des tauopathies dans le modèle de poisson zèbre : Implication des héparanes sulfates". Paris 7, 2014. http://www.theses.fr/2014PA077215.
Pełny tekst źródłaTauopathies are a class of neurodegenerative diseases that include Alzheimer's disease and frontotemporal dementia. A cardinal feature of tauopathies is hyperphosphorylation and aggregation of tau protein in brain. The pathophysiology of tauopathies is poorly understood, and to date there is no measure to prevent or even slow the progression of disease. -Several studies indicate that heparan sulfates (polymers of sulfated polysaccharides attached to a core protein) play a significant role in tau hyperphosphorylation, but the nature of the heparan sulfates involved in the pathological processes and their precise function in the pathogenesis of tauopathy remains unknown. The aim of my thesis was to shed light on the role of heparan sulfates in tauopathies. For my work, I used the transgenic zebrafish line Tg[HuC::hTauP301L/DsRed] that expresses the human tau protein carrying the P301L mutation responsible for frontotemporal dementia and parkinsonism linked to chromosome 17. This transgenic line reproduces an important pathophysiological feature of tauopathies: abnormal hyperphosphorylation of the tau protein. In the first part of my thesis, I participated in research designed to investigate the role of 3-O-sulfotransferase-2 (an enzyme involved in the synthesis of heparan sulfate) in tau hyperphosphorylation, using the Tg[HuC::hTauP301L/DsRed] line. With a genetic approach,. Ie. Inactivation of 3-0- sulfotransferase-2 by injection of antisense morpholino oligonucleotides in Tg[HuC::hTauP301L/DsRed] embryos, I have shown that this enzyme (and therefore the heparan sulfates with sulfated residues in position 3 of glucosamine) play a key role in pathological tau hyperphosphorylation. Indeed, partial inactivation of the 3-0- sulfotransferase-2 in these embryos induces a 60% decrease in the accumulation of hyperphosphorylated forms of tau. This work points to heparan sulfates as a candidate therapeutic target for the treatment of tauopathies, including Alzheimer's disease. In the second part of my thesis, I worked on finding small molecule antagonists of heparan sulfates capable of inhibiting the abnormal hyperphosphorylation of tau protein. I discovered that two heparan sulfate antagonist molecules (surfen and oxalyl-surfen) not only significantly decrease tau hyperphosphorylation in Tg[HuC::hTauP301L/DsRed] embryos but can also partially rescue the axonal defects and fasciculation of primary motor neurons caused by expression of the mutated human tau. Taken together, my findings highlight the key role of heparan sulfate in the pathophysiology of tauopathies, and open promising perspectives in the search for therapeutic strategies for tackling these disorders
Sikora, Anne-Sophie. "Étude de la régulation des enzymes de modification des héparanes sulfates en condition inflammatoire". Thesis, Lille 1, 2015. http://www.theses.fr/2015LIL10208.
Pełny tekst źródłaHeparan sulfates (HS) are produced from a non-sulfated precursor, which is then subjected to the actions of several sulfotransferases. Thereafter, HS can undergo a last modification catalyzed by secreted 6-O-endosulfatases named Sulfs. These modifications do not take place uniformly in the same chain, resulting in a complex organization that influences the functions of many binding proteins. Recent works have highlighted the involvement of HS in the regulation of the inflammatory response. However, little is known about the mechanisms that regulate the expression of HS-modifying enzymes. Thus, my thesis focused on the regulation of the HS biosynthetic machinery in response to inflammatory stimuli. In the first part, I studied the variations of expression of 3-O-sulfotransferases (3-OSTs) in monocytes. This study showed that 3-OST3B was rapidly up-regulated in response to TLR agonists and TNF-α. Thereafter, the high level of expression was stabilized by post-transcriptional mechanisms. The second part of my thesis was dedicated to the regulation of HS 6-O-sulfation. Although the expression of 6-O-sulfotransferases was not modified in response to inflammatory stimuli, the expression of Sulf-1 was strongly induced in fibroblasts exposed to TNF-α. The high expression of Sulf-1 was accompanied by a decrease in the rate of 6-O-sulfated HS and by the desensitization of fibroblasts to FGF-1. Altogether, these results suggest that 3-OST3B and Sulf-1 could participate in the regulation of the inflammatory response by modifying HS structure
Xu, Yan. "Caractérisation des interactions du virus de l'hépatite C avec les protéoglycanes à héparane sulfate". Thesis, Lille 2, 2014. http://www.theses.fr/2014LIL2S021/document.
Pełny tekst źródłaHepatitis C virus (HCV) entry into hepatocytes is a complex multistep process involving a series of cellular factors. HCV entry is initiated by the binding of viral particles to cell surface heparan sulfate (HS) structures. However, due to the lipoprotein-like structure of HCV, the exact contribution of virion components to this interaction remains controversial. Here, we investigated the relative contribution of HCV envelope proteins and apolipoprotein E in the HS-binding step. Deletion of hypervariable region 1, a region previously proposed to be involved in HS-binding, did not alter HCV virion binding to HS, indicating that this region is not involved in this interaction. Neutralizing monoclonal antibodies recognizing different regions of HCV envelope glycoproteins were also used in a pull-down assay with beads coated with heparin, a close HS structural homologue. Although isolated HCV envelope glycoproteins could interact with heparin, none of these antibodies was able to interfere with virion-heparin interaction, strongly suggesting that, at the virion surface HCV envelope glycoproteins are not accessible for HS binding. In contrast, results from kinetic studies, heparin pull-down and inhibition experiments with anti-apolipoprotein E antibodies indicate that this apolipoprotein plays a major role in HCV-HS interaction. Finally, characterization of HS structural determinants required for HCV infection by silencing enzymes involved in the HS biosynthesis pathway and by competition with modified heparin indicated that N- and 6-O-sulfation but not 2-O-sulfation are required for HCV infection, and that the minimum HS oligosaccharide length required for HCV infection is a decasaccharide. Together, these data indicate that HCV hijacks apolipoprotein E to initiate its interaction with specific HS structures
Mathieu, Cyrille. "Pathogenèse de l’infection par le virus Nipah". Thesis, Lyon 1, 2011. http://www.theses.fr/2011LYO10287.
Pełny tekst źródłaNipah virus (NiV) is a highly pathogenic zoonotic Paramyxovirus that emerged in 1998 in Malaysia from frugivorous bats. The outbreaks of this encephalitic virus still occur annually in India and Bangladesh with the mortality rate reaching up to 90%. The lack of an effective vaccine or treatment limits experimentation with live virus to specially equipped BioSafety Level 4 laboratories. Studies of the interaction between the virus and blood cells revealed that NiV uses Heparan sulfates to stick on the surface of leukocytes for its dissemination within the host and reach endothelial cells. Heparin provided de possibility to inhibit this mechanism of transinfection, such as the infection in vitro and in vivo, opening new perspectives of low cost treatment for emerging countries. Then, transcriptomic analysis of NiV infected endothelial cells revealed the importance of cytokine in the pathogenesis. While CXCL10 appears as a good marker of encephalitis, interferon type 1 explains why mice are resistant to the infection with NiV. Finally, we show the essential role of the non structural C protein of NiV in its virulence, by limiting the interferon response, unbalancing the chemokine response during the infection and through the regulation of the genomic/antigenomic balance during the viral replication cycle. These results shed new light on NiV related pathogenesis and open new perspectives of treatment against this highly lethal zoonotic virus
Colombier, Marie-Laure. "Effets d'un analogue des héparane-sulfates (CMDBS K) sur un modèle de plaie crânienne standardisée chez le rat". Paris 5, 1995. http://www.theses.fr/1995PA05M104.
Pełny tekst źródłaJaime, Rodríguez Juan Carlos. "Unveiling Heparin and Heparan Sulfate Conformations : a Journey into Paramagnetic NMR Analysis". Electronic Thesis or Diss., université Paris-Saclay, 2024. http://www.theses.fr/2024UPASF016.
Pełny tekst źródłaHeparin (HP) and heparan sulfates (HS) are linear and sulfated polysaccharides that play various biological roles, including cell growth, adhesion, viral recognition, and cancer metastasis. Their molecular diversity and sulfation pattern contribute to their biological versatility. Furthermore, their conformational flexibility has been studied through methods such as X-ray crystallography and NMR. Despite advancements, interpreting these features remains challenging, especially for long saccharides. This thesis proposes the use of paramagnetic NMR, particularly pseudo-contact shifts (PCS) measurements, in studying the conformation of HS molecules. Results obtained on an HS octasaccharide show a correlation between experimental PCS and molecular dynamics simulations, suggesting specific conformations of IdoA motifs. These findings expand the applications of paramagnetic NMR, paving the way for a thorough analysis of protein-polysaccharide interactions
Hellec, Charles. "Implication des héparanes sulfates 3-O-sulfotransférases (HS3STs) dans les processus cellulaires associés au cancer". Thesis, Lille 1, 2018. http://www.theses.fr/2018LIL1S107/document.
Pełny tekst źródłaHeparan sulfate (HS) is a linear polysaccharide in which the sulfation pattern determines the biological properties. The last step of HS maturation is catalyzed by the HS 3-O-sulfotransferases (HS3ST), which are represented by seven isozymes. The functions of HS3STs in cancer progression are still controversial. In this context, we focused our investigations on the roles of these enzymes in MDA-MB-231 breast cancer cells. First, we found that transient expression of HS3ST2, 3B and 4 enhanced their proliferation and survival. It turns out that these effects are related to an increase in the activation of Src and Akt. Complementary to this, we observed an increase in the activation of the NF-κB pathway and the expression of anti-apoptotic proteins. In line with these findings, we showed that HS3ST-transfected cells were more resistant to cell death induced by pro-apoptotic stimuli or NK cells. These results suggest that, in addition to increasing cellular growth, 3-O-sulfated HS can also protect cancer cells against the immune system. Neuropilin-1 was recently described as a preferential ligand of 3-O-sulfated HS. Thus, we investigated the role of this co-receptor in MDA-MB-231 cells that carry a stable expression of HS3ST3B. We demonstrated that silencing neuropilin-1 resulted in reduced proliferation and survival, which was associated with a strong decrease in Src and Akt activation. These last results support a model in which HS3ST-modified HS may display tumor-promoting functions through the interaction with neuropilin-1. Overall, our findings suggest that the expression of certain HS3STs in cancer cells could be associated with a bad prognosis
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.
Pełny tekst źródłaInduction 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
Pegeot, Mathieu. "Etudes structurales par RMN des profils Saccharidiques d'Héparanes sulfates et de leur régulation cellulaire : Mise en place d'un protocole de marquage, de purification et d'analyse de chaines entières". Thesis, Grenoble, 2014. http://www.theses.fr/2014GRENV056/document.
Pełny tekst źródłaGlycosaminoglycans (GAGs) belong to a linear polysaccharide family which are found within all tissues, at the extracellular matrix and cell surfaces levels. Heparan Sulfates (HS) are one of the major members of this family, they are bound to a core protein to form altogether the so-called proteoglycan (PG). Depending on the localization and on the core protein, the HS – composed of a N-acetylglucosamine (GlcNAc) and a glucuronic acid (GlcA) [-4GlcAβ1-4GlcNAcα1-] building block – undergo various modifications. Indeed, HS can be sulfated at different positions on both monosaccharide and the GlcA can be epimerized into an iduronic acid (IdoA). The fine structures of the polysaccharide will be able to interact with a large range of proteins and play a plethora of roles such as in inflammation processes, cell proliferation, angiogenesis, immune responses, viral attachment…The HS structural studies, due to the flexibility and heterogeneity of the polysaccharide, have so far been restricted to HS fragments able to bind proteins. The depolymerization techniques induce valuable information losses such as epimerization.In this work, we have successfully developed a nuclear magnetic resonance (NMR)-based approach to study HS features from 13C metabolically enriched cells. For this, an effective protocol to label and purify HS has been set up. By integrating peaks' volumes at well-resolved 1H-13C chemical shifts by NMR, the sulfation, epimerization and disaccharide profile can be determined from full-length HS. This method has been used to study HS from various cell types and is of important interest to better understand changes in HS structures that occur through physiologic and pathologic events.The results obtained open the way to analyze HS directly at the cell surface via solid state NMR techniques. In this context, these studies are a major challenge to decipher the different roles of HS and their ability to interact with so many partners in vivo
Macchi, Magali. "Etude du rôle des héparans sulfates protéoglycanes dans la mobilisation post-lesionnelle des progéniteurs oligodendrocytaires chez la souris adulte". Thesis, Aix-Marseille, 2015. http://www.theses.fr/2015AIXM4069.
Pełny tekst źródłaIn the mammal’s nervous system, the ongoing production of new myelinating cells on has open news therapeutic perspectives for demyelinating diseases. An endogenous regeneration process involving the generation of oligodendrocytes can occur following demyelination. This process relies on the mobilization of an endogenous reservoir of progenitor cells located in the adult brain: The parenchymal oligodendrocyte precursors and the subventricular zone derived neural progenitors. However, these endogenous repair attempts do not permit an efficient functional recovery. These failures are mainly due to mobilization, differentiation or to the generation of a hostile environment for the repair process. Our work is focusing on the identification of factors regulating those events. Our data show the reexpression of CNTF and overexpression of heparan sulphate proteoglycans (HSPGs) following a focal demyelination of the corpus callosum in adult mice. These environmental changes favor myelin repair. We show a direct impact of the post-lesional expression of CNTF on the mobilization of both cellular sources. Using various in vitro assays, we showed that CNTF is acting on the two cellular sources as a chemoattractant factor. Our data also show that sulfation modifications of HSPGs performed by the deacetylase-N-sulfotransferase 1 (Ndst1) on oligodendrocyte lineage cells occurred around the lesion and created a permissive microenvironment for the regenerative process. Various in vitro and in vivo functional assays demonstrated the key role of HSPGs in demyelination and remyelination dynamic by controlling mobilization of the oligodendrocyte lineage cells and microglial activation
Vivès, Romain R. "Héparanes sulfate : Structure, fonctions, régulation". Habilitation à diriger des recherches, Université de Grenoble, 2011. http://tel.archives-ouvertes.fr/tel-01063291.
Pełny tekst źródłaMothere, Mouna. "Caractérisation des glycosaminoglycannes au cours de la croissance tumorale. Développement d’un nouvel outil pour leur étude : l’impression moléculaire". Thesis, Paris Est, 2013. http://www.theses.fr/2013PEST0113.
Pełny tekst źródłaGAGs, and particularly heparan sulfate (HS) and chondoitin sulfate (CS), are linear and sulfated polysaccharides located at the cell surface and extracellular matrix from where they influence the functions of cells. GAGs are known to bind and regulate the activity of a number of distinct proteins known as ‘heparin binding proteins' including chemokines, growth factors, enzymes and adhesion molecules. In the case of tumor development, heparanase over-expression has been observed. As a consequence, a variety of HS and CS oligosaccharides are released which structures and biological effects are unknown.Many tools exist for GAG characterization and a need to develop a new technology to isolate fragments of endogenous HS is required. In this context, we propose to use molecular imprinting technology that could allow to obtain polymers owing cavities able to recognize specific types of HS mimetic oligosaccharides and therefore the endogenous HS.GAGs extracted from xenografted tumors and blood, at 3 to 8 weeks during tumor growth, were quantified by a colorimetric assay. We observed a decrease in the amount of GAGs tumors and an increase of GAGs blood, during the tumor growth. Moreover, tumor GAGs were tested by competition toward growth factor with enzyme immunoassay showing increasing affinity for FGF-2 during tumor growth.We investigated the applicability of ‘Molecular Imprinting Technology' to the generation of imprinted hydrogels able of specifically recognize fondaparinux, an oligosaccharide analogue of heparin. We have prepared a library of imprinted hydrogels in order to optimize their synthesis and obtain materials that specifically and selectively recognize that oligosaccharide. Our results show that, by a careful control of the stoichiometry and crossliking choice for their synthesis and by adapting rebinding conditions, namely the temperature, imprinted hydrogels can readily be prepared to specifically recognize the HS mimetic used as model.This work opens an interesting outlook to analyze GAGs extracted from a biological medium by molecular imprinting technology
Lortat-Jacob, Hugues. "Caractérisation de récepteurs matriciels aux cytokines : modulation de l'activité interféron-gamma par l'héparane sulfate des membranes basales". Compiègne, 1991. http://www.theses.fr/1991COMPD356.
Pełny tekst źródłaDong, Dengxiang. "Oligosides et dérivés de cyclodextrines : apport de la synthèse organique". Paris 6, 2006. http://www.theses.fr/2006PA066023.
Pełny tekst źródłaEl, Masri Rana. "Remodeling of heparan sulfate : functional and structural characterization of human endosulfatase HSulf-2 The sweet side of extracellular sulfatases Expression and purification of recombinant extracellular sulfatase HSulf-2 allows deciphering of enzyme sub-domain coordinated role for the binding and 6-O-desulfation of heparan sulfate". Thesis, Université Grenoble Alpes (ComUE), 2019. http://www.theses.fr/2019GREAV037.
Pełny tekst źródłaHeparan Sulfate (HS) are complex polysaccharides involved in many biological processes. The structure of HS is regulated at the cell surface by unique extracellular endosulfatases, the Sulfs. Sulfs dramatically change HS functional properties, thereby being implicated in many physiopathological processes including cancer. Sulfs features two domains: a catalytic domain (CAT) that comprises the active site, and an hydrophilic basic domain (HD) responsible for HS binding. The aim of my PhD project is to characterize the structural and the functional properties of the human for HSulf-2, which remains poorly understood. In this context, we have first studied the enzyme/substrate recognition mechanisms. We identified two novel HS binding motifs on these enzymes implicated in their activity. In addition, using natural and synthetic oligosaccharides, we demonstrated that the HD is not essential for HS recognition, but is directs the processive and orientated desulfation of the polysaccharide. Moreover, we showed that a tetrasaccharide is the minimal oligosaccharide size required for HSulf-2 activity. Our results enabled us to propose a new model depicting the desulfation process of HS by the Sulfs. Second, we have shown that HSulf-2 is a proteoglycan, given that it harbors a unique PTM (Chondroitin Sulfate, CS chain) on its HD domain. This chain decreases enzyme activity and HS binding in vitro. In the tumoral microenvironment, using a murine orthotropic mammary tumor model, we showed that the CS chain is lost by proteolytic processing, leading to the activation of HSulf-2, and the promotion of tumor growth, vascularization and metastasis. Finally, we have undertaken the structural characterization of the Sulfs. For this, we decided to study separately the two domains found in these enzymes (CAT and HD). Crystallogenesis assays were undertaken for the CAT domain to solve its structure by X-ray crystallography, but were unsuccessful. Regarding the HD, we set up a protocol of production and purification of recombinant HD and we initiated NMR studies and other biophysics analyses in order to structurally characterize the domain and to identify the HS binding sites. Our preliminary results suggest that the HD is an unstructured domain, except for its N- and C-terminal parts. Overall, our data provide significant insights into this critical regulatory step of HS function
Bret, Caroline. "Biologie de syndecan-1 au cours du myélome multiple : synthèse, modifications et inhibition". Thesis, Montpellier 1, 2010. http://www.theses.fr/2010MON1T012.
Pełny tekst źródłaMultiple 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
Jeanbat-Mimaud, Viviane. "Synthèse et étude structure/fonction de polymères mimétiques des héparanes sulfates". Paris 12, 1997. http://www.theses.fr/1997PA120094.
Pełny tekst źródłaVanpouille, Christophe Guy Éric. "Rôle des protéoglycannes à chaînes héparanes sulfates dans la fixation et l'activité pro-adhésive de la CyPB". Lille 1, 2003. https://pepite-depot.univ-lille.fr/LIBRE/Th_Num/2003/50376-2003-203-204.pdf.
Pełny tekst źródłaSaesen, Els. "Bases structurales de la régulation des cytokines par les héparanes sulfates : régulation génique et optimisation d’un inhibiteur de l’interféron-gamma". Thesis, Grenoble, 2013. http://www.theses.fr/2013GRENV004/document.
Pełny tekst źródłaInterferon-γ (IFNγ) is a strong immunomodulating cytokine with some antiviral activity. It has two ligands for which it has high affinities: a receptor through which it transmits its signals, and complex polysaccharides of the heparan sulphate (HS) family. Both are situated on the cellular surface. In vivo, binding on the HS permits local concentration of the cytokine, and regulates its biological activity via a partial protection of the C-terminal region. This C-terminal region, characterised by two basic domains, D1 and D2, is implicated in the recognition of the receptor and the HS. In this context, we investigated the structural features for the interaction of IFNγ, and more specifically the importance of his C-terminus, with both of his cellular ligands. Therefore, we produced, purified and examined various mutants of IFNγ, including points, multiples and deletions mutants. There ability to bind to HS and the IFNγ receptor is examined by SPR and there influence on IFNγ's antiviral activity is determined. The thermodynamics complexation of IFNγ with the HS-oligosaccharides is examined. Moreover, we have prepared an oligosaccharidic library derived from HS. By screening this library for its capacity to bind IFNγ, we have demonstrated that the cytokine recognizes a particular sulphated pattern. Finely, we tried to crystallize the IFNγ:HS-oligosaccharide complex, without obtaining diffracting crystals yet. These studies contribute to clarify the mechanism of recognition of IFNγ by the HS. This would enable us to design a mimic of the interaction site for IFNγ on the HS, who inhibits inappropriate signaling of the cytokine. Finely, a detailed comprehension of the interaction of IFNγ with his receptor and with the HS needs to be established to fully understand how IFNγ migrates for the HS to its receptor
Wojcinski, Alexandre. "Etude du rôle de la modification de l'état de sulfatation des héparanes sulfates protéoglycanes (HSPGs) par la protéine DSulf1 dans la régulation de la voie de signalisation Hedgehog (Hh) chez la drosophile". Toulouse 3, 2011. http://thesesups.ups-tlse.fr/1209/.
Pełny tekst źródłaThe positional information during multicellular organisms development is, in most cases, given by molecules called morphogens. These molecules are synthesized in a localized fashion and spread in target tissues, establishing a decreasing concentration gradient and regulate the expression of target genes in a dose dependant manner. Among morphogens, molecules of the Hedgehog family (Hh) are involved in regulating many developmental processes in both Drosophila and vertebrates. A key step in regulating this pathway is the molecular mechanisms that control the formation of concentration gradient in the target territory. Several factors regulating the movement of Hh in the extracellular space, have been identified among which the macromolecules belonging to the family of heparan sulfate proteoglycans (HSPG). The HSPG are extracellular components consisting of a core protein which is linked covalently to polysaccharide chains. During their biosynthesis, these chains, called HS chains, can be modified by the addition of sulfate groups at different positions leading to establishment of distinct profiles and thus a great variety of HSPGs. The recent identification of secreted sulfatases that catalyze the specific removal of sulfate groups in position 6-O oh HS (6-O-endosulfatase) indicates that the sulfation pattern of HSPG may also be modulated in the extracellular space. During my thesis work, we identified DSulf1, the only gene encoding for a 6-O-endosulfatase in Drosophila as a novel regulator of the Hh signaling pathway during wing development. In particular, I showed that DSulf1, by modulating the distribution of Hh morphogen at the apical pole of cells, can accurately position the expression domains of Hh target genes in the wing imaginal disc, larval structure giving rise to the adult wing. Interestingly, we demonstrated that this enzyme, by the same effects on Hh release, has two distinct functions in this tissue. Indeed, DSulf1 behaves as a positive regulator in Hh producing cells, allowing an enhanced release of the Hh morphogen towards its target field. Conversely, in the target tissue, it acts as a negative regulator, likely by destabilizing the binding of Hh/ HSPG interaction required for efficient activation of the signal transduction pathway. We have also shown that Dsulf1 expression is dynamic and it starts secondarily to the expression of Hh target genes. Our work shows that Dsulf1 expression depends on EGFR signaling pathway, which is itself positioned by the Hh morphogen. These results enabled us to propose that DSulf1 is part of a feedback loop that maintains in space and time expression domains of Hh target genes during Drosophila wing development
Couderc, Guilhem. "Rôle des facteurs de croissance liant les héparance sulfates dans le myélome multiple". Montpellier 1, 2000. http://www.theses.fr/2000MON11106.
Pełny tekst źródłaOuidja, Mohand Ouidir. "Nouvelles approches thérapeutiques des maladies à prions : étude des mimétiques des héparanes sulfates". Aix-Marseille 3, 2008. http://www.theses.fr/2008AIX30078.
Pełny tekst źródłaTransmissible spongiform encephalopathies (TSEs) or commonly called prion diseases, are group of fatal neurodegenerative disorders with long incubation periods. TSEs are characterized by the accumulation in the brain of an abnormal isoform (PrPres) of the host encoded prion protein (PrPc). PrPres is the only specific marker of the infection, and the inhibition of its accumulation is often used to evaluate the efficacy of therapeutic drugs. There are currently no effective therapies for TSEs. Thus, the development of new therapeutics strategies is of crucial importance. The study consists of three parts 1) the work implicate in, the chemical synthesis of a library of the molecules (family of heparan mimetics (HM)) containing various sulfations, carboxymethylation levels. These molecules have different molecular sizes and are substituted or not by different hydrophobic cores. 2) These synthesized HMs were evaluated for their capacitie to bind to PrPrec 3) and to inhibit the accumulation of PrPres in chronically infected cells (ScGT1-7). These studies were used to study the effect of structural changes of these molecules on the "anti-prion" activity and select the most active compounds in vitro. We have shown that the "anti-prion" activity can be optimized especially with medially sulfated molecules and that these activities can be improved by the introduction of a hydrophobic core. This study has also shown that molecules of low molecular weight called the HM-oligosaccharides are also effective in inhibiting the accumulation of pathological prion protein (PrPres) that heparan mimetic polyanions with high molecular weight. In addition, we have demonstrated in vitro the ability of these oligomeric molecules to cross the blood-brain barrier (BBB). These molecules are at present potential therapeutic tool for treating prion diseases or even other neurodegenerative diseases where heparan sulfate appear to have roles as regulators in Parkinson's or Alzheimer's disease
Dos, Santos Morgan. "Rôle des protéoglycannes à héparane sulfate des lames basales au cours du vieillissement cutané". Thesis, Lyon 1, 2011. http://www.theses.fr/2011LYO10205.
Pełny tekst źródłaAmong basement membrane heparan sulphate proteoglycans (HSPGs), perlecan is known to be involved in epidermal formation and renewal by regulating keratinocyte survival and differentiation. HSPGs are known to be regulators of growth-factor signalling through different mechanisms. We have investigated the expression of perlecan during skin ageing and have examined whether its expression correlates with age-dependant modifications of the epidermal compartment. The immunohistochemical analysis of perlecan in a cohort of human skin samples from donors of ages ranging from 22 to 73 years revealed a strong decrease of its expression with age in good correlation with reduction of the epidermal thickness. Genomic analyses of keratinocytes isolated from these biopsies combined with further characterization of perlecan from aged donors revealed that the observed decreased expression is most likely a consequence of a reduced synthesis rather than a protein degradation or a deficient supramolecular exposure. The design and characterization of human skin models engineered with cells from donors of various ages confirmed this hypothesis and revealed that aged keratinocytes showing deficiency in perlecan production and deposit in the basement membrane, also displayed inability to form a multilayed epidermis. Addition of purified perlecan in the culture medium of these skin equivalents enhanced the epidermal thickness and restored a well-differentiated multilayed epithelium. Biological screening of a library compounds allowed the selection of candidates able to increase the expression of epithelial and endothelial-derived perlecan with high specificity. Skin engineering models mimicking ageing human skin demonstrates the capacity of one candidate to restore the perlecan functional failure in promoting epidermal renewal and morphogenesis. Our results suggest that the presence of perlecan in the skin basement membrane appears to be crucial for the maintenance of the epidermal integrity and that its decrease with age may contribute to the epidermal thinning
Matou, Sabine. "Effet de polysaccharides sulfatés naturels sur l'angiogenèse". Paris 13, 2001. http://www.theses.fr/2001PA132030.
Pełny tekst źródłaHeparin (sulfated polysaccharide extracted from pig intestinal mucosa) is the most frequently used drug in venous thrombosis prevention and treatment. Fucoidans (sulfated polysaccharides from brown algae) revealed antithrombotic properties in an animal model of venous thrombosis. They are intensively studied for a potential therapeutic use as they are devoid of any risk of transmis6ion of conventional contaminant agents
Sepulveda-Diaz, Julia. "Studies on the Role of Cellular Heparan Sulfate on Tau Pathology in Alzheimer's Disease and Related Tauopathies". Thesis, Paris Est, 2013. http://www.theses.fr/2013PEST0121.
Pełny tekst źródłaAccording to its higher prevalence worldwide among all dementia cases, Alzheimer's disease (AD) is placed as the first pathology affecting people aged of more than 65 years old. Since it first description in 1907, profound research and groundbreaking observations have been made concerning the histopathological and molecular aspects of its associated neurodegeneration. However, the molecular mechanisms of AD pathogenesis and progression remain still poorly understood. In addition, an efficient therapeutic approach to either prevent or stop the disease progression has not yet been developed. It becomes hence crucial to develop research in emerging areas raising from groundbreaking concepts and supported by new mechanistic approaches in order to unveil novel aspects of the physiopathology of neurodegeneration and therefore design new therapeutic approaches to treat these pathologies.The present study is focused on the role of heparan sulfate (HS), a particular member of the glycosaminoglycan family, in the physiopathology of neurodegenerative disorders, such as AD and related dementias, termed tauopathies. Based on numerous separate observations suggesting an association between tau pathology characteristic of tauopathies and HS, this research explores the pathological implications of such interaction by the means of molecular, cellular, and animal studies. As a result, I hereby present evidence suggesting a crucial involvement of HS in tau pathological events, such as abnormal phosphorylation, inclusion formation, and assembly propagation.Globally, the present work unveils a strong implication of highly sulfated HS in tau pathology associated to AD and related tauopathies, and opens a wide array of novel research pathways to deepen into the characterization of tau /HS interplay and its pathophysiologic consequences. In addition, it suggests alternative pharmacological targets that could bring some hope in finding an effective treatment for AD
Lallam-Laroye, Corinne. "Régénération par un mimétique des héparanes sulfates des tissus parodontaux détruits par une parodontite expérimentale". Paris 5, 2007. http://www.theses.fr/2007PA05M002.
Pełny tekst źródłaPeriodontitis are bacterium-driven inflammatory diseases that destroy tooth-supporting tissues whose complete restoration is not currently possible. RGTA, a new class of agents, behaving like a heparan sulfate mimetic, have this capacity in an animal model : periodontitis induced in hamsters. The three perodontium compartments were evaluated by immunohistochemistry and morphometry. The gingival extracellular matrix disorganized by inflammation was restoring under treatment. The collagen network was repaired. The amount of alveolar bone increased and the interradicular bone was rebuilt. The root cementum was thickened and the number of proliferating cells in the periodontal ligament was increased close to the cementum. RGTA treatment induces potent anabolic reactions in the extracellular matrices of the different tissues of the periodontium and recruitment of progenitors
Dilhas, Anna. "Etude des interactions glycosaminoglycanes-cytokines : nouvelles méthodes pour la synthèse combinatoire de fragments d'héparine/héparane sulfate". Paris 11, 2004. http://www.theses.fr/2004PA112221.
Pełny tekst źródłaThe subject is about glycosainoglycan familly (GAG) and in particular heparin/heaparan sulfate. This linear polysaccharide comprises the repetition of a basic disaccharide in which a uronic acid (D-glucuronic or L-iduronic) is 1,4-linked to a 2-deoxy-2-aminglucose. HS is one of the most heterogeneous biopolymer since variuos epimerisation and sulfation patterns may occur along the chain. HS chains, either at tha cell surface or in the extracellular matrix interact and regulate the activity of numerous proteins. We have prepared complex ttrasaccharides in a combinatorial way. They will be used to prepare hexa and octasaccharides with 3 disaccharide building blocks and interaction of these HS fragments with protein SDF-1 that is a chemokine that play an important role against HIV, will be studied. We have optimised the synthesis of the iduronic monosaccharide as well as coupling reactions that leads to disaccharides. A new access to final disaccharides has been found that lays on totally regioselective reductive opening of a 2',4'-O-paramethoxybenzylidene group on the iduronyle unity. Tetrasaccharide libraries got after combinatorial coupling were deacetylated, reduced, sulfated, saponified then tetrasaccharides were isolated and caracterised
Deligny, Audrey. "Rôle des glucosaminyl sulfotransférases dans la biosynthèse de motifs héparanes sulfates impliqués dans la fixation et l’activité de facteurs inflammatoires". Thesis, Lille 1, 2009. http://www.theses.fr/2009LIL10093/document.
Pełny tekst źródłaHeparan sulfate (HS) are synthesized from a non-sulfated precursor, formed by the repetition of the disaccharide unit [GlcUA ß1,4 GlcNAc]. This precursor is subsequently modified by a set of enzymes of maturation, N-deacetylase/N-sulfotransferases (NDSTs), O-sulfotransferases (OSTs) and C5-epimerase. These enzymes, whose expression is dependent on cell type, exhibit fine differences in activity and substrate specificity, which confer a large structural heterogeneity in HS species and offer a plethora of binding sites for proteins. It is now well established that HS proteoglycans regulate the binding and activity of a number of inflammatory factors. However, little is known about the structural features of HS sequences involved in these interactions. The aim of these works was to correlate the cell-type specific expression of HS biosynthetic enzymes to the generation of specialized HS motifs with binding properties for inflammatory factors
Maiza, Auriane. "Implication of 3S-HS and HS3ST2 in synaptic stability under physiological conditions and in Alzheimer's disease-related tauopahty". Thesis, Paris Est, 2019. http://www.theses.fr/2019PESC0032.
Pełny tekst źródłaAlzheimer’s disease (AD), the main form of dementia in the world, is characterized by brain accumulation of amyloid plaques formed of amyloid beta, and neurofibrillary tangles (NFT) made of tau protein in an abnormally hyperphosphorylated form (P-tau). Strong evidences show that synaptic changes are central to the disease process. Moreover, previous observations in AD have shown that heparan sulfates (HS), typically present outside the cell , accumulate inside neurons of AD in where they interact with tau. Recently, the CRRET laboratory demonstrated that the neural 3-O-sulfotransferase 2 (HS3ST2), which generates 3-O-sulfated HS (3S-HS) of still unrevealed physiological roles, is involved in the mechanisms leading to tauopathy. Since it was unknown whether HS3ST2 and 3S-HS are expressed at the synapse and if there they participate to tauopathy development and/or evolution, the objectives of this work were: 1) to determine if HS3ST2 and 3S-HS are present at the synapse and to get insights on their physiological role; 2) to investigate whether 3S-HS accumulate intracellularly in hippocampal cells and/or in synaptosomes from a mice model of tauopathy; and 3) to investigate whether intracellular 3S-HS made by HS3ST2 are involved in tauopathy development and/or evolution at the synaptic level.We described here the presence of 3S-HS and HS3ST2 at the synapse and the role that may play 3S-HS in maintaining synaptic transmission and stability in primary cell culture from mice. These roles are the results of potential multiple implications of 3S-HS in various processes. Secondly, we implement and characterized the rTg4510 mice model of AD-related tauopathy and set primary cultures of hippocampal cells from these mice. In the tauopathic cells, we showed the intracellular accumulation of 3S-HS and HS3ST2 overexpression. Finally, we cleaned P-tau in synaptosomes from the rTg4510 mice aged of 2 months by digesting HS.The present work reveals, for the first time, the presence and a possible fundamental role of HS3ST2 and 3S-HS at the synapse. We give evidences of an interplay between 3S-HS, produced by HS3ST2, and tau and the synaptic level, leading to its abnormal phosphorylation. The results of these work open a new way to understand the phenomenon leading to synaptic impairment in AD patients and could reveal new targets to elaborate protection strategies against the AD pathological lesions
Birmelé, Béatrice. "Etude des héparanes sulfates de cellules glomérulaires in vitro dans le syndrome néphrotique idiopathique de l'enfant". Tours, 2000. http://www.theses.fr/2000TOUR3310.
Pełny tekst źródłaLiu, Wenqing. "Méthodologies de synthèses pour la préparation de ‘puces à SAS’ : vers de nouveaux outils pour l’étude des interactions héparane sulfate /protéines". Thesis, Paris 11, 2015. http://www.theses.fr/2015PA112006/document.
Pełny tekst źródłaHeparan sulfate (HS) is a linear polysaccharide found in animal tissues at the cell surface or in the extracellular matrix. HS chains display alternating highly negatively charged regions (S) and less charged ones (A). SAS domains with different topologies can thus be exposed at the cell surface with the aim of interacting specifically with different proteins. Gamma interferon (INF-γ) is a cytokine that binds tightly to HS chains. This interaction allows controlling numerous bioactivities of the cytokine (accumulation and location in tissues as well as blood clearance). The discovery of HS fragment able to modulate the activity of IFN-γ could open the way to new innovative therapeutics. To this aim we launched a program aiming at synthesizing mimetic of the SAS motifs found in HS. We devised a strategy allowing linking two synthetic S fragments of HS through a spacer. To this aim we selected two click chemistry reactions: the "CuAAC" triazole formation and "oxime ligation". To implement this strategy, we optimized, on a disaccharide model derived from cellobiose, a methodology allowing the functionalization of the reducing and non-reducing end of synthetic oligosaccharides by to orthogonal reactive functions. Then we extended the methodology to a HS tetrasaccharide fragment. In this work, we optimized two key reactions: an anomeric alkylation in water and a hydroxyl allylation in neutral condition
Laffont, Isabelle. "Interaction de l'apolipoprotéine E avec les héparanes sulfate : implication dans la signalisation cellulaire et conséquence de la glycation". Nancy 1, 2002. http://www.theses.fr/2002NAN12510.
Pełny tekst źródłaTang, Lu. "Nanoparticules mimes des propriétés biologiques des GAGs : vers un inhibiteur sélectif de CXCL12". Thesis, Université Paris-Saclay (ComUE), 2015. http://www.theses.fr/2015SACLS072.
Pełny tekst źródłaHéparan Sulfate (HS) is a linear polysaccharide that modulates the biological activities of numerous proteins. In order to elucidate the interaction between HS and proteins, the synthesis of HS is an invaluable tool, but the synthesis is sometimes difficult. Our group has demonstrated that the combinatorial mixtures obtained by self-assembly of different combinations of disaccharide derivatives (lactose and persulfated lactose) on gold plan surfaces could recognize specifically some HS binding proteins, such as the isoforms of the chemokine CXCL12 or IFNγ. Because of the toxicity of gold nanoparticles, we have also adapted this method to lipid nanoparticles. Using the conditions that have already improved during the synthesis of lactose and persulfated lactose derivatives, we have synthesized two other disaccharide derivatives, which were closer to the real structure of HS. These new derivatives were used to prepare the gold and lipid nanoparticles at the aim of comparing the properties with lactose and persulfated lactose. The tests of affinities with different proteins are in progress
Rouet, Vincent. "Étude des interactions du VEGF (Vascular Endothelial Growth Factor) et de biomimétiques des héparanes sulfates, les RGTA (ReGeneraTing Agents)". Paris 12, 2004. https://athena.u-pec.fr/primo-explore/search?query=any,exact,990002147210204611&vid=upec.
Pełny tekst źródłaAngiogenesis is a process involved in the growth of new blood vessels capillaries that is dependant on both growth factors like VEGF (Vascular Endothelial growth Factor) and extracellular matrix components like heparan sulfate (HS). RGTA are HS mimetics whose chemical composition is controlled and defined that act in vivo as wound healing and angiogenesis stimulators. This study showed that RGTA bound with high affinity to VEGF. They enhance the fixation of VEGF to its high affinity receptors and are involved in VEGF biological activities potentializatio. Including the proliferation and migration of endothelial cells in vitro and angiogenesis in an in vivo assay. In a structure-function relationship study, ve showed that the carhoxymethylated and sulfated residues were involved in the RGTA effects. A carboxymethylated and sulfated RGTA named D120 is c efficient in potentializating angiogenesis in a model of muscular regeneration, as observed with angiogenesis related-gene expression analyses throughout skeletal muscular ischemia kinetic study. In conclusion, this study has begun to elucidate both structural requirements and functional implications of RGTA and VEGF interaction and its biological impact on physiolocical angiogenesis
Leroux, Dorothée. "La réponse immune sous héparine : études évaluant le rôle de la structure de l'héparine et du sulfate de protamine". Thesis, Tours, 2013. http://www.theses.fr/2013TOUR3313.
Pełny tekst źródłaThe immune response under heparin (H) treatment is associated with IgG antibodies (Abs) synthesis against heparin-modified Platelet Factor 4 (PF4). These Abs bind FcγRIIa receptors via their Fc fragment and promote strong platelet activation. Low Molecular Weight Heparins are complex mixtures of polysaccharide fragments. These oligosaccharides (OS) have a variable structure due to variations in the type of sugar units and the number of sulphate groups. We demonstrated that OS longer than 10 saccharides and with a large number of sulphate groups are likely able to modify PF4 and allow the binding of heparin-dependent Abs. Cardiac surgery is associated with strong platelet activation and high doses of unfractionated heparin are administered to patients during surgery, and then neutralized with protamine sulfate (SP) at the end of the intervention. 30 to 50% of patients develop anti H/PF4 Abs, but we demonstrated that 25% do synthethized anti H/SP Abs able to activate platelets in vitro. The pathogenic role of these Abs to H/SP in vivo is controversial
Jaffuel, Aurore. "Résolution de mélanges complexes d'oligosaccharides sulfatés par chromatographie 2D et spectrométrie de masse : application aux héparines thérapeutiques". Thesis, Lyon, 2016. http://www.theses.fr/2016LYSE1150.
Pełny tekst źródłaMock-Joubert, Maxime. "Synthèses d’inhibiteurs sélectifs des endosulfatases humaines H-Sulf 1 et 2". Thesis, Université Paris-Saclay (ComUE), 2017. http://www.theses.fr/2017SACLS137.
Pełny tekst źródłaHuman endosulfatase (H-Sulf 1 and 2) catalyse heparan 6-O-sulfate hydrolysis. Thanks to this hydrolysis they change the heparan sulfate proteoglycan activity. Many studies have shown that H-Sulf 2 are surexpressed in many cancer (lung, breast, pancreas etc...) The decrease of the activity of this enzyme in the case of the mouse allows a decrease of the size of the tumor and an extension of the mouse life. The aim of this thesis is to synthetise a library of endosulfatase specific inhibitors. A preliminary study was made on a monosaccharide carrying a sulfamate. This fonctional group have shown that it is able to inhibate the sulfatases. This project thesis is to synthetise heparan sulfate oligsaccharides carrying this sulfamate moeity. We apply an iterative process to make this oligosaccharide, thanks to a high stereoselective glycosylation. Finaly a reductive opening of benzylidène acetals, a sulfamoylation have been examinated, functionalization and deprotection are still in progress for get the full library
Cardon, Sébastien. "Étude quantitative du rôle spécifique de glycosaminoglycanes dans le mécanisme d'internalisation de l'homéoprotéine engrailed 2". Thesis, Paris Sciences et Lettres (ComUE), 2017. http://www.theses.fr/2017PSLEE041.
Pełny tekst źródłaHomeoproteins are important transcription factors during the development of living organisms, and are able to travel from cell to cell. These proteins contain a long N-terminal extremity structurally disordered, followed by three α helices separated by a U-turn. Structure-activity relation studies have shown that in these proteins, some cationic domains (rich in K and R) confer them the cellular transfer properties, allowing them to be secreted by and internalized into cells. These processes imply that the hydrophilic proteins are able to cross plasma membrane. Indeed, the plasma membrane possess a hydrophobic heart and is composed by a lipidic bilayer, in which numerous proteins are inserted, such as proteoglycans carrying glycosaminoglycan (GAG) ramifications, that belong to anionic polysaccharids. In order to understand the entry process of homeoproteins into eukaryotic cells at a molecular level, different proteic constructions have been produced and studied: the cell penetrating peptide corresponding to the third α helix (H3), the sequence corresponding to its homeodomain (HD), the homeodomain with an added putative GAG-binding domain (NLS-HD), and the wild-type protein Engrailed 2 (En2). The absolute mass spectrometry quantification of the peptide and proteins in cells shows a range of internalization efficiency as follows: H3 > NLS - HD > HD. It also highlights the importance of cell-surface GAGs in the internalization and more particularly that of heparan sulfates (HS). Complementary experiments of ITC, circular dichroism and NMR have shown two interaction sites for the heparin (one principal site of high affinity and a secondary site showing a lower affinity) both interacting mainly with polysaccharidic residues using electrostatic interactions. In fine, these studies lead to a better molecular understanding of homeoproteins internalization process in eukaryotic cells
Saesen, Els. "Bases structurales de la régulation des cytokines par les héparanes sulfates : régulation génique et optimisation d'un inhibiteur de l'interféron-gamma". Phd thesis, Université de Grenoble, 2013. http://tel.archives-ouvertes.fr/tel-00949161.
Pełny tekst źródłaElbaz, Benjamin. "Glycosaminoglycanes à visée antithrombotique héparines de bas poids moléculaires-dermatan sulfate structure-préparation- mécanismes d'action". Paris 5, 1991. http://www.theses.fr/1991PA05P027.
Pełny tekst źródłaSeffouh, Ilham. "Analyse protéomique des endosulfatases humaines HSulfs, enzymes clés de la modulation de la sulfatation de l’héparane sulfate". Thesis, Université Paris-Saclay (ComUE), 2018. http://www.theses.fr/2018SACLE031/document.
Pełny tekst źródłaThe human 6-O-endosulfatases HSulf-1 and -2 (HSulfs) catalyze the regio-selective hydrolysis of the 6-O-sulfate group of glucosamine residues within sulfated domains of heparan sulfate (HS), thereby ensuring a unique and original post-biosynthetic modification of the cell surface proteoglycans. Through their activity, the HSulfs enzymes modulate the interaction properties of HS and they are thus involved in crucial physiological processes as well as in pathological conditions, particularly in cancer. Therefore, HSulf-2 is considered as a valuable therapeutic target in cancer research. There is no crystallographic structure available for HSulfs so that their structural organization in two chains remains poorly understood. In this study, we report the first characterization by mass spectrometry (MS) of HSulf-2. An average molecular weight of 133115 g.mol-1 was determined for the whole enzyme by MALDI-TOF MS, i.e. higher than the naked amino acid backbone (98170 g.mol-1), highlighting a significant contribution of post-translational modifications (PTMs). The HSulf-2 protein sequence was determined by nano-LC-MS/MS, revealing four glycosylated sites at Asn 108, 147, 174 and 217. Besides, a unique O-glycosylation has been evidenced. By combining electrophoresis methods (SDS-PAGE / C-PAGE) and MS analysis (MALDI-TOF / HILIC-ESI-MS), we have identified this PTM as a glycosaminoglycan (GAG) of chondroitin sulfate/dermatan sulfate type. The MALDI-TOF analysis of the HSulf-2 modified form in which the two GAG binding sites have been impaired indicated a contribution of 34964 g.mol-1 for the whole PTMs, including 24727 g.mol-1 for the GAG chain only. This GAG chain is covalently linked to the HD domain within the C-terminus of HSulf-2. It is an unprecedented post-translational modification of an enzyme, providing the first example of a catalytic proteoglycan. N-glycans dispatched on both HSulf-2 long (N-terminus) and short (C-terminus) chains account for the remaining PTMs mass contribution 10237 g.mol-1. Overall, these results provide a bioanalytical platform for further structural investigations of the HSulf enzymes, aiming at deciphering the role PTMs and of each chain in the substrate binding and specificities and in the catalytic activities, and for the discovery of specific HSulfs inhibitors
Barbosa, Isabelle. "Étude in vivo et in vitro de la myogenèse et des GAG naturels associés : effets des RGTA, mimétiques fonctionnels des héparanes sulfates". Paris 12, 2003. https://athena.u-pec.fr/primo-explore/search?query=any,exact,990002110990204611&vid=upec.
Pełny tekst źródłaAdult skeletal muscles have a high capacity to regenerate after experimental, accidental or genette injuries. This regeneration is ensured by activation, proliferation and differentiation of muscle precursor cells or satellite cells. This process involves many actora, of which enzymatic activities and the growth factors play a prominent role. Proteoglycans and their associated GAG are matrix and cellular proteins, whitch play an important role in muscle regeneration by their capacity to interaet with some enzymatic proteins (elastase, heparanase) and with heparin binding growth factora. This work explains the results of the study of the effect of HS mimetics on myogenesis in vitro and in vivo in adults rats. HS mimetics were obtained by chemical modifications of dextran polymer. They are named RGTAs for ReGeneRaTing Agents, due to their ability to stimulate tissue repair in several modela including the skeletal muscle. RGTAs increased the in vitro proliferation and differentiation of primary culture satellite cella and myoblasts cells lines C2. 7. Stimulation of the proliferation was partially due to the potentiatton of FGF2 by RGTAs. These HS mimetics also stimulated the synthesis of total GAG during myogenic differentiation and modified the quality of the GAGs that were expressed at the cell surface during myogenesis. They increased the proportion of HS, mainly in the celfular fraction. In vivo, during the regeneration of a crushed and denerved muscle, the quantity of GAGs largely decreased during myolyse and inereased progressively during the reconstruction of fibres. This increase was accentuated by RGTA treatment. These results confirmed the importance of GAGs in these modela during rnyogeneais and demonstrated that one of the various mechanisms involved in the stimulatory effect ofthe RGTAs comes, at least in part, from the potentiation of the growth factor effect and a modulation of the expression of the natural GAGs. These results contributed to extend the knowledge of the mechanisms of RGTA, these molecules could be considered as a new therapeutic in muscle pathology
Garcia-Filipe, Stéphanie. "Les glycosaminoglycannes sulfatés et leurs implications au cours de la cicatrisation cutanée : effet de leurs mimétiques de synthèse". Paris 12, 2006. https://athena.u-pec.fr/primo-explore/search?query=any,exact,990002533550204611&vid=upec.
Pełny tekst źródłaGlycosaminoglycannes (GAG), and particularly the heparan sulfates, are major constituents of the extracellular matrice (ECM) currently recognized as a novel class of multifunctional cell regulators. In function of their structures, GAG can specifically bind a large number of specific proteins with diverse biologic functions as growth factors. The major objective of this work was to progress in the comprehension of roles of sulfated GAG during wound healing by studying variations of their content, of their structures and of their functional qualities. A second objective of fundamental and pharmacological interest is to study the effect of OTR4120, a GAG mimetic member of the RGTA, for " ReGeneraTing Agents ", family of molecules during skin wound healing. The OTR4120 effect was demonstrated in a thermal burn model and in a necrotic ulcer model. In both cases, the GAG mimetic showed an anti-fibrotic activity by favoring selective ECM degradation. This molecule allows acceleration of re-epithelialisation and wound healing and seems to be responsible of the regulation of the HS and CS proportions without modifying expression of the enzymes implicated in their metabolism. Its action mechanism has not yet been completely clarified but results presented in this work comfort the hypothesis in which they can substitute endogenous GAG and in which they might regulate their proportions. The functional interest of GAG in skin tissue homeostasis is comforted by the stimulating role of their mimetics. In fact, results concerning the study of GAG during spontaneous wound healing indicate that these endogenous molecules are directly implicated in various mechanisms notably favoring re-epithelialisation and that these mechanisms are directly related to GAG structures, to the regulation of their biosynthesis and to the post-synthesis modifications of their structures. This work demonstrates that endogenous GAG are major actors on skin wound healing
Wu, Danjun. "Multifunctional Chitosan-based Complexes for Nanomedicine". Thesis, Lyon 1, 2015. http://www.theses.fr/2015LYO10294.
Pełny tekst źródłaThis work is devoted to the elaboration of nano-polyelectrolyte complexes (PECs) systems with improved stability in physiological media and to the establishment of their high potential of applications as bioactive (macro) molecule delivery systems. Chitosan as polycation were complexed with four natural polyanions of different charged groups and densities (-COO- and SO3 - as negative charges), namely hyaluronan (HYA), chondroitin sulfate (ChonS), dextran sulfate (DS) and heparin (HEP). The factors impacting the formation and physical-chemical properties of chitosan-HYA nanocomplexes were investigated. However, these nanovectors lost their colloidal character in physiological media. To improve their colloidal stability in physiological conditions, an innovative stabilization strategy was designed, involving zinc ion. This stabilization strategy proved versatile and was extended to chitosan-ChonS PECs. Though a long-term stability was achieved, this strategy was only applicable to cationic PECs. Therefore, an alternate approach enabled the improvement of the colloidal stability in physiological media of both positive and negative colloids by designing core-shell ternary polyelectrolyte nanocomplexes composed of strong polyacid (DS or HEP)-chitosan PECs as core and a chitosan-HYA complex as shell. Furthermore, all of the stabilized nanocomplexes allowed the encapsulation of active molecules anti-retroviral drug tenofovir and surface functionalization with targeting IgAs. In vitro, these nanovectors exhibited an inhibition of infection of PBMCs by HIV-1 virus which could be superior to the free drug
Marques, Pereira Patricia. "Effets morphologiques et fonctionnels des RGTAs : analogues des héparanes sulfates,dans un modèle de lésion cholinergique septo-hippocampique chez le Rat adulte". Université Louis Pasteur (Strasbourg) (1971-2008), 2004. http://www.theses.fr/2004STR13196.
Pełny tekst źródłaThe first part of this work aimed at studying the effects of heparan sulfate analogs, RGTAs, in a partial immunotoxic lesion model of the cholinergic septo-hippocampal pathways. Our results showed that the partial lesion of the cholinergic neurons and of their hippocampal fibers induced a decrease of the muscarinic autoreceptors sensitivity and learning deficits (evaluated in the Hebb-Williams maze test). The learning set deficits were correlated with the cholinergic and GABAergic neurons death. RGTAs, which are able to cross the blood-brain-barrier, attenuated the cholinergic cell and fiber death and restored the muscarinic autoreceptor sensitivity. RGTAs also attenuated the GABAergic cell death occuring secondarily to a more extended cholinergic lesion. In the second part of this work, we studied the RGTAs effects on the development of intrahippocampal foetal septal cell grafts and the behavioural effects of these two treatments in an extended cholinergic lesion model. Our results showed that such an extensive lesion induced working-memory and learning-set deficits. Grafts, which appeared well integrated in the host tissue, tended to attenuate working memory deficits, but had no effects on learning-set performance. Unfortunately, no RGTAs effects were demonstrated on the development of the grafts or on the mnesic processes. Taken together, these results confirm that the cholinergic and also GABAergic components of the septo-hippocampal pathway are involved in memory processes. RGTAs appear to be a promising tool for neuroprotection in the central nervous system. However, the question of beneficial effects of RGTAs at a behavioural level remains to be addressed in other testing models
Delehedde, Maryse. "Implication des protéoglycannes de type héparane sulfate dans le contrôle de l'activité biologique du FGF-2 sur les cellules de cancer du sein". Lille 1, 1996. http://www.theses.fr/1996LIL10003.
Pełny tekst źródłaAfin d'explorer le rôle des hspg dans la sensibilité des cellules épithéliales mammaires au fgf-2, nous avons purifié et caractérisé les protéoglycannes (pg) après marquage métabolique par le #3#5s sulfate, chromatographies échangeuse d'ions et de tamisage moléculaire. Nos résultats montrent que les cellules mda-mb-231 synthétisent deux fois plus d'hspg que les cellules mcf-7. Pour les cellules mda-mb-231, la plus grande proportion d'hspg est trouvée dans la couche cellulaire alors que pour les cellules mcf-7, les hspg sont principalement libérés dans le milieu de culture. Les capacités d'interaction des pg avec le fgf-2 ont été étudiés à l'aide de #1#2#5i fgf-2, sur les cellules en culture ou après immobilisation des pg sur des membranes cationiques. Les cellules mcf-7 fixent significativement moins de #1#2#5i fgf-2 que les cellules mda-mb-231. Par contre, la fixation du fgf-2 est importante au niveau des hspg libérés dans le milieu de culture et ce pour les deux types cellulaires. Les capacités des pg à modifier l'activité du fgf-2 sur les cellules épithéliales mammaires ont ensuite été analysées après modification structurale des pg à l'aide d'enzymes ou d'un inhibiteur de la sulfatation, le chlorate de sodium. La dégradation des hspg des cellules mcf-7 ou leur désulfatation empêche l'action mitogène de ce facteur de croissance
A l'inverse, pour les cellules mda-mb-231, une désulfatation limitée permet d'obtenir une stimulation de la prolifération par le fgf-2. Cependant, une désulfatation plus importante rend à nouveau les cellules insensibles au fgf-2. Ceci indique que les hspg sont indispensables a l'activité du fgf-2 mais peuvent également en fonction de leur degré de sulfatation et/ou de leur quantité, réguler négativement l'activité de ce facteur de croissance. L'ensemble de nos résultats démontre le rôle primordial des hspg dans le contrôle de l'activité du fgf-2 et de la prolifération des cellules de cancer du sein
Hu, Zhaoyu. "Préparation et oligomérisation d’une brique trisaccharidique issue de ressources renouvelables : vers la simplification d’un inhibiteur d’entrée du VIH ?" Thesis, Paris 11, 2013. http://www.theses.fr/2013PA112049.
Pełny tekst źródłaThis work aims at simplifying the preparation of a new type of HIV entry inhibitor, conceived, synthesized and validated within a collaboration between our group, the "Institut de Biologie Structurale" (Grenoble) and the Institut Pasteur (Paris). This prototype is composed of a CD4 functional mimetic linked to a dodecasaccharide fragment of Heparan Sulfate, whose synthesis is complex. In order to determine if Heparan Sulfate may be replaced by simpler sulfated oligosaccharides, we decided to prepare a set of sulfated oligomaltosides.To this goal, we first optimized the synthesis of an oligomerizable maltotrioside building block in eight steps and 38% global yield from maltotriose, a commercial and biosourced trisaccharide. In this work, we had to address three major points: the allylation of the reducing end of maltotriose, the introduction of a paramethoxybenzylidene group between positions O-4III and O-6III and the selective protection of the remaining primary positions O-6I and O-6II by a silylated protecting group. Each step has been optimized to minimize the amount of secondary products and thus to enhance its yield. The resulting synthesis was thus shown to be highly reproducible up to ten grams scale.Then, glycoside acceptors and donors were prepared from the oligomerizable maltotrioside building block and we studied their behaviors in glycosylation reactions. We found that trichloroacetimidate activation led to poor glycosylation yields, due to the competitive formation of trichloroacetamidyl glycoside rearrangement product. Gratifyingly, N-phenyltrifluroacetimidate activation solved the rearrangement problem, but yields sometimes remained low. Indeed, we were able to demonstrate that the nature of the protecting group in position O-6I of the donor strongly influenced both the stereoselectivities and yields of the glycosylations: a bulky or ester group is needed in this position to obtain a full alpha stereoselecticity. To date, the highest yield obtained is 56 %.Ongoing optimizations will allow us to enhance the yields and to prepare the targeted sulfated oligomaltosides in a near future in order to test their biological activity
Matz-Knittel, Delphine. "Etude durôle de la stabilité et de la capacité à lier les héparanes sulfates dans la présentation et dans l'immunogénicité de protéines antigéniques". Paris 7, 2014. http://www.theses.fr/2014PA077021.
Pełny tekst źródłaIn this thesis, I evaluated whether three specific characteristics of a protein Ag can control some key events in the adaptative immune response. At first, I have shown that the stability of a protein and the position of the epitope in the protein structure can influence the way of cross-presentation and level of stimulation of T-CD8+ cells in vitro. The stability of the protein antigen also influences the humoral and cellular immune responses in vivo. The second characteristic I studied was the ability possessed by some Ag to bind heparan sulfate (HS), sulfated polysaccharides ubiquitously distributed on the cell surface and in the extracellular matrix. This feature allows to increase the presentation of the antigenic proteins and the cytotoxic immune response. Finally, I studied the ability of an antigen to bind HS in a pH-dependent manner. I have shown that diphteria toxin (DT) binds HS at acidic pH but not at neutral pH and that this feature allows the immune system to better take charge of it under conditions of acidosis. Understanding these mechanisms opens perspectives in the development of new proteic vaccines
Geneste, Ambre. "Mécanisme d'association de deux protéines amyloïdogènes de l'héparane sulfate protéoglycane. Rôle du pH et de l'activité protéasique de la transthyrétine". Thesis, Besançon, 2014. http://www.theses.fr/2014BESA3012/document.
Pełny tekst źródłaThe analysis of the heparan sulfate proteoglycan (HSPG) association mechanism withamyloid proteins and the effect of physiological parameters (pH,…) on this mechanism allowa better understanding of the mechanisms leading to amyloidogenesis.Transthyretin (TTR), which circulates in both plasma and cerebrospinal fluid, is one of theproteins involved in amyloidosis. It leads to TTR amyloidosis and plays a role in Alzheimer’sdisease in sequestrating the beta-amyloid (Aβ) protein. Biochromatography is an effectivetool for the analysis of the mechanism involved between a ligand and its receptor inadjustable conditions which could be close to biological conditions. Moreover, carbonnanotubes can be used to detect or to carry molecules which bind on its external surface andcould interact with other molecules. In this work, a particulate support was used where the HSPG was immobilized on the silica particles preactivated by amine residues. This support filling a column was used to study andcompare association mechanisms between HSPG and a wild type TTR form and a senile formof the TTR which was was extracted from a patient who died of cardiac failure with a senilesystemic amyloid. This study showed that the association between wild type TTR and HSPGwas independent of the pH and involved weak interactions.For the senile TTR, this association was dependent on pH. At pH<6,5, a histidine residue wasprotonated. Moreover, the study of both thermodynamical parameters and enthalpy-entropycompensation showed a change in the association mechanism with involvement of more ionicinteractions at pH<6,5. An acidic pH was necessary to dissociate and partially denaturate theTTR. The affinity of the TTR with HSPG depends on the tetrameric quaternary structure ofthe TTR which presents some residues which are able to create interactions.In a second time, this column was used to evaluate the effect of both the TTR and the pH onAβ/HSPG binding. As previously, the protonation of a histidine residue present on Aβ wasobserved at pH<6,5. This result confirmed studies on the Aβ precursor. Thermodynamicalvalues highlighted that the affinity of Aβ for l’HSPG decreased with the increase of TTRconcentration, and the study of the chromatograms associated showed that TTR sequestratedAβ and cut Aβ in smaller fragments which decreased its affinity for HSPG. In Alzheimer’sdisease, TTR has a proteolytic activity on Aβ.In a third time, the effect of the carbon nanotubes (CNTs), immobilized on TTR, on theTTR/HSPG binding was studied. Results showed that interactions between TTR-NTC andHSPG are van der Waals and hydrogen. Thermodynamical data of TTR/HSPG et TTRNTC/HSPG bindings are similar at pH>6. At pH<6, no differences between values obtainedat all pH values for TTR-NTC. NTCs would avoid ionic interactions formations