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Dissertations / Theses on the topic 'Integrin modulation'
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1
Buttery, Robert Christians. "Integrin affinity modulation and lung cancer." Thesis, University of Edinburgh, 2006. http://hdl.handle.net/1842/29025.
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Recent work has shown that the transmembrane protein CD98 is able to influence the affinity with which β1 integrins bind to extracellular ligands. The first part of this thesis presents confocal microscopy and co-immunoprecipitation experiments that confirm the physical juxtaposition of the two proteins within the cell membrane, suggesting a direct functional link between the two. It also demonstrated that cross-linking CD98 stimulates both phosphoinositide 3-kinase intracellular signalling and increased β1 integrin-dependent cellular adhesion. Because of the role of CD98 in integrin affinity modulation, the immunohistochemical expression of CD98 and its ligand, galectin-3, was studied in a variety of human ling diseases including lung cancers. The major finding of this work was a striking distinction between high expression of galectin-3 in non-small cell lung cancer and low expression in small cell lung cancer. This may hag significant implications for the differing clinical behaviours of these two groups of cancers. The final section of this thesis returns to describe experiments aimed at defining the molecular regulators of integrin affinity more clearly. A genetic screen of a cDNA library was undertaken to identify candidate genes coding for proteins able to rescue integrins from the low affinity state induced by the small signalling protein H-Ras. This identified a candidate cDNA 480, recognised to be part of a novel gene Nessie, which codes for a large protein with multiple transmembrane domains. Both 480 and Nessie appear to have the ability to rescue integrin affinity from H-Ras suppression.
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Coppolino, Marc Gabriel. "Modulation of integrin function by calreticulin." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp02/NQ35131.pdf.
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Elliott, Paul Anthony. "Integrin affinity modulation and survival signalling." Thesis, University of Edinburgh, 2008. http://hdl.handle.net/1842/4393.
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Integrins are heterodimeric transmembrane proteins that provide a bi-directional link between the cell’s internal biological mechanisms and the extracellular environment. During inside-out signalling, intracellular messages converge on the integrin cytoplasmic domain to induce a conformational change. This is transmitted to the extracellular domain where it results in an alteration in affinity for integrin ligands such as fibronectin and laminin. In this way the cell has developed the ability to modulate the critical functions of adhesion and cell movement. In outside-in signalling, the integrin performs a more complex function than simple adhesion; upon binding to ligand, the integrin extracellular domain undergoes a conformational change which is transmitted to the cytoplasmic domain. This alters the integrin’s cytoplasmic domain affinity for intracellular signalling proteins and results in the activation of intracellular second messenger pathways. In this way, the extracellular milieu is able to influence intracellular signalling including those involved in apoptosis. This thesis demonstrates data which provide original insights into bi-directional integrin signalling: Inside-out signalling: Constitutively active Notch1 increases β3-integrin affinity and abrogates Hras-mediated integrin suppression without increasing expression of β3- integrin. Dominant-Negative Rras blocks Notch-mediated integrin activation and Notch1-mediated reversal of Hras and Raf-mediated integrin suppression and this is independent of erk phosphorylation. Notch1 induces Rras activation. Functional adhesion assays confirm that Notch1IC increases K562 adhesion in a β1-integrin dependent manner and this is abrogated by Dominant-Negative Rras. This data supports a mechanism in which Notch1 increases integrin affinity via activation of Rras. Outside-in signalling: Evidence is presented demonstrating that extracellular matrix proteins, laminin and fibronectin, activate β1-integrins to protect SCLC cells against the apoptotic effects of etoposide and ionizing radiation via PI3Kinase activation. This occurs in two ways: 1) PI3Kinase-dependent β1-integrin signalling resulting in phosphorylation of Bad and reduced caspase-9 cleavage and 2) a β1-integrinmediated over-riding of etoposide and radiotherapy-induced cell cycle S phase delay and G2/M arrest. β1-integrin-mediated outside-in survival signalling was investigated further in the in vivo setting; MatrigelTM, a basement membrane product rich in extracellular matrix proteins, promoted SCLC xenograft survival and growth in a β1-integrin and tyrosine kinase-dependent manner. This data provides novel insights into the critical functions that integrins play in adhesion and survival signalling.
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Lad, Yatishkumar. "Integrin affinity modulation by Ras signalling molecules." Thesis, University of Edinburgh, 2002. http://hdl.handle.net/1842/24800.
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In this thesis I have sought to understand the mechanism by which H-Ras and its effectors modulate integrin affinity. H-Ras is a member of the Ras superfamily of small GTP binding proteins. Expression of the constitutively active variant of H-Ras (Ras G12V) within an integrin affinity reporter system (αβ-py cells) reduced integrin affinity (suppressed integrin). Ras effector mutants revealed that integrin suppression is mediated by Raf-dependent and Raf-independent signalling pathways. Raf-independent signalling pathways activated by Ral-GEFs and PI3-kinase were not recognisable for integrin suppression. An active variant of R-Ras (R-Ras G38V) reversed integrin suppression by both Raf-dependent and - independent pathways, indicating that these pathways may converge at a point proximal to the integrin. Raf initiates a protein signalling cascade leading to ERK activation that is responsible for many of the Ras/Raf-dependent biological functions. However, Raf-dependent integrin suppression was insensitive to MEK inhibition with the PD098059 compound. A novel Raf mutant (T481A) that fails to bind to MEK was also capable of mediating integrin suppression in the absence of ERK activation. Surprisingly, Raf-BxB T481A-mediated integrin suppression was sensitive to expression of MKP-1. Taken together it is proposed that Raf may mediate integrin suppression via a MEK-independent pathway that may utilise a member of the MAP kinase superfamily. In conclusion, integrin suppression by Ras is mediated by both Raf-independent and dependent pathways. Signalling by Raf may utilise components other than those present in the classical Ras to ERK protein cascade.
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El-Aouni, Chiraz. "In Vivo modulation of integrin linked kinase using transgenic mice." Diss., lmu, 2006. http://nbn-resolving.de/urn:nbn:de:bvb:19-61756.
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van, Wieringen Tijs. "Intra- and Extracellular Modulation of Integrin-directed Connective Tissue Cell Contraction." Doctoral thesis, Uppsala universitet, Institutionen för medicinsk biokemi och mikrobiologi, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-102349.
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All blood vessels in the microvasculature are embedded in loose connective tissue, which regulates the transport of fluid to and from tissues. The intersti-tial fluid pressure (IFP) is one of the forces that control this transport. A lowering of IFP in vivo results in an increased transport of fluid from the circulation into the underhydrated connective tissues, resulting in edema formation. During homeostasis, contractile connective tissue cells exert a tension on the connective tissue fibrous network by binding with β1 in-tegrins, thereby actively controlling IFP. During inflammation, the IFP is lowered but platelet-derived growth factor (PDGF)-BB induces an IFP nor-malization dependent on integrin αVβ3. We demonstrate that extracellular proteins from Streptococcus equi subspecies equi modulated cell-mediated and integrin αVβ3-directed collagen gel contraction in vitro. One of these proteins, the collagen- and fibronectin binding FNE, stimulated contraction by a process dependent on fibronectin synthesis. This study identified a pos-sible novel virulence mechanism for bacteria based on the ability of bacteria to modulate the edema response. Another protein, the collagen-binding pro-tein CNE, inhibited contraction and this led to the identification of sites in collagen monomers that potentially are involved in connecting αVβ3 to the collagen network. PDGF-BB and prostaglandin E1 (PGE1) stimulate and inhibit collagen gel contraction in vitro and normalize and lower IFP, respec-tively. We showed that these agents affected both similar and different sets of actin-binding proteins. PDGF-BB stimulated actin cytoskeleton dynamics whereas PGE1 inhibited processes dependent on cytoskeletal motor and adhesive functions, suggesting that these different activities may partly ex-plain the contrasting effects of PGE1 and PDGF-BB on contraction and IFP. Mutation of the phosphatidylinositol 3’-kinase (PI3K), but not phospholipase C (PLC)γ activation site, rendered cells unable to respond to PDGF-BB in contraction and in activation of the actin binding and severing protein cofilin. Ability to activate cofilin after PDGF-BB stimulation correlated with ability to respond to PDGF-BB in contraction, suggesting a role for cofilin in this process downstream of PDGF receptor-activated PI3K. Many proteins can modulate contraction either by affecting the extracellular matrix and cell adhesions or by altering cytoskeletal dynamics. Knowledge on how these proteins might influence IFP is likely to be of clinical importance for treat-ment of inflammatory conditions including anaphylaxis, septic shock and also carcinoma growth.
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Walsh, Erin. "Crossreactivity of alpha9beta1 integrin with p75NTR in modulation of proinvasive activities of glioma cells." Diss., Temple University Libraries, 2011. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/143048.
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BiologyPh.D.
Gliomas are the most common and difficult to treat tumors of the central nervous system. Current treatments often fail to slow progression of disease due to the high invasive nature of glioma leading to a high percentage of recurrence. Our previous studies have demonstrated that the levels of alpha; 9 beta; 1 integrin found on high grade glioma were significantly increased in comparison to normal brain tissue where the levels were negligible. We also found that interaction between alpha; 9 beta; 1 integrin and nerve growth factor (NGF) plays a major role in progression of experimental tumor. Another receptor for NGF the common neurotrophin receptor p75NTR is also overexpressed in high grade glioma. p75NTR forms a high affinity complex with the specific NGF receptor, TrkA leading to an increase in cell proliferation and survival. In the absence of an association, p75NTR is involved in transferring pro-apoptotic signals through the JNK pathway. We have found that the α 9 integrin subunit of α 9 β 1 forms a stable, cation independent complex with p75NTR on the cell membrane of glioma both in vitro using glioma derived immortalized cells lines and in vivo using glioma tissue. The co-expression of p75NTR with α 9 β 1 integrin led to optimization of integrin-dependent cellular activities such as cell survival, proliferation, and migration. Co-expression of p75NTR was also required for implanted glioma cells to migrate in a glioma-like perivascular manner away from the site of implantation as was seen in the in vivo quail chorioallantoic membrane assay.
Temple University--Theses
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Coyer, Sean R. "Modulation of cell adhesion strengthening by nanoscale geometries at the adhesive interface." Diss., Georgia Institute of Technology, 2010. http://hdl.handle.net/1853/34763.
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Cell adhesion to extracellular matrices (ECM) is critical to many cellular processes including differentiation, proliferation, migration, and apoptosis. Alterations in adhesive mechanisms are central to the behavior of cells in pathological conditions including cancer, atherosclerosis, and defects in wound healing. Although significant progress has been made in identifying molecules involved in adhesion, the mechanisms that dictate the generation of strong adhesive forces remain poorly understood. Specifically, the role of nanoscale geometry of the adhesive interface in integrin recruitment and adhesion forces remains elusive due to limitations in the techniques available for engineering cell adhesion environments. The objective of this project was to analyze the role of nanoscale geometry in cell adhesion strengthening to ECM. Our central hypothesis was that adhesive interactions are regulated by integrin clusters whose recruitment is determined by the nanoscale geometry of the adhesive interface and whose heterogeneity in size, spacing, and orientation modulates adhesion strength.
The objective of this project was accomplished by 1) developing an experimental technique capable of producing nanoscale patterns of proteins on surfaces for cell adhesion arrays, 2) assessing the regulation of integrin recruitment by geometry of the adhesive interface, and 3) determining the functional implications of adhesive interface geometry by systematically analyzing the adhesion strengthening response to nanoscale patterns of proteins. A printing technique was developed that patterns proteins into features as small as 90nm with high contrast and high reproducibility. Cell adhesion arrays were produced by directly immobilizing proteins into patterns on mixed-SAMs surfaces with a protein-resistant background. Colocalization analysis of integrin recruitment to FN patterns demonstrated a concentrating effect of bound integrins at pattern sizes with areas equivalent to small nascent focal adhesions. At adhesion areas below 333 × 333 nm2, the frequency of integrin recruitment events decreased significantly indicating a threshold size for integrin clustering. Functionally, pattern sizes below the threshold were unable to participate in generation of adhesion strength. In contrast, patterns between the threshold and micron sizes showed a relationship between adhesion strength and area of individual adhesion points, independent of the total available adhesion area. These studies introduce a robust platform for producing nanoscale patterns of proteins in biologically relevant geometries. Results obtained using this approach yielded new insights on the role of nanoscale organization of the adhesive interface in modulating adhesion strength and integrin recruitment.
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Lygoe, Kate Alexandra. "Modulation of the myofibroblast phenotype is via the interaction of extracellular matrix proteins with integrin receptors." Thesis, University College London (University of London), 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.411053.
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Hönig, Ellena [Verfasser], and Ralf [Akademischer Betreuer] Jacob. "Modulation der β1-Integrin-Lokalisation an der apikalen Plasmamembran durch Galektin-3 / Ellena Hönig ; Betreuer: Ralf Jacob." Marburg : Philipps-Universität Marburg, 2017. http://d-nb.info/1129358348/34.
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Brown, Ashley Carson. "Modulation of pulmonary epithelial to mesenchymal transitions through control of extracellular matrix microenvironments." Diss., Georgia Institute of Technology, 2011. http://hdl.handle.net/1853/44827.
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Epithelial to mesenchymal transition (EMT), the transdifferentation of an epithelial cell into a mesenchymal fibroblast, is a cellular process necessary for embryonic development and wound healing. However, uncontrolled EMT can result in accumulation of myofibroblasts and excessive deposition of ECM, contributing to the pathological progression of fibrotic diseases such as pulmonary fibrosis. The ability to control EMT is important for development of novel therapeutics for fibrotic pathologies and for designing novel biomaterials for tissue engineering applications seeking to promote EMT for development of complex tissues. EMT is a highly orchestrated process involving the integration of biochemical signals from specific integrin-mediated interactions with extracellular matrix (ECM) proteins and soluble growth factors such as TGFβ. TGFβ, a potent inducer of EMT, is activated via cell contraction-mediated mechanical release of the growth factor from a macromolecular latency complex. Thus TGFβ activity and subsequent EMT may be influenced by the biochemical and biophysical state of the surrounding ECM. Based on these knowns, it was hypothesized that both changes in integrin engagement and increases in substrate rigidity would modulate EMT due to changes in epithelial cell contraction and TGFβ activation. Here we show that integrin-specific interactions with fibronectin (Fn) fragments displaying both the RGD and PHSRN binding sites facilitate cell binding through α5β1 and α3β1 integrins, and lead to maintenance of epithelial phenotype, while Fn fragments displaying only the RGD site facilitate cell binding through αv integrins and lead to EMT. An in depth investigation into α3β1 binding to Fn fragments indicates that binding is dependent on both the presence and orientation of the PHSRN site. Studies investigating the contribution of ECM stiffening on EMT responses show that increasingly rigid Fn substrates are sufficient to induce spontaneous EMT. Analysis of TGFβ-responsive genes implicate TGFβ-expression, activation or signaling as a mechanism for the observed EMT responses. Together these results suggest that the ECM micromechanical environment is a significant contributor to the onset of EMT responses and provide insights into the design of biomaterial-based microenvironments for the control of epithelial cell phenotype.
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Kamboj, Sahil. "Outils avancés pour la modulation du trafic des intégrines dans le cancer de l'ovaire." Electronic Thesis or Diss., CY Cergy Paris Université, 2024. http://www.theses.fr/2024CYUN1300.
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Les intégrines sont des récepteurs hétérodimériques de surface cellulaire qui jouent un rôle essentiel dans la gestion des interactions cellule-cellule, lesquelles influencent ensuite des processus biologiques à plusieurs échelles tels que le comportement cellulaire, le remodelage de la matrice extracellulaire et la formation des tissus. Ces processus s'étendent de quelques millisecondes à plusieurs jours. Les méthodologies existantes pour étudier la fonction des intégrines à différentes échelles biologiques - des cellules individuelles aux tissus entiers - s'avèrent souvent chroniques et manquent de capacité pour cibler des interactions cellule-cellule spécifiques de manière aiguë.Pour remédier à cette limitation, nous avons conçu des cellules qui modifient rapidement leur comportement en régulant à la baisse la population de surface des intégrines α5β1 par le biais d'un processus d'endocytose médiée par la clathrine à chaud. Cette méthode innovante permet d'induire une internalisation spécifique des intégrines α5β1 et d'obtenir une régulation négative aiguë dans diverses lignées cellulaires en l'espace de 5 à 30 minutes. Nos résultats démontrent que cette internalisation induite des intégrines α5β1 entraîne une diminution de la surface cellulaire, favorise l'absorption de la fibronectine extracellulaire et réduit le taux de compaction des sphéroïdes tumoraux.Ce contrôle ciblé de processus à plusieurs échelles par la régulation négative rapide des intégrines α5β1 met en évidence l'utilité de l'endocytose à chaud en tant qu'outil puissant pour moduler de manière aiguë la biologie cellulaire. Notre approche offre une vitesse sans précédent dans l'ajustement du microenvironnement cellulaire, présentant de nouvelles avenues thérapeutiques et des stratégies innovantes pour l'ingénierie tissulaire en ciblant rapidement les interactions cellule-microenvironnementIntegrins are heterodimeric cell surface receptors that play a critical role in governing cell-cell interactions, which subsequently influence multiscale biological processes such as cell behaviour, extracellular matrix remodeling, and tissue formation. These processes span from milliseconds to several days. Existing methodologies to study integrin function across different biological scales—from single cells to whole tissues—often prove to be chronic and lack the capability to target specific cell-cell interactions acutely.To address this limitation, we engineered cells to rapidly alter their behavior by downregulating the surface population of α5β1 integrins through a process of hot-wired clathrin-mediated endocytosis. This innovative method enables inducible, specific internalization of α5β1 integrins, achieving acute downregulation across various cell lines within 5-30 minutes. Our findings demonstrate that this induced internalization of α5β1 integrins results in a decrease in cell area, promotes the uptake of extracellular fibronectin, and reduces the rate of tumor spheroid compaction.This targeted control of multiscale processes through the rapid downregulation of α5β1 integrins highlights the utility of hot-wired endocytosis as a potent tool for acutely modulating cell biology. Our approach offers unprecedented speed in tuning the cellular microenvironment, presenting novel therapeutic avenues and innovative strategies for tissue engineering by quickly targeting cell-microenvironment interactions
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Chilcoat, Clayton Douglas. "Protein Kinase A Regulates β2 Integrin Avidity Activation and Subsequent Neutrophil Activation via Modulation of Myosin Light Chain Kinase." NCSU, 2005. http://www.lib.ncsu.edu/theses/available/etd-03312005-093042/.
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β2 integrins are adhesion molecules on the surface of neutrophils. Avidity activation of β2 integrins includes transportation of pre-formed integrins to the cell surface and a conformational change in the integrin to a high-binding state. Upon binding ligand, β2 integrins initiate a signaling cascade that results in activation of the neutrophil to a pro-inflammatory state, and the inhibition of this signal can prevent further activation of the neutrophil. cAMP and it effector protein kinase A (PKA) exert a generally inhibitory effect upon neutrophil activation. PKA has been shown to inactivate myosin light chain kinase (MLCK). Myosin light chain (MLC) phosphorylation is crucial for actin-myosin complex formation, which is required for stability and contraction of the actin cytoskeleton in neutrophils as well as β2 integrin-dependent adhesion. We hypothesize that the inhibitory effect of PKA upon neutrophils is due to inhibition of β2 integrin avidity activation resulting in the subsequent inhibition of neutrophil activation. Furthermore we hypothesize that the effect of PKA upon β2 integrin avidity activation is mediated through PKA?s effect upon MLCK. We demonstrate that inhibition of PKA induces β2 integrin-dependent adhesion and that augmentation of cAMP prevented β2 integrin-dependent adhesion and subsequent respiratory burst activity. Further, we demonstrate via flow cytometric detection of antibodies directed against β2 integrins that pharmacologic inhibition of PKA activity results in overall increased β2 integrin expression on the neutrophil surface, as well as increased expression of the activated form of the integrin. This upregulation and activation of β2 integrins due to inhibition of PKA is abolished by pharmacologic MLCK inhibition. Inhibition of MLCK also blocked β2 integrin-dependent neutrophil adhesion achieved by inhibition of PKA, as well as neutrophil migration along towards a PKA inhibitor. These findings demonstrate that PKA regulation of β2 integrin affinity activation and subsequent neutrophil activation is via an MLCK-dependent pathway.
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Lidén, Åsa. "Integrin αVβ3-Directed Contraction by Connective Tissue Cells : Role in Control of Interstitial Fluid Pressure and Modulation by Bacterial Proteins." Doctoral thesis, Uppsala University, Department of Medical Biochemistry and Microbiology, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-6601.
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This thesis aimed at studying mechanisms involved in control of tissue fluid homeostasis during inflammation.
The interstitial fluid pressure (PIF) is of importance for control of tissue fluid balance. A lowering of PIF in vivo will result in a transport of fluid from the circulation into the tissue, leading to edema. Loose connective tissues that surround blood vessels have an intrinsic ability to take up fluid and swell. The connective tissue cells exert a tension on the fibrous network of the tissues, thereby preventing the tissues from swelling. Under normal homeostasis, the interactions between the cells and the fibrous network are mediated by β1 integrins. Connective tissue cells are in this way actively controlling PIF.
Here we show a previously unrecognized function for the integrin αVβ3, namely in the control of PIF. During inflammation the β1 integrin function is disturbed and the connective tissue cells release their tension on the fibrous network resulting in a lowering of PIF. Such a lowering can be restored by platelet-derived growth factor (PDGF) -BB. We demonstrated that PDGF-BB restored PIF through a mechanism that was dependent on integrin αVβ3. This was shown by the inability of PDGF-BB to restore a lowered PIF in the presence of anti-integrin β3 IgG or a peptide inhibitor of integrin αVβ3. PDGF-BB was in addition unable to normalize a lowered PIF in β3 null mice. Furthermore, we demonstrated that extracellular proteins from Streptococcus equi modulated αVβ3-mediated collagen gel contraction. Because of the established concordance between collagen gel contraction in vitro and control of PIF in vivo, a potential role for these proteins in control of tissue fluid homeostasis during inflammation could be assumed. Sepsis and septic shock are severe, and sometimes lethal, conditions. Knowledge of how bacterial components influence PIF and the mechanisms for tissue fluid control during inflammatory reactions is likely to be of clinical importance in treating sepsis and septic shock.
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Lionello, Valentina Maria. "Modulation of BIN1 expression rescues different forms of centronuclear myopathies in murine models." Thesis, Strasbourg, 2019. http://www.theses.fr/2019STRAJ010.
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Les myopathies centro-nucléaires (CNM) sont un groupe de maladies musculaires sévères caractérisées par une faiblesse musculaire générale. La forme la plus sévère est la CNM liée à l’X (XLCNM), causée par des mutations de la Myotubularine (MTM1). D’autres formes autosomales existent et sont causées par des mutations de l’Amphiphysine2 (BIN1) et de la Dynamine2 (DNM2). Les mécanismes pathologiques menant aux CNMs restent à éclaircir et à ce jour aucune thérapie n’est disponible pour traiter les patients. Nous avons modulé les niveaux de protéines de MTM1, BIN1 et DNM2 dans des modèles murins de CNMs. Nous avons découvert que la sous-régulation de DNM2 sauvait le modèle murin de XLCNM et que la sur-expression de la protéine BIN1 humaine sauvait le modèle murin XLCNM ainsi que la forme autosomale causée par les mutations DNM2. Nous avons montré que MTM1 contrôlait l’adhésion cellulaire et le recyclage de l’intégrine dans les cellules musculaires. Nous avons observé que la sur-expression de BIN1 sauvait la dérégulation du recyclage de l’intégrine dans le modèle murin de XLCNM, ce qui suggère un lien fonctionnel entre BIN1 et MTM1 nécessaire pour l’adhésion focale au niveaux musculaire. Notre étude montre que MTM1, BIN1 et DNM2 participe à une voie de signalisation commune et que BIN1 et DNM2 représentent de nouvelles cibles thérapeutiques pour le traitement des CNMCentronuclear myopathies (CNM) are a group of severe muscle disorder characterized by general muscle weakness. The most severe form is the X-linked CNM (XLCNM), caused by mutations in Myotubularin (MTM1). Others autosomal forms are caused by mutations in Amphiphysin 2 (BIN1) and Dynamin 2 (DNM2). The CNM pathomechanisms are still unclear and to date there are no therapies available to the disease. To investigate the pathways dysregulated in CNM and to identify new therapeutic strategies, we modulated MTM1, BIN1 and DNM2 protein levels in the CNM mouse models. We discovered that DNM2 downregulation rescued the XLCNM mouse model and that the overexpression of human BIN1 rescued the XLCNM and the autosomal dominant CNM form due to DNM2 mutations. We have also showed that MTM1 controls cell adhesion and integrin recycling in mammalian skeletal muscle and BIN1 overexpression rescued the integrin recycling alteration in XLCNM mouse model suggesting that MTM1 and BIN1 are functionally linked and necessary for focal adhesions in muscle. Therefore, our studies highlight that MTM1, BIN1 and DNM2 are in a common pathway and, BIN1 and DNM2 could be new therapeutic targets to treat the different CNM forms
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Asanbaeva, Anna. "Cartilage growth and remodeling modulation of growth phenotype and tensile integrity /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2006. http://wwwlib.umi.com/cr/ucsd/fullcit?p3223030.
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Thesis (Ph. D.)--University of California, San Diego, 2006.Title from first page of PDF file (viewed September 21, 2006). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references.
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Masi, Alessia. "Targeting integrins and modulating invasion and metastasis with metal-based drugs." Doctoral thesis, Università degli studi di Trieste, 2010. http://hdl.handle.net/10077/3615.
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2008/2009Distant metastases of solid tumours are the major cause of cancer death. To improve the effectiveness of chemotherapy, only marginally active on secondary tumours, anti-metastatic agents are needed, i.e. compounds that display the capacity to selectively interfere with metastatic formation and growth. Among metal compounds, NAMI-A, HIm[Ru(III)Cl4Imdmso], has repeatedly shown a peculiar and selective anti-metastatic activity being able to prevent the formation, and to inhibit the growth of established secondary tumours. On these bases, the first phase of the project was aimed to investigate how variations on the NAMI-A chemical structure can influence the anti-metastatic activity. For this purpose, some representative complexes have been chosen: two heterocyclic compounds KP418, HIm[Ru(III)Cl4(Im)2], and KP1019, HInd[Ru(III)Cl4(Ind)2], presenting a different N-donor ligand, and three organometallic compounds, RM175, [(η6-biphenyl)Ru(II)Cl-(ethylendiamine)]PF6, its osmium congener AFAP51, [(η6-biphenyl)Os(II)Cl(ethylene-diamine)]BF4, and RAPTA-T, [RuCl2(η6-toluene)PTA], carrying a PTA ligand instead of ethylendiamine. The effects of the compounds on the interference with some steps of the metastatic progression are evaluated with appropriate in vitro tests, comparing the behaviour of the human MDA-MB-231 highly invasive breast cancer cells to that of human HBL-100 non tumorigenic mammary epithelial cells. To validate the model, the in vitro effects are compared with the in vivo anti-metastatic activity studied in the MCa mammary carcinoma of the CBA mouse. The results obtained highlight the selective activity of the organometallic compound RAPTA-T towards the highly invasive cell line in vitro, accompanied by a selective inhibition of metastasis development in vivo. RAPTA-T seems to act through the modulation of tumour cells-extracellular matrix interactions, and of cell motility. In particular RAPTA-T induces a cytoskeleton remodelling, mainly through the formation of stress fibres, that causes a stiffening of the cell body, particularly evident on MDA-MB-231 cells grown on ECM components. These effects, selectively identified in the highly invasive MDA-MB-231 cells, can be related to the higher ruthenium uptake, detected in this cell line. Cell adhesion, migration and invasion are directly related to actin assembly and disassembly, phenomena regulated by the RhoGTPases. RAPTA-T completely counteracts the increase of trypsin mediated cell detachment induced by the RhoGTPases inhibitor C3 transferase, in MDA-MB-231 cells grown on fibronectin and collagen IV, and on HBL-100 cells grown on collagen IV. These molecular events might stem from the cell surface and involve integrin adhesion molecules, as suggested by the role of ECM components in the functional tests and by the preference of RAPTA-T to bind them, above all, collagen IV, with which RAPTA-T interacts chemically as confirmed by an NMR analysis. The effect of RAPTA-T on cells immediately after the adhesion on the substrate, i.e. mainly adherent with integrinic receptors, suggests that RAPTA-T interacts mainly with integrins in the form already bound with the substrate. Le metastasi dei tumori solidi sono una delle principali cause di morte. Per migliorare l’effetto della chemioterapia, che è attiva solo marginalmente sui tumori secondari, sono necessari agenti anti-metastatici, cioè composti che si mostrino capaci di interferire selettivamente con la formazione e la crescita delle metastasi. Tra i vari composti di sintesi il NAMI-A, HIm[Ru(III)Cl4Imdmso], ha ripetutamente mostrato una selettiva azione anti-metastatica dimostrandosi capace di prevenire la formazione e di inibire la crescita di metastasi già formate. Su queste basi, la prima fase di questo progetto ha avuto lo scopo di indagare come variazioni nella struttura chimica del NAMI-A potessono influenzare l’azione anti-metastatica. A questo scopo sono stati scelti alcuni composti rappresentativi: due composti eterociclici il KP418, HIm[Ru(III)Cl4(Im)2], e il KP1019, HInd[Ru(III)Cl4(Ind)2], e tre composti organometallici, RM175, [(η6-biphenyl)Ru(II)Cl-(ethylendiamine)]PF6, il suo congenere a base di osmio AFAP51, [(η6-biphenyl)Os(II)Cl(ethylene-diamine)]BF4, e RAPTA-T, [RuCl2(η6-toluene)PTA], che al posto dell’etilendiamina presenta il ligando PTA. Gli effetti dei composti sull’interferenza con alcuni step della progressione metastatica sono stati valutati con alcuni test in vitro, paragonando il comportamento della linea cellulare altamente invasiva MDA-MB-231 proveniente da carcinoma mammario, con quello delle HBL-100 linea cellulare dell’epitelio mammario non tumorigenica. Per validare il modello proposto in vitro gli effetti dei composti sono stati paragonati con la loro azione in vivo studiata sul carcinoma mammario (MCa) dei topi CBA. I risultati ottenuti mettono in luce la selettiva azione del composto organometallico RAPTA-T verso la linea cellulare altamente invasiva in vitro, accompagnata dalla inibizione selettiva dello sviluppo delle metastasi in vivo. Il RAPTA-T sembra agire attraverso la modulazione delle interazioni cellula-matrice extracellulare e della motilità cellulare. In particolare il RAPTA-T induce il rimodellamento del citoscheletro, principalmente attraverso la formazione di fibre da stress, questo genera irrigidimento del corpo cellulare, particolarmente evidente sulle MDA-MB-231 cresciute sui componenti della matrice extracellulare. Questi effetti, selettivamente identificati sulla linea altamente invasiva, MDA-MB-231, possono essere correlati ad un più alto assorbimento di rutenio che è stato rilevato in questa linea cellulare. L’adesione cellulare, la migrazione e l’invasione sono direttamente correlate al rimodellamento del citoscheletro actinico, e questi fenomeni sono regolati dalle RhoGTPasi. Il RAPTA-T reverte completamente l’aumentato distacco conseguente al trattamento con la C3 transferasi, agente che inibisce le RhoGTPasi, nelle MDA-MB-231 cresciute su fibronectina e collagene IV e sulle HBL-100 cresciute sul collagene IV. Questi eventi potrebbero coninvolgere l’adesione integrinica ai substrati, come suggerito dal ruolo dei componenti della matrice extracellulare nei test funzionali presi in considerazione, dalla preferenza del RAPTA-T per il legame con questi, e soprattutto il collagene IV con cui il RAPTA-T interagisce chimicamente, come confermato dall’analisi NMR. L’effetto del RAPTA-T su cellule appena dopo l’adesione al substrato, quindi prevalentemente legate attraverso i recettori integrinici, suggerisce che il RAPTA-T interagisca principalmente con le integrine nella forma già legata i substrati.
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Tupet-Defrance, Armelle. "Modulation de la fonctionnalité des integrines par les rayonnements ultraviolets A dans les fibroblastes du derme humain." Paris 7, 1999. http://www.theses.fr/1999PA077240.
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Pellegrino, Emilie. "Impact de Saccharomyces boulardii sur la restitution intestinale par modulations des molécules d'adhérences." Thesis, Aix-Marseille, 2013. http://www.theses.fr/2013AIXM4702.
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Les patients atteints de MICI (maladie de Crohn et recto-colite hémorragique) présentent souvent des lésions des cellules de l'épithélium intestinal. La rémission de ces maladies nécessite à la fois un arrêt de l'inflammation et une migration des entérocytes pour réparer les dommages épithéliaux. Cette migration cellulaire appelée restitution intestinale requiert des adhérences cellule-MEC et cellule-cellule réalisées par les complexes protéiques associés aux intégrines et cadhérines. Le but de cette thèse a été d'étudier l'impact deSaccharomyces boulardii (Sb) sur la réparation de l'épithélium intestinal lésé. Nous avons montré que le surnageant de Sb contenait des facteurs modulant la restitution de l'épithélium intestinal in vivo et in vitro sans affecter la prolifération des cellules épithéliales. Ces effets motogéniques du surnageant de Sb s'exercent via la modulation des molécules d'adhérence. En effet, le surnageant de Sb augmente l'affinité de l'intégrine α2β1 pour son ligand le collagène de type I mais entre en compétition avec les intégrine αvβ5, pour inhiber l'adhérence des entérocytes sur la vitronectine. Ces modifications de l'adhérence avec la matrice extracellulaire entraînent une régulation des voies de signalisation émanant des intégrines et une réorganisation des plaquesd'adhérence. Ces évènements vont accroître la migration des entérocytes. De plus, nos résultats préliminaires portant sur Sb et l'adhérence cellule-cellule durant la restitution intestinale ont montré une implication de la E-cadhérine dans la migration induite par SbIntestinal epithelial cell damage is frequently seen in IBD patients with ulcerative colitis or Crohn's disease. The remission of these diseases requires both the cessation of inflammation and the migration of enterocytes torepair the damaged epithelium. Adhesions with the ECM and the adjacent cells using complex of proteins associated with integrins and cadherins are necessary for this cell migration called intestinal restitution. Theaim of this thesis was to study the effect of S.boulardii on the resealing of a wound in intestinal epithelia. First of all, we demonstrated that the supernatant of S.boulardii contains factors that modulate intestinal epithelial cell restitution both in vitro and in vivo without affecting cell proliferation. We showed that the motogenic factors of S.boulardii act by modulating adhesion molecules. Indeed, the supernatant of S.boulardii increase the the affinity between 21 and it ligand the collagen type I, but also compete with integrin v5 to block theadhesion of enterocytes on vitronectin. These modifications of adhesion on extracellular matrix lead to aregulation of signaling pathway mediated by integrins, and a reorganization of focal adhesions. These eventscontribute to an increase of the migration of enterocytes. Add to this, our preliminaries results on S.boulardiiand cell-cell adhesion during intestinal restitution show an involvement of E-cadherin in the migrationS.boulardii-induced. With this work, we have demonstrated that heat-sensitive motogenic factors secreted by S.boulardii can enhance intestinal restitution with a dynamic regulation of adhesion between integrin and the ECM
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Schmidt, Katja [Verfasser]. "Cellular factors modulating the entry efficiency of West Nile virus – Involvement of integrins / Katja Schmidt." Hannover : Bibliothek der Tierärztlichen Hochschule Hannover, 2012. http://d-nb.info/1024516601/34.
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Thacker, Robert I. "Modulation of Human Dendritic Cell Activity by Adsorbed Fibrin(ogen)." University of Cincinnati / OhioLINK, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1218553202.
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Gray, Matthew Alan. "A comparative analysis of proportional-integral compensated shunt active power filters." Master's thesis, Mississippi State : Mississippi State University, 2004. http://library.msstate.edu/etd/show.asp?etd=etd-11092004-083404.
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Jain, Priyesh. "Design and Synthesis of Beta-Hairpin Peptidomimetics for Modulating Integrin Mediated Cell Adhesion, Abeta Fibrillogenesis and p53-MDM2 Protein-Protein Interactions." Scholar Commons, 2010. http://scholarcommons.usf.edu/etd/3458.
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Inhibiting therapeutically important protein-protein interactions has been a tremendous challenge for medicinal chemists. The folded 3D structures of peptides and proteins, mainly comprise secondary structural elements i.e α-helices and β-sheet have created an opportunity to design small molecules and peptidomimetic inhibitors of protein-protein interaction (PPI). Hence, information about the formation and stabilization of these secondary structures is vital for designing future drugs. In this dissertation, several cyclic beta-hairpin peptidomimetics that mimic the recognition surface have been designed and synthesized as inhibitors for different targets such as integrin mediated extracellular matrix -cell adhesion in multiple myeloma, p53-MDM2 PPI, amyloid beta fibrillogenesis inhibitor. Cyclization of linear peptides to restrict the number of conformations available to the linear peptide can increase its affinity for the target as well as increase its proteolytic resistance. In this study, different beta turn promoters that increase the propensity of cyclic peptides to adopt beta-sheet structures have been designed and synthesized. Chapter two discusses the design and synthesis of several cyclic III (Integrin Interaction Inhibitor) peptides that block adhesion of integrins to extracellular matrix components in Multiple Myeloma tumor cells. These cyclic peptides, as assayed by TOPRO 3 assay were more potent than the parent linear peptide with a bio-activity of 1.08 μM. We have also studied structure activity relationships (SAR) of these cyclic III peptide analogs to increase the potency and bioavailability of these peptides.
Chapter three describes the application of cyclic beta-hairpin peptidomimetics to inhibit abeta fibrillogenesis that is responsible for Alzheimer’s disease. We have successfully designed and synthesized cyclic peptides that target the hydrophobic region (17-21) of abeta fibril which is believed to cause self aggregation and plaque formation. We have also successfully explored these cyclic beta-hairpin peptides to disrupt p53-MDM2 interactions. Chapter five discusses the design and synthesis of novel cysteine based Peptide Nucleic Acid (PNA) monomers that are aimed to increase cellular uptake by introducing positively charged species attached to the cysteine side chain. We have successfully synthesized CPNA monomers and made efforts to make PNA oligomers.
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GUTIERREZ-MARTINEZ, CELSO. "Multiplexage par modulation de coherence en optique integree sur niobate de lithium (linbo3); etude et realisation de modulateurs rapides de coherence." Besançon, 1994. http://www.theses.fr/1994BESA2006.
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Cette these se situe dans le cadre general des travaux concernant le multiplexage optique par modulation de coherence. Cette technique repose sur le codage de signaux d'information sur des retards optiques entre les paquets d'onde emis par des sources optiques a faible longueur de coherence. Le multiplexage par modulation de coherence se presente comme une alternative potentielle parmi l'ensemble des techniques de multiplexage optique. Le but de cette these est de montrer la faisabilite de cette technique de multiplexage en technologie d'optique integree sur niobate de lithium (linbo3). Cette etude se developpe en deux parties qui se completent mutuellement: les chapitres 1 a 4 sont consacres respectivement: a la description des techniques de multiplexage optique, les principes du multiplexage de coherence, le modulateur birefringent, et la mise en oeuvre d'une liaison experimentale en architecture serie a deux canaux. Les chapitres 5 et 6 portent sur l'etude theorique et experimentale de la modulation electrooptique rapide afin de mettre en oeuvre des modulateurs de coherence fonctionnant dans le domaine des microondes
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Belkadi, Djilali. "Contribution à la modélisation et à la simulation des circuits intégrés analogiques : application aux systèmes échantillonnés et aux circuits linéaires de haute fréquence." Grenoble INPG, 1997. http://www.theses.fr/1997INPG0062.
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Ce travail est une contribution a la modelisation et la simulation temporelle des circuits integres analogiques. Suite au besoin de la conception descendante et aux limites de la simulation electrique, la conception sur differents niveaux d'abstraction est devenue necessaire. Puisque les circuits integres analogiques sont divers, nous en avons choisi deux types : les systemes echantillonnes et les circuits lineaires de haute frequence. Dans le premier genre, une methode de simulation est proposee. Elle est basee sur la linearisation du circuit par phase d'horloge et la resolution analytique des equations differentielles. La nouveaute qu'elle porte est de rendre la simulation transitoire du bruit physique possible en utilisant la notion du bruit gele. Quant aux circuits lineaires de haute frequence, une nouvelle methode appelee cifft est proposee afin de calculer une reponse impulsionnelle causale a partir des donnees frequentielles tabulees. En concretisation de ce travail, nous avons developpe deux modules delta sigma design kit et s-model (integre dans le simulateur eldo) pour la simulation transitoire des modulateurs - de type mash et les circuits definis par des donnees frequentielles tabulees.
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Maury, Ghislaine. "Mélange de signaux microondes par voie optique." Grenoble INPG, 1998. http://www.theses.fr/1998INPG0152.
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Nous avons etudie une solution originale de melange de signaux microondes par voie optique. Elle est fondee sur la conversion par un interferometre de la modulation de frequence de la lumiere, issue de la modulation directe d'une diode laser, en modulation d'intensite. L'interferometre etant un dispositif passif, cette technique presente plusieurs avantages par rapport aux techniques classiques necessitant des modulateurs actifs : elle peut etre facilement inseree dans un systeme de communications optiques avec multiplexage en longueurs d'onde, les pertes de conversion sont plus faibles, et enfin, la bande passante est reglable par simple choix de la geometrie de l'interferometre. Nous avons analyse theoriquement et simule plusieurs structures, avec differents types d'interferometres : mach-zehnder desequilibre, fabry-perot, et resonateur en anneau. Des mesures experimentales, realisees avec un mach-zehnder a fibres optiques, puis avec un michelson en optique de volume, ont permis de demontrer la faisabilite du melange. Nous avons ensuite realise un interferometre de mach-zehnder en optique integree sur verre car le controle en temperature de son substrat permet de maitriser le regime des interferences et d'optimiser la reponse de melange : les resultats des mesures ont alors ete stables et conformes aux simulations. Enfin, nous avons demontre l'interet pratique de la solution proposee en simulant une configuration dans laquelle un des deux signaux microondes d'entree est module par un signal numerique, ce qui est le cas dans les applications visees de telecommunications optiques.
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Hudson, Robert Dearn. "Development of an integrated co-processor based power electronic drive / by Robert D. Hudson." Thesis, North-West University, 2008. http://hdl.handle.net/10394/3723.
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The McTronX research group at the North-West University is currently researching self-sensing techniques for Active Magnetic Bearings (AMB). The research is part of an ongoing effort to expand the knowledge base on AMBs in the School of Electrical, Electronic and Computer Engineering to support industries that make use of the technology. The aim of this project is to develop an integrated co-processor based power electronic drive with the emphasis placed on the ability of the co-processor to execute AMB self-sensing algorithms.
The two primary techniques for implementing self-sensing in AMBs are state estimation and modulation. This research focuses on hardware development to facilitate the implementation of the modulation method. Self-sensing algorithms require concurrent processing power and speed that are well suited to an architecture that combines a digital signal processor (DSP) and a field programmable gate array (FPGA). A comprehensive review of various power amplifier topologies shows that the pulse width modulation (PWM) switching amplifier is best suited for controlling the voltage and current required to drive the AMB coils. Combining DSPs and power electronics to form an integrated co-processor based power electronic drive requires detail attention to aspects of PCB design, including signal integrity and grounding.
A conceptual design is conducted and forms part of the process of compiling a subsystem development specification for the integrated drive, in conjunction with the McTronX Research Group. Component selection criteria, trade-off studies and various circuit simulations serve as the basis for this essential phase of the project. The conceptual design and development specification determines the architecture, functionality and interfaces of the integrated drive. Conceptual designs for the power amplifier, digital controller, electronic supply and mechanical layout of the integrated drive is provided.
A detail design is performed for the power amplifier, digital controller and electronic supply. Issues such as component selection, power supply requirements, thermal design, interfacing of the various circuit elements and PCB design are covered in detail. The output of the detail design is a complete set of circuit diagrams for the integrated controller.
The integrated drive is interfaced with existing AMB hardware and facilitates the successful implementation of two self-sensing techniques. The hardware performance of the integrated coprocessor based power electronic drive is evaluated by means of measurements taken from this experimental self-sensing setup. The co-processor performance is evaluated in terms of resource usage and execution time and performs satisfactorily in this regard.
The integrated co-processor based power electronic drive provided sufficient resources, processing speed and flexibility to accommodate a variety of self-sensing algorithms thus contributing to the research currently underway in the field of AMBs by the McTronX research group at the North-West University.Thesis (M.Ing. (Electrical Engineering))--North-West University, Potchefstroom Campus, 2009.
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Ghassoul, M. "Organ preservation with spectral analysis testing based on a microprocessor : Preservation and testing isolated rat heart using a microcomputer on-line analysing the electrocadiogram using integral pulse frequency modulation." Thesis, University of Bradford, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.374904.
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Sanchez, Perez Célia. "Dispositifs optiques intègrés hybrides, verre / polymère électro-optique : applicationà un polariseur et à un modulateur de phase." Grenoble INPG, 2000. http://www.theses.fr/2000INPG0159.
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La generalisation actuelle des echanges d'information a conduit a une croissance des besoins en bande passante des systemes de telecommunication. Le traitement tout optique de l'information est devenu necessaire generant un besoin accru des dispositifs optiques pour stocker, controler et traiter d'importantes quantites d'informations. Dans le domaine de telecommunications, l'effet electro-optique des differents materiaux est souvent utilise pour la realisation des composants. Les materiaux organiques offrent de nouvelles perspectives pour le developpement de dispositifs electro-optiques performantes grace a son bon coefficient electro-optique et sa forte bande passante. De plus, la facilite des techniques de mise en uvre facilite leur integration avec d'autres materiaux pour former des composants hybrides multifonctions. Le travail presente a comme objectif la realisation et caracterisation de dispositifs optiques en technologie hybride : un guide de surface fabrique par echange ionique et un polymere electro-optique comme milieu actif. Un polariseur te a ete fabrique en utilisant une methode d'orientation par effet corona, un taux d'extinction de 40 db et des pertes d'insertion de 5 db ont ete obtenus. L'implementation des depots des electrodes transparentes en ito permet la realisation du polariseur te avec une methode d'orientation sous champ electrique par des electrodes. Dans ce cas, un taux d'extinction de 34 db et des pertes d'insertion de 9 db ont ete mesures. Par ailleurs, une modulation de phase electro-optique a ete montree experimentalement avec une tension demi-onde v = 200 v sur une longueur de modulation de 0,3 cm.
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Hayek, Dayana [Verfasser], Agnes [Akademischer Betreuer] Flöel, Alfons [Akademischer Betreuer] Hamm, Agnes [Gutachter] Flöel, Alfons [Gutachter] Hamm, Martin [Gutachter] Lotze, and Michael [Gutachter] Nitsche. "Association of cognitive performance with hippocampal network integrity of healthy adults and its modulation through non-invasive brain stimulation / Dayana Hayek ; Gutachter: Agnes Flöel, Alfons Hamm, Martin Lotze, Michael Nitsche ; Agnes Flöel, Alfons Hamm." Greifswald : Universität Greifswald, 2019. http://d-nb.info/1193177782/34.
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Hayek, Dayana [Verfasser], Agnes [Akademischer Betreuer] Flöel, Alfons [Akademischer Betreuer] Hamm, Agnes Gutachter] Flöel, Alfons [Gutachter] Hamm, Martin [Gutachter] Lotze, and Michael [Gutachter] [Nitsche. "Association of cognitive performance with hippocampal network integrity of healthy adults and its modulation through non-invasive brain stimulation / Dayana Hayek ; Gutachter: Agnes Flöel, Alfons Hamm, Martin Lotze, Michael Nitsche ; Agnes Flöel, Alfons Hamm." Greifswald : Universität Greifswald, 2019. http://nbn-resolving.de/urn:nbn:de:gbv:9-opus-29229.
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Bariteau, Jean-Marc. "Etude et réalisation d'anneaux résonnants en optique intégrée." Grenoble INPG, 1989. http://www.theses.fr/1989INPG0068.
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La technologie optique integree sur substrat silicium permet la realisation d'un microguide d'ondes en anneau couple a des microguides rectilignes formant ainsi une cavite resonante. Cette etude apporte des solutions theoriques et de premiers resultats experimentaux pour cet interferometre integre. Une presentation des resonances observables par interferences a ondes multiples est donnee puis l'influence des divers parametres sur les pics de resonance est etudiee. Une evaluation des pertes dues a la courbure de ces microguides est effectuee et le couplage entre microguides est calcule par la methode de perturbation. Les parametres technologiques utilisables sont ensuite determines pour differents rayons d'anneau et les caracteristiques de resonance des anneaux realises sont indiquees ainsi que les valeurs de pertes et de couplage qui s'en deduisent
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AUTIER, PHILIPPE. "Gravure ionique reactive des semiconducteurs iii-v avec controle in situ par interferometrie laser : applications a l'optique integree." Paris 6, 1989. http://www.theses.fr/1989PA066018.
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Cette these est une contribution a l'etude de la gravure ionique reactive (rie) des semiconducteurs iii-v en plasmas chlores cl#2/ch#4/h#2/ar. Une analyse in situ de la surface gravee a ete mise en uvre par une methode d'interferometrie laser sur des motifs de test constitues de reseaux. Les parametres caracteristiques de la surface gravee sont alors accessibles en temps reel. La rie offre un outil pour les applications a l'optique integree: realisation de dispositifs passifs (guides a faibles pertes, miroirs ou virages) et de dispositifs actifs (commutateurs, modulateurs, detecteurs, etc. ). La precision apportee par le systeme d'interferometrie laser donne un meilleur controle du confinement lateral: c'est un avantage pour realiser des structures qui font intervenir des phenomenes de conversion de modes ou de couplage par ondes evanescentes
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Boothe, Patricia. "Muc4, the Integral Membrane Modulator of ErbB2: The Effects of Muc4 Expression on ErbB2 and ErbB3 Phosphorylation, Receptor Levels and Sub-Cellular Localization In Breast Cancer Cells Treated With Neuregulin." Scholarly Repository, 2010. http://scholarlyrepository.miami.edu/oa_dissertations/670.
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Muc4, a heterodimeric transmembrane mucin containing EGF-like domains, has been described as an ErbB2-binding protein which modulates signaling via the ErbB2-ErbB3 pathway. In Muc4-transfected MCF-7 cells, Muc4 expression resulted in alteration of both the time course and phosphorylation levels of NRG beta 1 induced phosphorylation and activation of both ErbB2 and ErbB3. Muc4 significantly enhanced the autophosphorylation of ErbB2 over the early (defined 0-30 min) and intermediate (30-120 min) NRG beta 1 treatment times at three sites, Y1248, Y1221 and Y1139. The sites displayed differential maximal phosphorylation times. At Y1248 and Y1139, maximal phosphorylation occurred entirely during the early treatment phase. However, Y1221/2 showed maximal phosphorylation during the intermediate phase with a smaller peak during the early phase. The ratio of phosphorylated ErbB3 and total receptor level was significantly enhanced (in cells that expressed Muc4 compared without Muc4) over both the early and intermediate NRG beta 1 treatment time at the Y1289 site. This motif is one of several similar ErbB3 motifs whose phosphorylation mediates the binding of PI3-kinase. This phospholipid kinase is a key modulator of numerous cellular pathways leading to proliferation, motility and survival. Aberrancies in the ErbB2-ErbB3 signaling pathway have been implicated in the aggressive behavior of tumor cells, and the identification and characterization of modulators of this pathway are being sought as targets of potential therapeutic interventions. Muc4 significantly enhanced activated ERK in the absence of NRG beta 1 treatment while a NRG beta 1 mediated activation of AKT was observed. At early NRG beta 1 treatment time phases, Muc4 co-localized with phosphorylated ErbB2 (pY1248) independent of NRG beta 1 treatment; co-localization of Muc4 and ErbB2 receptor (activated/receptor forms) was observed at the apical surface or around the cell surface membrane. These data provide evidence in the Muc4-transfected MCF-7 cells for the biological NRG beta 1 mediated ErbB2 and ErbB3 activation. Our data suggests that Muc4 affects steady state phosphorylation levels and duration of the phosphorylation signal of both ErbB receptors, and that NRG beta 1 might affect ErbB2 and ErbB3 signaling differently. Additionally, the results of the timing of phosphorylation studies suggest the possibility that temporal aspects of phosphorylation at different sites may determine the pathways activated preferentially in the subsequent signaling cascades.
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ABAHAMID, ABDELOUAHAB. "Adaptation de cellules d'euglena gracilis au pentachlorophenol et au cadmium : modulations de l'expression de proteines de stress et d'enzymes de detoxication apparentees aux cytochromes p-450 (doctorat : structure et fonctionnement des systemes biologiques integres)." Paris 11, 1998. http://www.theses.fr/1998PA114825.
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Lestra, Alexis. "Contribution à l'étude de composants intégrés de type laser/modulateur pour transmissions optiques à haut débit." Grenoble INPG, 1996. http://www.theses.fr/1996INPG0142.
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Les liaisons optiques a une longueur d'onde de 1,55 micrometres necessitent des sources a faible fluctuations de frequences. Un laser de type dfb integre avec un modulateur externe a electro-absorption est un composant-cle pour ces transmissions. La section laser, utilisee en continu, doit constituer une source monomode a forte puissance. La modulation externe peut etre obtenue par effet stark confine au moyen d'un ruban haut debit de type v-loaded stripe ou ridge. Les deux sections sont integrees par couplage direct ; une methodologie est mise en oeuvre pour analyser la qualite de la zone de couplage. Les fluctuations de longueurs d'onde, induites par la realimentation du laser, constituent egalement un point critique qui est etudie theoriquement et experimentalement.
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Faderl, Ingo. "Étude et réalisation d'un modulateur électro-optique utilisant des polymères non linéaires dans un circuit optique intégré sur silicium." Grenoble INPG, 1994. http://www.theses.fr/1994INPG0102.
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La these demontre la faisabilite d'un modulateur electro-optique avec des polymeres non lineaires en optique integree sur silicium. Le modulateur est base sur un interferometre de mach-zehnder. L'originalite de ce travail repose sur l'hybridation d'un polymere non-lineaire sur un circuit optique integre passif. Seuls les guides actifs sont fabriques avec des polymeres non-lineaires. Le reste du modulateur est fabrique a l'aide de nitrure de silicium et de silice. Le premier chapitre rappelle les principes de l'optique non-lineaire avec les polymeres. La birefringence, l'absorption, le decalage du spectre d'absorption et le coefficient electro-optique ont ete exprimes en fonction de l'orientation des chromophores. Le deuxieme chapitre traite d'optique guidee dans les materiaux non lineaires. Des simulations ont ete entreprises dans le but de definir la structure guidante presentant le meilleur compromis entre l'utilisation optimale de la non-linearite et le minimum de perte lors du guidage optique. Ensuite, les principes de la fabrication du modulateur sont expliques. La compatibilite physico-chimique des polymeres avec la photo-lithographie et la gravure ionique reactive est un point important. La gravure ionique reactive est decrite en detail pour les polysiloxanes et le pmma. Finalement, le modulateur a ete caracterise en terme de pertes de propagation et de couplage, de coefficient electro-optique, de bande passante et de taux d'extinction
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De, Simone Mariarosaria. "Modulation of integrin activity for diagnostic and therapeutic applications." Tesi di dottorato, 2010. http://www.fedoa.unina.it/8209/1/de_simone_mariarosaria_23.pdf.
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SUMMARY
Over the past decade, the scientific research spent many efforts to develop therapeutic and diagnostic systems able to contact selectively the target cells and to minimize their diffusion in healthy organs. For this purpose the most diffuse approach was targeting the molecular markers overexpressed on the tissues of interest. In this contest, the integrin family of cell adhesion receptors was one of the most studied markers. (Tucker G.C., 2006).
In particular, among all integrins, v3 receptor was particularly studied in the last decade. Physiologically, it mediates many different biological processes such as intracellular signalling, cell migration, proliferation, and survival through interactions with ECM proteins such as vitronectin, fibronectin and osteopontin. The receptor mediates cell adhesion to extracellular matrix by recognizing the conserved Arg-Gly-Asp sequence of several plasma and matrix proteins. It is strongly overexpressed in activated EC, melanoma, glioblastoma and prostate cancers and in granulation tissue, whereas is not detectable in quiescent blood vessels or in the dermis and epithelium of normal skin. Therefore it can be considered a tumour and activated endothelium marker.
In the last decade several αvβ3 ligands able to modulate the receptor activity were developed as drugs for therapy, as tracers for diagnosis and as ligands for targeted drug delivery systems.
Among these molecules, the pentapeptide c(RGDf[NMe]V), also known as Cilengitide, is the most active , αvβ3/αvβ5 antagonist reported in literature and is in phase III clinical trials as antiangiogenic drug for glioblastoma therapy (Dechantsreiter M.A., et al., 1999; Reardon D.A., 2008; Tabatabai G., et al., 2010).
However, even if all v3 ligands reported in the literature have a good affinity for the receptor, they present a low selectivity and bind, even if with lower affinity, also other integrin receptors structurally homologues of v3 such as v5 integrin (Smith J.W., et al., 2003; Eskens F.A., et al., 2003). In contrast with v3 that has a relatively limited cellular distribution v5 is widely expressed by many malignant tumor cells.
Therefore, to target v3-mediated processes for diagnostic or therapeutic purposes, the development of new compounds that can discriminate between v3 and v5 is required to minimize the side-effects and increase the therapeutic effectiveness.
In 2006 our research group designed and synthesized a novel and selective peptide antagonist, referred to as RGDechiHCit, to visualize αvβ3 receptor on tumour cell (Del Gatto A., et al., 2006). It is a chimeric peptide containing a cyclic RGD motif and two echistatin C-terminal moieties covalently linked by spacer sequence. Cell adhesion assays showed that RGDechiHCit selectively binds, αvβ3 integrin and does not cross-react with, αvβ5 and, αIIbβ3 integrins (Del Gatto A., et al., 2006). Furthermore, PET and SPECT imaging studies confirmed that the peptide selectively localizes on αvβ3 expressing tumor cells in xenograft animal model (Zannetti A., et al., 2009). In this experimental setting, the chimeric RGDechiHCit was not able to detect a signal originating from the newly formed intratumoral blood vessels. This may be due to incomplete neovascularization and, hence, low levels of αvβ3 expression or to the murine origin of the integrin on newly formed blood vessels because the rational design of the chimeric RGD peptide was based on the crystal structure of the extracellular region of human αvβ3. Therefore the main purpose of the present PhD thesis was to evaluate in vitro and in vivo effects of RGDechiHCit on neovascularization.
In particular, we first assessed the in vitro peptide properties on bovine aortic ECs, VSMC and then in vivo, in Wistar Kyoto (WKY) rats and c57BL/6 mice, the ability of this cyclic peptide to inhibit angiogenesis in comparison with Cilengitide.
A major evidence that is brought up by our results is the peculiar selectivity of RGDechiHCit towards EC, as compared to c(RGDf[NMe]V). Indeed, RGDechiHCit fails to inhibit VSMC proliferation in vitro, opposite to c(RGDf[NMe]V). This feature could be due to the selectivity of such a novel compound towards , αvβ3, VSMCs indeed express αvβ3 only during embryogenesis (Eliceri B.P., et al., 1998; Illario M., et al., 2005), but express other integrins which may be blocked by c(RGDf[NMe]V). On the contrary, αvβ3 is expressed on ECs, thus conferring RGDechiHCit selectivity toward this cell type. It is only an indirect evidence, that needs further investigation in following experiments. Comparable results between the two antagonists were obtained on wound healing and Matrigel plugs invasion. Our data suggest that inhibition of the endothelial integrin system is sufficient to inhibit angiogenesis.
In conclusion the potential antiangionenic activity of the peptide opens new fields of application for the treatment of pathophysiological conditions associated to angiogenesis such as cancer, proliferative retinopathy and inflammatory disease.
In the nanotechnology field, gold nanoparticles (AuNPs) are playing a pivotal role in providing new types of targeted delivery systems to permit the selective entry of one or multiple drugs in the primary tumor, as well as at the site of metastasis and its microenvironment. AuNPs can be indeed used to deliver a cargo, such as an anticancer drugs, or a radionuclide to tumor sites as well they can be also employed in tumor phothermal therapy for their plasmon resonance properties (Melancon M., et al., 2009). In both cases the targeted drug approach is achieved by the exploitation of molecular markers over-expressed in cancerous tissues such as αvβ3 integrin.
Unfortunately, nanogold tend to aggregate in solution and so it is difficult to preserve them for long time. To solve this issue they can be functionalized with various organic ligands to create organic-inorganic hybrids with advanced functionality. It was recently reported the use of peptide sequences based on the GC repeats as stabilizing agents for the preparation of monolayer gold nanoparticles (Krpetić Z., 2009).
On the basis of this data, we designed and synthesized a new chimeric peptide (thereafter named RGD(GC)2, displaying motifs for both targeting and capping functions. A RGD-containing peptide, derived from the Cilengitide, was chosen as a targeting ligand for, αvβ3 integrin receptor and a GC including peptide was selected in order to stabilize the gold nanoparticles. AuNPs functionalised with this peptide were prepared and characterized by Uv-Vis, ATR-IR, XRD, NMR techniques and TEM microscopy. Finally we tested the ability of the obtained nanosystems, named RGD(GC)2AuNPs, to permeate the target cells membrane (U-87 MG, glioblastoma cells). In all these studies we used as negative control peptide named (GC)2 corresponding to the capping motif obtaining the gold nanoparticles named (GC)2AuNPs.
Our results encourage us to retain that this system could be a good starting point to develop selective gold nanodevices useful in the field of biotechnologies for therapeutic and diagnostic applications.
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Tsai, Cheng-Hsien, and 蔡承憲. "Electric field modulation of integrin polarization and directed cell migration." Thesis, 2011. http://ndltd.ncl.edu.tw/handle/19132907775205069771.
Full textAbstract:
碩士國立臺灣大學
醫學工程學研究所
99
Electrical stimulation is clinically used for the treatment of pain and to promote wound healing. In orthopaedic practices, applied electric fields (EFs) promote bone healing and improve lapine ligament repair in vivo. In the current study, several stimulation waveforms used in physical therapy were adapted to examine their effects on anterior cruciate ligament fibroblast (ACLF) migration and morphology. Most of the waveforms we tested resulted in enhanced fibroblast migration, while their effects on migration directionality were noticeably different. Furthermore, ACLFs elongation and alignment were only found in the DC groups. These findings suggest a decoupling of migration speed and directionality, which may arise from disparate mechanisms. We found that integrin acts as a major player of EF-induced directionality. We also found that integrin redistribution mediate the cathodal redistribution of RhoA. This introduces EF mediates one of the major signaling molecules, which is downstream from the integrin asymmetrically, with stronger redistribution on the cathode, is highly significant functionally. Results from this study may benefit our understanding the electro-therapy treatment on cell behavior and the relation between integrin and EF-induced directionality.
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Aouni, Chiraz el [Verfasser]. "In vivo modulation of integrin linked kinase using transgenic mice / by Chiraz El-Aouni." 2006. http://d-nb.info/982538030/34.
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Burzer, Klaus. "Modulation der Expression von Integrin-Beta4, Interleukin-1Beta und HMGA in humanen kolorektalen Karzinomzellen durch Butyrat." Doctoral thesis, 2003. https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-7840.
Full textAbstract:
Das kolorektale Karzinom ist das zweithäufigste Karzinom in der westlichen Welt. Schutz bieten Ballaststoffe, die zu kurzkettigen Fettsäuren, wie zum Beispiel Butyrat, fermentiert werden. Wir konnten mittels Western Blot eine Verringerung der Genexpression der Proteine Integrin-ß4 (Zelladhäsionsfaktor), Interleukin-1ß (Entzündungsfaktor) und HMGA (Transkriptionsfaktor) ab 48 Stunden Inkubationszeit mit 2mmol/l Butyrat in der gut-differenzierten HT-29-, der entdifferenzierten SW-480-Kolonadenokarzinomzelllinie sowie deren Metastasenzelllinie SW-620 zeigen. Unsere Ergebnisse weisen darauf hin, dass Butyrat die Zelladhäsion, die Progression, das metastatische Potential, die entzündliche Komponente und die Transkriptionsrate kolorektaler Karzinomzellen vermindert. Die erhöhte Expression der Proteine Integrin-ß4 und HMGA ist ein frühes Ereignis im Übergang zu malignen Formen. Somit könnten diese auch als diagnostische und prognostische Marker sowie als Ziel für Antikrebsmedikamente wie Butyrat dienenColorectal cancer is one of the most frequent cancers in our industrialized world. Butyrate production from dietary fibers by fermentation is protective against it. By western blot we could demonstrate the diminution of gene expression of the proteins integrin-ß4 (cell adhesion factor), interleukin-1ß (inflammatory factor) and HMGA (transcription factor) after 48 hours of incubation with 2mmol/l butyrate in well-differentiated HT-29-, not-differentiated SW-480-colonic adeno carcinoma cell lines and its metastatic cell line SW-620. Our examinations show that butyrate diminishes the cell adhesion, progression, metastatic potential, inflammatory component and rate of transcription in colonic carcinoma cells. The increased expression of the proteins integrin-ß4 and HMGA is an early event in the transition to malignant forms. Thus they could serve as diagnostic and prognostic markers and as a target for anticancer drugs like butyrate
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Burzer, Klaus [Verfasser]. "Modulation der Expression von Integrin-β4 [Integrin-Beta-4], Interleukin-1β [Interleukin-1-Beta] und HMGA in humanen kolorektalen Karzinomzellen durch Butyrat / vorgelegt von Klaus Burzer." 2004. http://d-nb.info/970170297/34.
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Driver, Glenn Alan. "Integrin-linked Kinase (ILK) expression in moderately differentiated human oesophageal squamous carcinoma cell lines: A growth factor modulation, activity and link to adhesion." Thesis, 2008. http://hdl.handle.net/10539/4842.
Full textAbstract:
Abstract
Integrin-linked Kinase (ILK) is an integrin-associated protein kinase, which regulates growth factor-signalling pathways and cell-ECM adhesion events. Abrogated ILK expression or activity has been implicated in contributing to oncogenic transformation. We examined the role played by ILK in growth factor-stimulated and integrin signalling events in five human oesophageal squamous cell carcinoma cell lines (HOSCCs), known to overexpress the EGF receptor. Western blot analysis revealed the presence of ILK (59kDa) in all the moderately differentiated HOSCC lines. ILK1 was confirmed as being the predominant isoform. Densitometrically analysed Western blots showed that, per unit of protein, ILK is expressed uniformly across the cell lines under standard culture conditions. Following EGF (10 ng/ml) and TGFβ1 (1 ng/ml) treatment, ILK expression increased in all five HOSCCs. Indirect immunofluorescence microscopy showed the majority of ILK to localise at a cytoplasmic/nuclear level, with a proportion of ILK localising at the membrane, which resembled the distribution pattern of the β3 integrin subunit. This membranal distribution most likely follows that of the adhesion plaques although lesser, and variable, amounts were also identified throughout the cytoplasm. The functionality of the ILK1 kinase domain was demonstrated using myelin basic protein (MBP)-based kinase assays. EGF and TGFβ1 treatment produced an increase in ILK activity in the WHCO3 cell line of 3.5 fold, but a decrease in activity in the other cell lines, which are suggested to involve the actions of PTEN. The identification of nuclear ILK was surprising, and the mechanism for nuclear ILK localisation was suggested to involve a caveolae-associated protein, caveolin-1. Cell adhesion assays revealed that KP-392-mediated inhibition of ILK resulted in a nonsignificant reduction in cell adhesion to collagen and fibronectin. These data provide distinctive evidence for the influence of growth factors on ILK expression, but a duality in the effect on ILK activity. This apparent dichotomy is noteworthy and may be of particular relevance in HOSCC. It is further suggested that KP-392-induced ILK inhibition destabilises the αβ integrin heterodimer and that PI3K acts upstream of ILK-mediated cell adhesion events in HOSCCs. This suggests that ILK mediates integrin associated processes in human oesophageal SCC cell lines.
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Chilcoat, Clayton D. "Protein kinase A regulates B2 integrin avidity activation and subsequent neutrophil activation via modulation of myosin light chain kinase." 2004. http://www.lib.ncsu.edu/theses/available/etd-03312005-093042/unrestricted/etd.pdf.
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Straube, Kathleen. "Modulation von Differenzierungsprozessen in der Mundschleimhaut (Maus) durch Inhibition des epidermalen Wachstumsfaktor-Rezeptors (EGFR): Immunhistochemische Untersuchungen." Doctoral thesis, 2017. https://ul.qucosa.de/id/qucosa%3A16728.
Full textAbstract:
Die strahleninduzierte Mucositis enoralis ist eine der bedeutendsten und häufig dosislimitierenden frühen Nebenwirkungen der Strahlentherapie fortgeschrittener Kopf Hals Tumoren. Bis heute hat sich noch kein allgemein gültiges Konzept zur Therapie und Prophylaxe der Mundschleimhautentzündung durchsetzen können. Ein Ansatz zur selektiven, auf der Tumorbiologie beruhenden Beeinflussung der Strahlenempfindlichkeit von Tumoren ist die Blockade des epidermalen Wachstumsfaktor-Rezeptors (EGFR). In Kombination mit Strahlentherapie sollen so die lokale Tumorkontrolle und die Heilungschancen verbessert werden. Die Wirkung der Tyrosinkinase-Inhibitoren BIBX1382BF und Erlotinib auf histomorphologische Parameter in der Mundschleimhaut sowie auf die Expression der als Stammzellmarker diskutierten Proteine p63, Integrin β1 und CD44 wurde in der vorliegenden Arbeit im Vergleich zur alleinigen fraktionierten Bestrahlung untersucht.
Für die histologischen Studien erfolgte die zweiwöchige fraktionierte Bestrahlung der Schnauzen von Mäusen des Inzuchtstammes C3H/Neu mit zehn Fraktionen zu je 3 Gy (Tag 0-4, Tag 7-11). Die Versuche gliederten sich in vier Gruppen:
• I/A (54 Tiere) und II/A (40 Tiere): fraktionierte Bestrahlung, keine weitere Behandlung
• I/B (51 Tiere): fraktionierte Bestrahlung, zusätzlich orale Gabe von BIBX1382BF, 50 mg/kg KG per os, von Tag 0-14 je 30 min nach der Bestrahlung
• II/B (35 Tiere): fraktionierte Bestrahlung, zusätzlich orale Gabe von Erlotinib, 50 mg/kg KG per os, von Tag 0-11 je 30 min nach der Bestrahlung.
Die Entnahme der Zungen erfolgte im Versuch I bei jeweils drei Tieren pro Tag von Tag 0 bis Tag 17. Im Versuch II wurden an den Tagen 0, 2, 4, 6, 8, 10, 12 und 14 jeweils die Zungen von fünf Tieren entnommen. Anschließend folgten die Fixierung der Zungen in Formalin, die Einbettung in Paraffin und die Anfertigung 3 µm dicker Gewebeschnitte. Die Zungenpräparate wurden für die histologischen Untersuchungen mit Hämatoxylin-Eosin gefärbt. Für die immunhistochemischen Färbungen wurde die ABC-Methode eingesetzt. Das Epithel der Zungenunterseite wurde lichtmikroskopisch hinsichtlich Zellzahl, Schichtdicke und Expression der potentiellen Stammzellmarker p63, Integrin β1 und CD44 ausgewertet. Aufgrund der geringen Gruppengröße (Versuch I: drei Tiere pro Datenpunkt; Versuch II: fünf Tiere pro Datenpunkt) wurde auf eine eingehende statistische Testung verzichtet. Die vorliegende Arbeit beschränkt sich auf eine beschreibende Darstellung des Verlaufs der Einzelparameter über den Gesamtzeitraum.
Die Zellzahlen verringerten sich während der ersten Bestrahlungswoche auf 60-70 % der Ausgangswerte, stagnierten in der zweiten Woche und stiegen schließlich bis zum Ende der Nachbeobachtung wieder an. Zwischen den nur bestrahlten und den zusätzlich mit BIBX1382BF behandelten Tieren war kein Unterschied feststellbar. Ein gleichsinniger Verlauf war auch in Versuch II zu beobachten, wobei die Zellzahlen der mit Erlotinib behandelten Tiere in der Funktionsschicht durchgängig höher ausfielen als in Versuchsreihe A. Die Dicke des Gesamtepithels bzw. der einzelnen Epithelschichten zeigte im Versuch I unter Bestrahlung große individuelle Schwankungen. Unter zusätzlicher BIBX1382BF-Gabe wurden oft niedrigere Werte gemessen. Im Versuch II blieb die Dicke des Gesamtepithels unter Fraktionierung konstant. Von Tag 0-12 wurden bei zusätzlicher Erlotinib-Applikation geringere Werte der Gesamtdicke gemessen als unter alleiniger Bestrahlung, ansonsten fielen die Veränderungen der Epitheldicke unabhängig von der Erlotinib-Gabe gering aus.
Der kurzzeitigen, mit dem allgemeinen Zellverlust einhergehenden Verringerung der p63-Expression zu Beginn der Bestrahlung folgt bis zum Ende des Beobachtungszeitraumes die Normalisierung der p63-positiven Zellen. Mit EGFR-Blockade sind gegenüber der alleinigen Bestrahlung keine Unterschiede in der p63-Expression festzustellen. Die Integrin β1-Expression nahm im Verlauf der Bestrahlung ab. Unter EGFR-Blockade mit BIBX1382BF zeigte sich an den Tagen 2-9 und 12-16 ein schwächeres Färbesignal als im fraktioniert bestrahlten Epithel, was für eine mögliche Interaktion des EGF-Rezeptors mit Integrin β1 spricht. Im Versuch II waren unabhängig von der Erlotinib-Gabe keine Unterschiede in der Expression von Integrin β1 feststellbar. Die CD44-Expression im Epithel wurde durch Bestrahlung gefördert. Übereinstimmend konnte in der vorliegenden Arbeit in beiden Versuchen eine Steigerung der CD44-Färbeintensität über den jeweiligen Referenzbereich festgestellt werden. Eine Blockade der EGFR-Aktivität durch Erlotinib reduzierte die Expression von CD44, wie in Versuch II/B im initialen Abfall der CD44-Färbeintensität deutlich wurde. Doch schon ab Tag 4 wurden im Versuch II/A und II/B gleich starke Färbesignale für CD44 erfasst.
Insgesamt ergaben sich unter EGFR-Inhibition mittels BIBX1382BF oder Erlotinib keine Hinweise auf Veränderungen der untersuchten Parameter während einer zweiwöchigen fraktionierten Bestrahlung. Ob diese Ergebnisse auch auf andere Tyrosinkinase-Inhibitoren bzw. unterschiedliche Wirkstoffklassen (z. B. Anti-EGFR-Antikörper) übertragbar sind, muss in weiteren Studien untersucht werden.Radiation-induced oral mucositis is one of the most important and often dose limiting early side effects of radiotherapy of advanced tumours in the head-and-neck region. To this day, no general concept for therapy and prophylaxis of the oral mucositis has been established. The inhibition of the epidermal growth factor receptor (EGFR) is one approach to a selective increase of the radiosensitivity of tumours based on the tumour biology. In combination with radiotherapy, application of EGFR-inhibitors is supposed to increase the local tumour control and the chances of cure. The aim of the present study was to investigate the effect of the tyrosine kinase inhibitors BIBX1382BF and Erlotinib on the radiation response of the oral mucosa and on the expression of different proteins that are discussed to be markers of epithelial stem cells. For the histological studies, the snouts of C3H/Neu mice were irradiated with ten daily fractions of 3 Gy over two weeks (on days 0-4, 7-11). The experiments comprised four treatment groups: • I/A (54 animals) and II/A (40 animals): fractionated irradiation, no further treatment • I/B (51 animals): fractionated irradiation, administration of BIBX1382BF, 50 mg/kg per os, once daily (days 0-14) 30 min after the radiation treatment • II/B (35 animals): fractionated irradiation, administration of Erlotinib, 50 mg/kg per os, once daily (days 0-11) 30 min after the radiation treatment. Between day 0 and 17, three animals of the groups I/A and I/B were euthanised per day. In the experimental arms II/A and II/B five mice were killed on day 0, 2, 4, 6, 8, 10, 12 and 14, respectively. The tongues were excised, fixed in formalin, embedded in paraffin and 3 µm thick sections were prepared. Subsequently, the tongue sections were stained with haematoxylin and eosin or with an ABC kit to visualise proteins of interest. The epithelium of the lower tongue was examined by light microscopy regarding the following parameters: cell numbers, thickness of epithelial layers and expression of the potential stem cell markers p63, integrin β1 and CD44. Due to the limited number of animals per data point (experiment I: three mice per data point; experiment II: five mice per data point), a detailed statistical analysis was not performed. The present study is determined to describe the parameter variations over the observation period. Cell numbers decreased to 60-70 % of the pre-treatment control values within the first week of irradiation alone, remained constant in the second week, and then slowly increased until the end of the observation period. There was no difference between radiotherapy alone or combined treatment with BIBX1382BF. In experiment II similar observations were made with higher cell numbers in the functional layer of the epithelium of the Erlotinib treated animals than in the irradiated group. The thickness of the epithelium and its individual layers showed high inter individual differences in experiment I. In treatment group I/B, lower values of thickness were often detected in comparison to group I/A. In experiment II the thickness of the epithelium remained constant under fractionated irradiation. Between day 0 and 12 the Erlotinib treatment slightly decreased the thickness of the whole epithelium in comparison to the irradiated group. Besides, there were only minor changes in the thickness of the different layers. Associated with the general loss of cells, radiation treatment led to a transient decrease in the expression of p63. The number of p63-positive cells recovered until the end of the observation period. A similar expression pattern of p63-positivity was found independent of EGFR inhibition. The expression of integrin β1 decreased during fractionated irradiation. On days 2-9 and 12-16, the changes were more pronounced in combination with BIBX1382BF treatment which indicates a potential interaction of the EGF receptor with integrin β1. In experiment II, no differences between the exclusively irradiated group and the combined treatment with Erlotinib were found for the expression patterns of integrin β1. Irradiation alone resulted in a higher epithelial expression of CD44. Accordingly, a general increase of CD44 staining intensity was observed in both experiments exceeding control values. Due to the EGFR inhibition with Erlotinib, the expression of CD44 initially decreased. However, by day 4 no persisting differences in staining intensity could be observed independent of EGFR inhibition. In summary, EGFR inhibition via BIBX1382BF or Erlotinib did not result in alterations of the analysed parameters during two weeks of fractionated irradiation. Further studies are required to demonstrate if the present findings are transferable to other tyrosine kinase inhibitors or different substance classes (e.g. inhibiting receptor antibodies).
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Si-YenLiu and 劉思顏. "The role of redox modulation in very late antigen-4 integrin mediated leukocyte activation and toluene diisocyanate induced airway inflammation." Thesis, 2010. http://ndltd.ncl.edu.tw/handle/18598603745207550572.
Full textAbstract:
博士國立成功大學
基礎醫學研究所
98
The trafficking of leukocytes from the blood into peripheral tissues through a multiple-step intercellular adhesion process is essential for selective recruitment of leukocytes to the inflammation sites. Like other immune reactions, a central question regarding the initiation and progression of allergic inflammation which leads to diseases like asthma is how cells responsible for stimulations are selectively recruited to the airway. We suggest that reactive oxygen species in the tissue microenvironments may participate in the regulation of immune responses by redox modulation and use in vitro and in vivo systems to address whether leukocyte-produced reactive oxygen species play an important role in leukocytes activation and allergic disease. Activation of leukocyte integrin is important for selective recruitment of cells to tissues. Our previous studies showed that the binding between the integrin very late antigen-4 (VLA-4) and vascular cell adhesion molecule-1 (VCAM-1) is modulated by reactive oxygen species. Here, we investigated the molecular nature of redox modulation on the activation states of VLA-4 induced exposure of sulfhydryl groups on the alpha 4 peptide. Low concentrations of exogenous hydrogen peroxide (5-10?M) enhanced the ligand binding ability of VLA-4 to VCAM-1 and cell rolling on VCAM-1, while higher concentrations of hydrogen peroxide (100?M) inhibited the binding ability. Low concentration hydrogen peroxide induced the S-glutathionylation on VLA-4 and the VLA-4 ligand binding activity modulated by redox modulation and required outside-in signaling and cytoskeleton rearrangement. These findings indicated that ligand binding of VLA-4 involves redox modulations which may play a pivotal role in regulating the activation states of VLA-4 in inflammatory tissues and hence direct leukocyte trafficking. To address the role of leukocyte-produced oxidants in airway inflammation, toluene diisocyanate, a low molecular weight compound noted for inducing occupational asthma, was used to induce airway inflammation in a mouse model. NADPH oxidase highly expressed in leukocytes has been known to be critical in reactive oxygen species production during tissue inflammation. Wild type B6 mice and NADPH oxidase deficiency (Ncf1-/-) mice were sensitized by intranasal sensitization and challenged by inhalation with toluene diisocyanate. Cell infiltration in lung tissue and leukocytes in bronchoalveolar lavage markedly decreased in the Ncf1-/- animals. Airway reactivity to methacholine challenge also was reduced to baseline level in Ncf1-/- mice. Toluene diisocyanate-induced inflammatory cytokines expression and redox-sensitvie nuclear factor activation in the lung tissue markedly decreased in NADPH oxidase deficient mice. Our findings suggest that leukocyte NADPH oxidase may be an essential regulator in toluene diisocyanate-induced airway inflammation.
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Marotta, Anthony. "Dysregulation of integrin-linked kinase (ILK) signaling during colorectal carcinogenesis : modulation of signaling pathways by non-steroidal anti-inflammatory drugs (NSAID)." Thesis, 2002. http://hdl.handle.net/2429/13101.
Full textAbstract:
One of the most common events involved in the development of human
colon cancer is the mutation of the adenomatous polyposis coli (APC) gene. This
protein through its interactions with Axin and GSK3β, serves to regulate the
cytosolic levels of β-catenin. Mutation of the APC gene, which impairs complex
formation, results in the stabilization of β-catenin. Stabilization is believed to
coincide with the translocation of β-catenin to the nucleus, where it up-regulates a
number of genes implicated in oncogenesis. Interestingly, stable over-expression
of the integrin-linked kinase (ILK) in rat intestinal epithelial cells has been
demonstrated to modulate p-catenin sub-cellular localization and function.
However, the significance of this finding in human colorectal carcinogenesis is
unclear. To determine if ILK signaling was disrupted in colorectal carcinogenesis,
this signaling pathway was characterized during various stages of development
beginning with the earliest lesion, the adenomatous polyp. The results from these
studies demonstrated that ILK was significantly overexpressed and exhibited an
increased phosphotransferase activity in polyps resected from patients
diagnosed with familial adenomatous polyposis. Changes in ILK activity reflected
changes on downstream targets, predominantly GSK3β. In addition to this,
dramatic increases in ILK immunoreactivity were observed in all abnormal crypts
from sporadic polyps, when compared with the normal appearing crypts, within
the same resected specimens. To delineate whether these changes in ILK
signaling could be generalized for colon cancer, this signaling nexus was also
investigated in both primary lesions as well as secondary deposits within regional
lymph nodes. The results from these studies demonstrate that ILK was
significantly hyperexpressed in malignant acini from either the primary or
secondary site in relation to the normal crypts within the same lesion.
Furthermore, over-expression of the ILK protein coincided with an increase in the
MBP phosphotransferase activity of the immunoprecipitated ILK in colon cancer
in approximately 63% of the primary lesions examined. In addition to this, the
data indicated that there was a direct correlation between the protein expression
of ILK and the protein levels of Lef-1 in the cases of colon cancer that were
analyzed. As aspirin and sulindac have been demonstrated to elicit
chemopreventative effects in colon cancer, I tested whether non-steroidal antiinflammatory
agents targeted the ILK signaling nexus in vivo. Both of these drugs
inhibited the serum-induced activation of ILK and PKB, modulated serine-9
phosphorylation on GSK3β, and down-regulated Tcf-4 transcriptional activity. In
addition to this, sulilndac was shown to also inhibit another protein kinase that is
known to influence p-catenin, protein kinase CK2. Furthermore, the data
demonstrated that over-expression of ILK, PKB or CK2 in a cell culture system,
inhibited NSAID mediated apoptosis. In conclusion, dysregulation of the ILK
signaling nexus appears to be an early event during the development of colon
cancer and it is possible that selective inhibition of this kinase might be an
important chemopreventative/chemotherapeutic strategy in the colon.
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Li, Mark. "Elucidating the Effects of Integrin-linked Kinase Modulation on Sarco/endoplasmic Reticulum Calcium ATPase Function in Human Induced Pluripotent Stem Cell-derived Cardiomyocytes." Thesis, 2013. http://hdl.handle.net/1807/43078.
Full textAbstract:
Integrin-linked kinase (ILK) is an important mechanoreceptor that mediates many cellular signaling pathways. Its dysregulation causes dilated cardiomyopathy and other complications in the heart. Restoration of ILK improves cardiac function and survival, but the exact mechanism is unknown. Recent studies in our lab suggest that the cardioprotective properties of ILK may be related to its regulation of sarco/endoplasmic reticulum calcium ATPase (SERCA2a). The protein expressions of ILK and SERCA2a are positively correlated based on adenoviral transduction of ILK and siRNA targeting ILK in human induced pluripotent stem cell-derived cardiomyocytes. From analysis of their calcium transients, ILK transduction resulted in increased beat rate and faster calcium clearance while siRNA knockdown produced the opposite effect. The use of SERCA-specific inhibitor thapsigargin nullified the observed effects of ILK transduction. Based on these results, we conclude that ILK’s cardioprotective properties are partly related to improving calcium handling in cardiomyocytes through the regulation of SERCA2a.
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Ifergan, Igal. "Modulation de la réponse immunitaire dans le cerveau par la barrière hémato-encéphalique : implication en sclérose en plaques." Thèse, 2011. http://hdl.handle.net/1866/7042.
Full textAbstract:
La sclérose en plaques (SEP) est une maladie inflammatoire du système nerveux central (SNC) caractérisée par une infiltration périvasculaire de cellules mononucléaires, telles que les lymphocytes T CD4+ et CD8+, les lymphocytes B ainsi que les cellules myéloïdes qui comprend les monocytes, les macrophages et les cellules dendritiques (DCs). Ce phénomène d’infiltration est dû à une fragilisation de la barrière hémato-encéphalique (BHE). L’entrée des cellules immunitaires au SNC va mener à la destruction de la gaine de myéline et donc à l’apparition de plaques de démyélinisation.
Ainsi, nous avons émis l’hypothèse que la migration des divers sous-types de cellules immunitaires du sang périphérique à travers la BHE est contrôlée par des mécanismes moléculaires distincts et spécifiques à chaque type cellulaire.
Afin de répondre à cette hypothèse, quatre différentes études ont été mises sur pieds. En premier lieu, nous démontrons un effet bénéfique des statines sur la BHE en SEP, en diminuant la migration des lymphocytes T et des monocytes, et en diminuant la diffusion de marqueurs moléculaire soluble. Ce phénomène s’opère via la suppression du processus d’isoprenylation, et en empêchant probablement la contraction des cellules endothéliales de la BHE.
De plus, nous démontrons que les monocytes qui migrent au SNC en condition inflammé sont en mesures de se différencier en DCs et d’induire une réponse inflammatoire de la part des lymphocytes T CD4+. La migration des monocytes à travers la BHE est contrôlée par une nouvelle molécule d’adhérence nommée Ninjurin-1. Le blocage de Ninjurin-1 conduit à une inhibition spécifique de la migration des monocytes in vitro, ainsi qu’à une amélioration des signes cliniques du modèle animal de la SEP, soit l’encéphalomyélite auto-immune expérimentale (EAE).
Finalement, nous démontrons que la migration des lymphocytes T CD8+ au SNC s’effectue via l’intégrine alpha-4. De plus, la majorité des lymphocytes T CD8+ que l’on retrouve dans le liquide céphalo-rachidien de patients SEP, dans le SNC de souris EAE ainsi que dans le SNC de souris infectée au virus de l’hépatite murine portent un phénotype effecteur mémoire. Ces données pourraient expliquer l’émergence de leucoencéphalopathie multifocale progressive observée chez certains patients SEP traités au natalizumab, un anticorps dirigé contre l’intégrine alpha-4.
En conclusion, notre étude a permis de démontrer l’importance des monocytes provenant de la périphérie dans le processus inflammatoire prenant part au SNC en SEP. L’inhibition d’entrée de ces cellules pourrait s’avérer bénéfique en SEP tout en permettant l’immuno-surveillance du cerveau, ce que l’anti-alpha-4 intégrine ne permet pas. Les statines pourraient s’avérer une autre option intéressante puisqu’elles agissent sur les processus inflammatoires impliqués dans la SEP.Multiple sclerosis (MS) is an immune-mediated disorder of the central nervous system (CNS) characterized by multifocal areas of leukocyte infiltration and demyelination associated with a breakdown of the blood-brain barrier (BBB). Typically, demyelination is centered around perivascular accumulation of CD4+ and CD8+ T lymphocytes, monocytes, macrophages and dendritic cells (DCs) that arise from migration of peripheral blood immune cells across the CNS microvascular endothelium. We have thus suggested that the migration across the BBB of immune cells subsets from the blood is controlled by molecular mechanism specific for each cell type. To answer this hypothesize, we have performed four different studies. We first show a beneficial effect of statins on the BBB, restricting the migration of lymphocytes and monocytes as well as the diffusion of soluble molecular tracers. This phenomenon is mediated through abrogation of isoprenylation processes that is probably inhibiting the ability of endothelial cells of the BBB to contract. We also show that CD14+ monocytes migrate across the inflamed human blood BBB and differentiate into DCs in response to BBB-secreted TGF-beta and GM-CSF. These DCs then promote the proliferation and expansion of inflammatory CD4+ T lymphocytes. We demonstrate that the migration of monocytes is controlled by a new adhesion molecule called Ninjurin-1. Ninjurin-1 neutralization specifically abrogated the adhesion and migration of human monocytes across endothelial cells of the BBB, without affecting lymphocyte recruitment. Moreover, Ninjurin-1 blockade reduced clinical disease activity and histopathological indices of experimental allergic encephalomyelitis (EAE). Finally we show that migration of CD8+ T lymphocytes across BBB is dependent on alpha-4 integrin. Also, the majority of CD8+ T lymphocytes found in the cerebrospinal fluid of MS patients, and in the CNS of EAE mice as well as the CNS of mouse infected with hepatitis virus are showing an effector memory phenotype. These data could explain the numerous cases of progressive multifocal leukoencephalopathy seen in natalizumab treated MS patients. In conclusion, our study unveils an important role of peripheral monocytes in MS. The inhibition of migration of these cells to the CNS could be a beneficial therapy since it would allow immune surveillance of the brain. The statins could also be a very interesting option since these molecules would reduce the inflammatory processes involved in MS.
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Teng, Hsun Yang, and 鄧勳陽. "A Compressed Sensing based Procedure Incorporating the Integral Pulse Frequency Modulation (IPFM) Model for Heart Rate Variability (HRV) Spectral Estimation." Thesis, 2013. http://ndltd.ncl.edu.tw/handle/07424272295241688545.
Full textAbstract:
碩士長庚大學
電子工程學系
101
Previous studies in literature have shown that Heart Rate Variability (HRV) can serve as a noninvasive for assessing autonomic control activities. Among HRV analysis technique, the Integral Pulse Frequency Modulation (IPFM) model is described as a functional mechanics for the cardiac pacemaker and generate a series of heartbeats. In this thesis, a Compressed Sensing (CS) based procedure incorporating the IPFM Model for HRV spectral estimation is proposed. Different from the traditional sampling theory, the theory of CS can be possibly reconstructed almost the same signal as origin, especially the sparse or compressible signal in nature, from fewer measurements under no resample. In fact, using the IPFM model, we can transform the heart rate signal into this problem that can be processed by CS method. Furthermore, we compared the proposed method with unevenly sampled Lomb in the numerical experiment, and showed the method we proposed has more accurate spectral estimation. In other hand, the new method can reduce the storage of data, and predict the HRV spectrum earlier.