Дисертації з теми "Beta-matrice"
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Aubert, Alexandre. "Implication des membres de la famille des Ténascines dans la régulation de la biodisponibilité du TGF-β latent". Thesis, Lyon, 2020. http://www.theses.fr/2020LYSEN088.
Повний текст джерелаTenascin is a family of complex glycoproteins of the extracellular matrix composed offour members: Tenascin-C (TN-C), Tenascin-R (TN-R), Tenascin-W (TN-W) andTenascin-X (TN-X). These proteins have very specific expression profiles in adultwhich are often deregulated during tumor progression. It has been shown that TN-X,in addition to its architectural function within the extracellular matrix, is also able toregulate cell signaling. Indeed, TN-X activates latent Transforming Growth Factor(TGF)-Beta, a cytokine secreted by cells in an inactive form, thanks to its C-terminaldomain resembling to the fibrinogen (FBG-like domain). This domain is highly conserved between Tenascin family members. Thus, we demonstrated that TN-C, TNR and TN-W are also able to activate latent TGF-Beta through their FBG-like domainsin vitro. Such activation presents mature TGF-Beta to cell surface, leading to the activation of a functional TGF-Beta/Smad intracellular pathway. We also found thatFBG-like domain of Tenascins induce cytostasis and trigger epithelial-tomesenchymaltransition in epithelial cells, two responses induced by bioactive TGFBeta. Finally, we started a side project aiming at the characterization of FBG-Xvariations found in patients suffering from classical-like Ehlers-Danlos syndrome. This study investigates the impact of these variations on TN-X ability to activate latent TGF-Beta
Villard, Orianne. "Effets des cellules stromales pancréatiques immortalisées humaines sur les cellules bêta humaines." Thesis, Montpellier, 2019. http://www.theses.fr/2019MONTT024.
Повний текст джерелаIntroduction : The efficacy of islet transplantation is well established. However, the procedure still needs improvements in the quality of grafted islets, often weakened by the loss of their surrounding tissue during the isolation process. In this respect, mesenchymal stromal cells (MSC) represent an interesting tool as they have immunomodulatory and anti-inflammatory properties and are known to secrete proteins involved in creating a favorable microenvironment. This work aims to investigate the effect of human pancreatic stromal cells on human β-cells.Methods : We characterized the mesenchymal profile of cells, previously immortalized in our lab from human islets of Langerhans adherent cells, hereafter named hISC (human islet-derived stromal cells). We seeded human β-cells (EndoC-βH1 cell line or primary β-cells) on hISC-conditioned medium (hISC-CM) used as coating of Petri dishes. We assessed spreading, survival, proliferation and glucose-induced insulin secretion of β-cells cultured on hISC-CM as compared to poly-L-lysine coating.Results : Phenotypic and transcriptomic profiles of hISC are close to bone-marrow MSC. The hISC have an immunomodulation capacity. They express and secrete extracellular matrix proteins known to be present around and within human islet such as types I, IV and VI collagens, laminin and fibronectin. EndoC-βH1 seeded on hISC-CM adhere and spread on cell culture surface. We show that hISC-CM has positive effects on EndocC-βH1 proliferation, survival and glucose-induced insulin secretion, as compared to poly-L-lysine. From mechanistic point of view, hISC-CM induces FAK (focal adhesion kinase) and ERK (extracellular signal-regulated kinases) phosphorylations. The β1-integrin subunit is involved in both adhesion and increased insulin secretion of β cells induced through hISC-CM.Conclusion : Our work demonstrates a promising interest of hISC as support cells for human β-cells by scaffolding factors secretion. It opens new perspectives for conditioning human β-cells in a more physiological microenvironment to preserve their functional quality before and after transplantation
FRITEAU, LAURENCE. "Action de l'interleukine-1 beta et d'autres facteurs de croissance sur le comportement des fibroblastes dermiques humains. Etude de l'influence de la matrice de collagene." Paris 6, 1992. http://www.theses.fr/1992PA066484.
Повний текст джерелаSalza, Romain. "Les réseaux d’interactions de l’endostatine, de l’angiogenèse à la maladie d’Alzheimer." Thesis, Lyon 1, 2015. http://www.theses.fr/2015LYO10119.
Повний текст джерелаThe extracellular matrix include approximately 300 proteins and proteoglycans which constitute the matrisome and 800 associated proteins (Naba et al., 2012a) and glycosaminoglycans. It is an under-explored proteome which is modified in many diseases. Extracellular matrix bioactives fragments (matricryptins) are able to regulate physiopathological process like angiogenesis and cerebral disorders (Ricard-Blum and Salza, 2014). About 90 % of patients with Alzheimer's disease (AD) have cerebral amyloid angiopathy. Angiogenesis contributes to the development of AD. We are studying endostatin (ES), a matricryptin of collagen XVIII which has anti-angiogenic and anti-tumoral activities and is also present in amyloid plaques in AD patients. ES is released by neurons and is able to form amyloid fibrils in vitro (Kranenburg et al., 2003). This anti-angiogenic matricryptin could therefore be involved in AD. We have shown that ES is present in the cerebrospinal fluid of AD patients and the ratio of its concentrations to conventional markers of AD improves the diagnosis of patients with frontotemporal dementia (FTD) and discriminate AD patients from those suffering from FTD and pathology noAD/noDFT. We have established the extracellular interactions repertoires of the -amyloid peptide (1-42) in monomeric, oligomeric, fibrillar or aggregated forms and showed that the oligomerization and fibrillogenesis increase the interaction capacity of the -amyloid peptide. We have established the global interaction network of endostatin by surface plasmon resonance imaging and identified 21 new partners of this matricryptin. Specifically, we characterized its interaction with the Procollagen C-Proteinase Enhancer-1, a protein which gives rise to an anti-angiogenic matricryptin. We finally built networks of specific extracellular interactions of angiogenesis and of Alzheimer's disease and amyloid process to identify proteins connecting these two processes that are potential therapeutic targets. These interaction networks have been built using 239 interactions including those we have identified experimentally and those described in the literature. This data will be available in the database specific of extracellular interactions created in the laboratory, MatrixDB, in the new version of which we contributed
Bourgeat, Johan. "Etude du thyristor en technologies CMOS avancées pour implémentation dans des stratégies locale et globale de protection contre les décharges électrostatiques." Toulouse 3, 2011. http://thesesups.ups-tlse.fr/5671/.
Повний текст джерелаThe research work presented in this thesis addresses the issues related to the protection against electrostatic discharges (ESD) of integrated circuits in advanced technology nodes, CMOS45nm and CMOS32nm. The lithography dimension shrinking and the introduction of new technological process steps contribute to increase the ESD sensitivity. Excellent IC environment control together with the addition of dedicated protection circuits enable to decrease ESD failures. Thus, this research work consists to propose new protections based on the use of silicon controlled rectifier (SCR) devices. For that reason, a thorough study of the SCR behavior during ESD events has been carried out using three-dimensional TCAD simulations. This study enables the optimization of the main SCR parameters to improve its performance. To allow the SCR utilization as a local ESD protection with a power IO, a trigger circuit has been studied and firstly validated in CMOS45nm technology. Then, the trigger circuit optimization has been realized with SPICE simulations. The full protection has been developed in CMOS32nm and improved with bidirectional SCR (Triac). Finally, a new global protection strategy based on one network of three bidirectional SCRs, called "Beta-Matrix" has been investigated. A first study is focused on the development of its trigger circuit and a second one on the optimization of the "Beta-Matrix" topology. This protection strategy has been fully validated in CMOS32nm node
Bouvet, Céline. "Interactions cellule-matrice associées au remodelage et au vieillissement vasculaires." Phd thesis, Université d'Angers, 2007. http://tel.archives-ouvertes.fr/tel-00346381.
Повний текст джерелаBrunner, Molly. "L’intégrine β1 et de son régulateur ICAP-1α dans l’ostéogenèse : rôle dans la prolifération, la différenciation et la fonction ostéoblastiques". Thesis, Grenoble, 2013. http://www.theses.fr/2013GRENV043/document.
Повний текст джерелаΒ1 integrins belong to a large family of receptors that have been shown to be of paramount importance for cell/extracellular matrix interactions. The ablation of the specific β1 integrin regulator ICAP-1α results in severe bone and mineralization defects. By combining mouse and cell biology we could demonstrate that loss of ICAP-1α was accompanied by an increase of β1 integrin activity that affects fibronectin and collagen deposition. Moreover, we could show that ICAP-1 is an important negative regulator of kindlin-2 recruitment on β1 integrin cytoplasmic domain (Brunner et al. JCB 2011). We then wanted to address the functional role of β1 integrin per se in osteogenesis and to understand how osteoblasts integrate environmental cues to coordinate bone formation and remodeling. For this we generated osteoblast specific β1 integrin deficient mice. These mice showed severe bone defects characterized by reduced bone mineralization and dynamic, as well as bending and fractures reminding human Juvenile Osteoporosis symptoms. In vitro analyses of β1 integrin deficient osteoblasts revealed proliferation defect which is not due to defective canonical MAPK/ERK pathway, but rather to defective activity of the co-transcription factor YAP. Then, we showed that β1 integrins are regulating cAMP level in osteoblasts and that the cAMP level correlates with YAP inactivation. We also linked YAP inactivation with raft endocytosis. Finally, in vivo and in vitro analyses revealed a functional incapacity of β1 integrin deficient osteoprecursors. We could show that the lazy phenotype of β1 integrin deficient osteoblasts is likely due to a reduced response to BMP signaling, a major osteoblast growth factor. Taken together, our findings demonstrate that β1 integrin is a key regulator of YAP-dependent osteoblast proliferation and BMP signaling allowing osteoblast functionality, mineralization and bone formation
Pelletant, Aurelien. "Elaboration de matériaux composites céramiques à faible coefficient de dilatation thermique pour des applications spatiales." Thesis, Lyon, INSA, 2012. http://www.theses.fr/2012ISAL0018.
Повний текст джерелаHigh resolution satellite imagery from space optical systems is mainly limited by the mirror size and the mass of structures supporting the mirror. Nowadays, the development of light athermal systems is the major challenge to improve these optical systems. So, light materials having good mechanical properties (E/ρ3 > 10, σf > 100 MPa) and thermal stability (< 2.0e-6/K) are required. Within this context, our project consists in processing new ceramic composites by combining positive thermal expansion coefficient (TEC) materials having good mechanical properties (alumina or ceria doped zirconia) and negative TEC materials (zirconium tungstate or β-eucryptite) The processing of zirconium tungstate-based materials showed several decomposition and chemical reactions with some oxide matrix leading to its giving up. In the case of β-eucryptite, vermicular phenomenon occurs during sintering leading to the formation of intragranular porosity. Sintering parameters optimization can limit this porosity. The study of the thermal behavior of pure β-eucryptite materials shows that the very negative TEC results from microcracking, generated by the TEC anisotropy of its crystal lattice. This microcracking depends on the grain size and the aggregate size in the case of powder materials. Despite the fact that the TEC of its lattice (called intrinsic TE C equals to -0.4e-6/K) is very low, its bulk (or extrinsic) TEC can reach values until -10.9e-6/K according to the processing conditions. In this work, two strategies for developing composites were studied. The first one consists in decreasing the matrix TEC using an uncracked β-eucryptite powder (-0.4e-6/K) while the second one consists in elaborating near zero TEC materials from a microcracked β-eucryptite powder (-3.0e-6/K). When ceria-doped zirconia is used, ceria content must be adjusted in order to limit zirconia phase transformation. This transformation is driven by tensile stresses induced by the β-eucryptite and modifies the composite thermal behavior linearity. In both studied cases, dense composites show a modification of the β-eucryptite intrinsic TEC from -0.4e-6/K to more than +3.2e-6/K as a consequence of compressive stresses applied by the oxide matrix. An uncompleted densification of composites is required to relax these stresses. Taking into account these observations, several very low TEC composites were elaborated. However, the uncompleted densification of composites and the β-eucryptite microcracking greatly decrease the mechanical properties of these materials
Alcaraz, Lindsay. "Rôle de la Ténascine-X dans l’activation du TGF bêta latent." Thesis, Lyon 1, 2015. http://www.theses.fr/2015LYO10112.
Повний текст джерелаTenascin-X (TNX) is an architectural glycoprotein of the extracellular matrix. Beyond this role, TNX is also considered as a matricellular protein that is able to regulate the behavior of normal and tumor cells. However, no molecular and cellular mechanism has been described to explain TNX cellular effects before our study. In the laboratory, we showed that the C-terminal fibrinogen-like domain (FBG) of TNX was able to induce the latent transforming growth factor (TGF beta activation. Indeed, the three TGF beta isoforms are secreted as inactive complexes formed from non-covalent bonds between the mature TGF beta and its N-terminal propeptide, called LAP (Latency Associated Peptide). We showed that the FBG domain of TNX physically interacted with the latent TGF beta, in vitro and in vivo, and induced a conformational change of the latent complex to allow its activation into a bioactive molecule. Furthermore, we identified alpha1 beta1 integrin as a cell-surface receptor for TNX and showed that this integrin was crucial for the FBG-induced latent TGF beta activation. We also demonstrated that Meprins alpha and beta, two proteases belonging to the astacin family, could cleave the TNX, thereby releasing fragments containing the FBG domain capable of activating latent TGF beta. Finally, we have initiated a study regarding the biological relevance of latent TGF beta activation by TNX in vivo by analyzing the TGF beta signaling pathway in wild type or TNX-deficient mice
Désert, Romain. "Effets phénotypiques de deux mécanismes d’activation de la voie Wnt/beta caténine dans le carcinome hépatocellulaire." Thesis, Rennes 1, 2016. http://www.theses.fr/2016REN1B044/document.
Повний текст джерелаHepatocellular carcinoma (HCC) is the third cause of cancer-related death worldwide. Half of them show activation of Wnt/β-catenin pathway, caused by activating CTNNB1 exon 3 mutation of by stimulation of FRZD receptor. Transcriptomic based HCC classifications showed that this two types of activation were associated with distinct tumor subtypes. We tried to better understand the molecular phenotypes and the clinical features associated with these subtypes. In a first part, we linked extracellular Wnt activation with a stem/progenitor phenotype and with fibrous hotspot in HCC. Fibrous hotspot, which were called “fibrous nest”, can be detected by routine anatomic pathology analyses. We also showed that HAPLN1, an extracellular matrix protein induced by Wnt3a in progenitor HepaRG cells, was a new marker of stemness and bad outcome in HCC. Those results shows the associations between extracellular Wnt activation, extracellular matrix remodeling and tumor aggressiveness. In a second part, a transcriptome meta-analysis of 1133 HCCs highlighted 4 robust subclasses. CTNNB1 mutation, predicted by a 5-genes score based method, was associated with one of these subclasses and with good clinical features. We also highlighted a new subclass of CTNNB1 wild type HCCs associated with tumor differentiation, signatures of periportal metabolism and good outcome. This subclass was probably a confounding factor in survival studies comparing HCCs carrying mutant versus those carrying wild-type CTNNB1. Finally, we highlighted strong negative associations between CTNNB1 mutation and inflammation as well as tumor fibrosis in three independent cohorts. Preliminary results of in vitro HepaRG cells mutated for CTNNB1 in T41 and stimulated by LPS suggest an inhibitory effect of β-caténine on NF-κB. In conclusion, our results show that the two types of Wnt activation in HCC are associated with very distinct molecular phenotypes and clinical features
Lapointe, Vincent. "Essays on corporate social responsibility and socially responsible investment." Thesis, Aix-Marseille, 2013. http://www.theses.fr/2013AIXM1093/document.
Повний текст джерелаOur thesis examines corporate social responsibility (CSR) and how it is linked to a firm’s economic and financial performance, as well as socially responsible investment (SRI). With the current environmental and economic uncertainty, these issues are attracting increasing interest. Our thesis is organized in four chapters. Chapter 1 is a literature review on CSR and SRI. We propose an interdisciplinary review of the academic literature in both economics and management sciences (ethics applied to business, strategy and finance). Chapter 2 is an empirical analysis of the relationship between CSR and a firm’s financial performance in terms of cost of capital. We look at the impact of publishing an evaluation of the firm’s involvement in CSR on the liquidity of its stocks and the size of its investor base. Chapter 3 and Chapter 4 are analyses of the characteristics of SRI portfolios built according to new allocation methodologies. We analyze how risk-based allocations impact the performance of the portfolios of financial products of issuers involved in CSR, and reciprocally, how a universe of investment composed of the financial products of issuers involved in CSR impacts the properties of these alternative allocations
Le, Quéré Hervé. "Caractérisation fonctionnelle de la voie de signalisation des "Transforming Growth Factor beta" chez l'huître creuse Crassostrea gigas : implications du ligand Cg-TGF-beta." Caen, 2009. http://www.theses.fr/2009CAEN2028.
Повний текст джерелаTo complete the full repertoire of the TGF-beta pathway components in Lophotrochozoans, an Activin type II receptor (Cg-ActRII) was characterized from the oyster Crassostrea gigas. This receptor showed highest identity with human ActRIIB and demonstrated high expression during the first stages of oyster development and in the nervous tissues. It was found functional in zebrafish used as reporter organism and appeared to behave in a way similar to its zebrafish counterpart playing seemingly a dual role in both activin and BMP pathways. To decipher how, the various TGF-beta pathway components characterized in oyster interact to each other, Cg-TGF-beta ligand as well as various combinations of TGF-β receptors were co-expressed in mammalian cell lines. The results show interactions between Cg-TGF-β and two type I receptors (TbetaRI/ALRI) in the TGF-betass/Activin pathway. The receptor Cg-Tbeta sfRII seems to inhibit this pathway but activates the BMP pathway in presence of Cg-BMPRI and recombinant BMP2 though discrete Cg-ALR1 also activates this pathway. Since Cg-TGF-β is structurally related to the vertebrate TGF-βss family, its activity was investigated on Rabbit Articular Chondrocytes. Although Cg-TGF-beta inhibits their proliferation and promotes the transcription of some extracellular matrix components like Agrecan or type II Collagen, Cg-TGF-b activity was distinct from that of its vertebrate counterpart. This study suggests a preservation of the functionality of the TGFbeta pathway components in Lophotrochozoans, a relative conservation of the hierarchy but a versatility of the interactions between the various components which constitutes the central mechanism for fine tuning cellular responses
Bontorin, alves Guilherme. "Intelligent multielectrode arrays : improving spatiotemporal performances in hybrid (living-artificial), real-time, closed-loop systems." Thesis, Bordeaux 1, 2010. http://www.theses.fr/2010BOR14056/document.
Повний текст джерелаThis thesis presents a promising new bioelectronics system, the Hynet. The Hynet is a Hybrid (living-artificial) Network, developed to study the long-term behavior of electrogenic cells (such as Neurons or Beta-cells), both individually and in a network. It is based on real-time closed-loop communication between a cell culture (bioware) and an artificial processing unit (hardware and software). In the first version of our Hynet, we use commercial Multielectrode Arrays (MEA) that limits its spatiotemporal performances. A new Intelligent Multielectrode Array (iMEA) is therefore developed. This new analog/mixed integrated circuit provides a large-scale, high-density, and adaptive interface with the Bioware, which improves the real-time data processing and the low-noise acquisition of the extracellular signal
Esta dissertação de doutorado apresenta um sistema bioeletrônico auspicioso, o Hynet. Esta Rede Híbrida (viva e artificial), é concebida para o estudo do comportamento à longo prazo de células eletrogeneradoras (como neurônios ou células beta), em dois aspectos : individual e em redes. Ele é baseado na comunicação bidirecional, em laço fechado e em tempo real entre uma cultura celular (Bioware) e uma unidade artificial (Hardware ou Software). Um primeiro Hynet é apresentado, mas o uso de Matrizes de Eletrodos (MEA) comerciais limita a performance do sistema. Finalmente, uma nova Matriz de Eletrodos Inteligente (iMEA) é desenvolvida. Este novo circuito integrado fornece uma interface adaptativa, em alta densidade e grande escala, com o Bioware. O novo sistema melhora o processamento de dados em tempo real e a aquisição baixo ruído do sinal extracelular
Karajić, Aleksandar. "Development of electrode architectures for miniaturized biofuel cells." Thesis, Bordeaux, 2015. http://www.theses.fr/2015BORD0305/document.
Повний текст джерелаThe increasing demand for miniaturized and eventually implantable electrochemicaltools such as biosensors, biofuel cells and batteries has led to the development of newtechnologies to overcome existing problems related to large dimensions, low current densities,and insufficient power output of such devices. In the present work we describe new approachesfor the fabrication of miniaturized, macroporous and coaxial electrode architectures that couldfind their practical application for the fabrication of the systems mentioned above.Furthermore, we have demonstrated the functionality of macroporous electrodes with respectto the design of miniaturized glucose/oxygen biofuel cells. Preliminary results regarding thedesign of a new type of whole-cell based glucose biosensors are also presented.The first part of this work is focusing on different strategies for the fabrication of colloidalcrystals (Chapter 1) that can be used for the synthesis of macroporous electrodes (Chapter2) byfollowing the so-called hard template approach. The synthesis of macroporous electrodes isbased on the potentiostatic electrodeposition of conductive materials (such as metals in thepresent work) into a silica based colloidal template that has been synthesized by the Langmuir-Blodgett procedure. This method has been used for the design and fabrication of miniaturizedcoaxial and macroporous two electrode-electrochemical cells by following two different andcomplementary procedures: 1. The first fabrication procedure is based on the electrodepositionof alternating gold-nickel-gold metal layers, subsequent etching of the intermediate nickel layerand a structural stabilization; 2. The second alternative and complementary strategy for thefabrication of coaxial and macroporous double electrochemical cells relies on assembling thefinal architecture from two independently prepared and electrochemically addressablecylindrical macroporous electrodes. The main difference between these two approaches is therange of inter-electrode distances (from tens of micrometers (first approach) to hundreds ofmicrometers that can be achieved by second fabrication procedure). Also, we demonstrate theelectrochemical functionality of both electrode architectures by cyclo-voltammetricinvestigation of the oxygen reduction reaction that takes place at the surface of bothelectrodes.The biggest advantage of the presented strategies is the possibility to fine tune the electrodethickness (and therefore active surface areas), the spatial separation between inner and outerelectrode (the volume of electrolyte that can be stored between them) and the pore size (bychanging the diameter of silica colloidal particles).In the following segment (Chapter 3), we demonstrate the possibility to use macroporouselectrodes for the fabrication of an enzymatic biocathode. The macroporous gold substrateswere chosen as promising candidates to improve the electrochemical performances (currentand power output) of an enzymatic glucose/oxygen biofuel cells due to their high active surface area. [...] Finally, our contribution to the development of a new type of whole cell based biosensor isdescribed in Chapter 4. [...]
Nguyen, Huu-Hiep. "Social Graph Anonymization." Thesis, Université de Lorraine, 2016. http://www.theses.fr/2016LORR0168/document.
Повний текст джерелаPrivacy is a serious concern of users in daily usage of social networks. Social networks are a valuable data source for large-scale studies on social organization and evolution and are usually published in anonymized forms. This thesis addresses three privacy problems of social networks: graph anonymization, private community detection and private link exchange. First, we tackle the problem of graph anonymization via uncertainty semantics and differential privacy. As for uncertainty semantics, we propose a general obfuscation model called Uncertain Adjacency Matrix (UAM) that keep expected node degrees equal to those in the unanonymized graph. We analyze two recently proposed schemes and show their fitting into the model. We also present our scheme Maximum Variance (MaxVar) to fill the gap between them. Using differential privacy, the problem is very challenging because of the huge output space of noisy graphs. A large body of existing schemes on differentially private release of graphs are not consistent with increasing privacy budgets as well as do not clarify the upper bounds of privacy budgets. In this thesis, such a bound is provided. We introduce the new linear scheme Top-m-Filter (TmF) and improve the existing technique EdgeFlip. Thorough comparative evaluation on a wide range of graphs provides a panorama of the state-of-the-art's performance as well as validates our proposed schemes. Second, we present the problem of community detection under differential privacy. We analyze the major challenges behind the problem and propose several schemes to tackle them from two perspectives: input perturbation (LouvainDP) and algorithm perturbation (ModDivisive)
Moreau, Simon. "Modifications de la matrice extracellulaire dans la rigidité artérielle." Thèse, 2010. http://hdl.handle.net/1866/5103.
Повний текст джерелаWithin the vascular wall, endothelial cells, vascular smooth muscle cells and fibroblasts are surrounded by a complex and structured network of secreted macromolecules and proteins, the extracellular matrix. Reciprocal interactions between matrix and cells are essential to growth, development and remodeling. However, in pathological situations, the alteration of these interactions can lead to the development of different disease states. With aging, the extracellular matrix of large elastic arteries undergoes several modifications. The elastic lamellae are fragmented or degraded and calcify, whereas more rigid proteins, such as collagen, accumulate and cause fibrosis. These alterations are associated with the stiffening of arteries, which results in the development of isolated systolic hypertension. In order to study the sequence of events occuring in the development of this pathology, we used an animal model of calcification based on the inhibition of a matrix Gla protein, which physiologically prevents calcification, with warfarin. We observed an acute and transient activation of MMP-9 and TGF-ß, which preceded the phenotypic modulation of vascular smooth muscle cells, calcification and changes to hemodynamic parameters. Moreover, the inhibition of MMPs and TGF-ß prevented vascular calcification. We also studied the role of an extracellular matrix enzyme, transglutaminase 2, in the development of vascular calcification associated with isolated systolic hypertension. Using a novel inhibitor of this enzyme, we established a key role for transglutaminase 2 in this pathological process. This thesis demonstrates the relevance of directly targeting the extracellular matrix, particularly MMP-9, TGF-ß and transglutaminase 2, as a novel therapeutic avenue in the treatment of isolated systolic hypertension.
Tisserand, Vincent. "De BABAR à LHCb, en passant par CKMfitter. Physique du B et de CP dans les désintégrations charmonium et supprimées de couleur. Mesure des angles CKM beta et gamma." Habilitation à diriger des recherches, 2009. http://tel.archives-ouvertes.fr/tel-00486903.
Повний текст джерелаBullone, Michela. "Reversibility of airway remodeling in equine asthma : contribution of anti-inflammatory and bronchodilator therapies." Thèse, 2016. http://hdl.handle.net/1866/18381.
Повний текст джерелаAirway remodeling and inflammation are the hallmarks of asthma. Both airway smooth muscle (ASM) mass and extracellular matrix (ECM) deposition are increased in the central and peripheral airways of asthmatic patients, which contribute to airway obstruction. Few studies have investigated the ability of current asthma medications to reverse airway remodeling, especially the increased ASM mass. Inhaled corticosteroids (ICS) and long-acting β2-agonist combinations (ICS/LABA) are more effective than ICS monotherapy to control asthma exacerbations. However, their efficacy at modifying bronchial inflammation and remodeling at the peripheral level of the lung is not well-described. In fact, most work has been performed using endobronchial biopsy samples obtained from asthmatic subjects, which completely disregard the alterations occurring in peripheral airways. Ethical considerations limit the possibility of biopsying the peripheral airways in humans due to the invasiveness of the procedure. Equine asthma, or heaves, is a naturally-occurring disease of adult horses and a recognized animal model of human asthma characterized by neutrophilic inflammation as well as ASM and ECM remodeling of peripheral airways. This thesis has assessed the contribution of ICS and LABA, alone or combined, to the reversal of remodeling and inflammation in central and peripheral airways using the equine asthma model. To attain this goal, we have first optimized and validated the application of endobronchial biopsy and endobronchial ultrasound (EBUS) in the equine species. EBUS reliably estimates the bronchial ASM. Subsequently, asthmatic horses with ongoing airway remodeling and inflammation were treated with ICS, LABA, ICS/LABA, or antigen avoidance. Lung function, airway remodeling and inflammation were then assessed weekly for 3 months. Our results demonstrated a 30% decrease of peripheral ASM remodeling attained with ICS and ICS/LABA pharmacological treatment. A decrease of a similar magnitude of peripheral ASM was previously reported after 6 and 12 months of ICS monotherapy and antigen avoidance, respectively. A synergistic effect of ICS/LABA was observed on ECM deposition and airway lumen neutrophils. ICS/LABA decreased the ECM fraction of the ASM layer both peripherally and centrally, while the same effect on the lamina propria was observed only in central airways. Both ICS/LABA and ICS monotherapy decreased submucosal inflammation in central airways, while only ICS/LABA and antigen avoidance decreased bronchoalveolar neutrophilia. In conclusion, our results suggest that the enhanced therapeutic effect of ICS/LABA over ICS monotherapy in asthmatic horses was associated with a reduction of ECM deposition, mainly observed within the large airways, and possibly also with a decreased airway neutrophilia. However, ICS/LABA did not provide additional benefit to ICS monotherapy in terms of peripheral ASM remodeling as both induce a 30% decrease of the ASM mass in 3 months.