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Sayyad, Wasim Amin. "Role of Myosin II and Arp 2/3 in the motility and force generation of Neuronal Growth Cones." Doctoral thesis, SISSA, 2015. http://hdl.handle.net/20.500.11767/3890.
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Differentiating neurons have to find chemical cues to form the correct synaptic connections with the other neurons so that they can create a functional neuronal network. During their development differentiating neurons project neurites, at the distal part of which there is a growth cone (GCs). The growth cone has highly motile structures, referred as lamellipodia and filopodia. Lamellipodia and filopodia sense the environment and process the mechanical and chemical stimulus and also exert forces. During my work for the completion of my PhD thesis, I used Optical Tweezers, video imaging and immunocytochemistry to quantify the motility and the force exerted by lamellipodia and filopodia from Dorsal Ganglion (DRG) neurons. I have also precisely quantified the role of some proteins and signaling pathways which regulate the motility of the DRG GCs.
The first part of my results entitled, “The role of myosin-II in force generation of DRG filopodia and lamellipodia”, characterizes the role of Myosin II in growth cone dynamics. Myosin II has been shown to control the retrograde flow of actin polymers, to be involved in the orchestration of actin and microtubules (MTs) dynamics and to possess contractile activity. GCs advance due to combined effects of the adhesion of lamellipodia and filopodia on the substrate and the contractile activity of Myosin II. Therefore, I probed the functional role of Myosin II on GCs dynamics by using its specific inhibitor, Blebbistatin. I show that the force exerted by lamellipodia decreased but surprisingly the force exerted by filopodia increased upon treatment with Blebbistatin. Moreover I show that the well organized and distributed structures of lamellipodia and filopodia of the GCs depend on the activity of Myosin II and confirmed the
coupling between actin and microtubule dynamics.
The next chapter, “The role of Rac1 in force generation of DRG neurons”, describes the function of Rac1 and its downstream effector Arp2/3 in lamellipodia and filopodia formation and dynamics. It is well known that Rac1 Rho-GTPase acts as a switch between GTP bound active state and GDP bound inactive state. I observed that GCs retract following partial inhibition of Arp2/3 but recover their usual motility within 5-10 minutes. I found that this
recovery is caused by the activation of Rac1. This indicates that Rac1 acts as switch and activates upon Arp2/3 inhibition, possibly through integrin pathways. I also confirmed that the activity of Arp2/3 not only regulates the formation of lamellipodia but also controls the dynamics and formation of filopodia.
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Choi, Mi-Yon. "P53 mediated cell motility in H1299 lung cancer cells." VCU Scholars Compass, 2010. http://scholarscompass.vcu.edu/etd/109.
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Studies have shown that gain-of- function mutant p53, AKT, and NFκB promote invasion and metastasis in tumor cells. Signals transduced by AKT and p53 are integrated via negative feedback between the two pathways. Tumor derived p53 was also indicated to induce NFκB gene expression. Due to the close relationship between p53/AKT and p53/NFκB, we hypothesized that AKT and NFκB can enhance motility in cells expressing mutant p53. Effects on cell motility were determined by scratch assays. CXCL5- chemokine is also known to induce cell motility. We hypothesized that enhanced cell motility by AKT and NFκB is mediated, in part, by CXCL5. CXCL5 expression levels in the presence and absence of inhibitors were determined by qRT-PCR. We also hypothesized that gain-of-function mutant p53 contributes to the activation of AKT. The effect of mutant p53 on AKT phosphorylation was investigated with a Ponasterone A- inducible mutant cell line (H1299/R175H) and vector control. These results indicated that AKT and NFκB enhance motility in cells expressing mutant p53 and this enhanced motility is, in part, mediated by CXCL5. However, AKT phosphorylation was independent of mutant p53.
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Yang, Lingyan. "The role of reduced-on random-motile (ROM) in the regulation of lung cancer cell migration and vesicle trafficking." Thesis, The University of Sydney, 2010. https://hdl.handle.net/2123/28847.
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Cancer is a complex disease, with over 100 different types and subtypes. Based on clinical features and biological properties, lung cancers can be separated into two major categories: non-small cell lung cancer and small cell lung cancer. In this study, we explore the function of the Reduced On-random Motile (ROM) protein in the regulation of non-small cell lung cancer cell migration and vesicle trafficking.
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Biondini, Marco. "RALlying through cell motility and invasion." Thesis, Paris 11, 2014. http://www.theses.fr/2014PA11T042.
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La formation des métastases est un processus en plusieurs étapes à travers lequel les cellules néoplasiques se détachent de la tumeur primaire pour constituer des tumeurs secondaires à distance. Les capacités à migrer et à envahir, des cellules tumorales sont cruciales dans la cascade métastatique. Selon le type cellulaire et les stimuli présents dans le microenvironnement tumoral, les cellules peuvent se déplacer collectivement ou individuellement selon un programme de migration mésenchymateuse ou amiboïde. Différentes voies de signalisation sont liées à la régulation de la motilité cellulaire. Les GTPases Rho (Rac1, Cdc42 et RhoA) contrôlent la migration en régulant la dynamique du cytosquelette d’actine, la contraction acto-myosine et les microtubules. Rac1 régule la motilité mésenchymateuse en favorisant la formation des lamellipodes via un complexe multiprotéique, le « Wave Regulatory Complex (WRC) » et RhoA contrôle la motilité amiboïde en favorisant la contraction du cytosquelette d'acto-myosine. Les protéines Ral (RalA et RalB) appartenant à une autre famille de petites G, ont été récemment impliquées dans la régulation de la migration cellulaire. RalB, à travers le complexe « Exocyst » joue un rôle essentiel dans la motilité. Dans ce travail de thèse, nous avons étudié les mécanismes moléculaires par lesquels la voie RalB/Exocyste contrôle la motilité et l'invasion cellulaire. La première partie de ce travail démontre que l’Exocyste interagit avec SH3BP1, une protéine GAP (GTPase Activating Protein) (projet 1). Nous montrons que l’interaction entre SH3BP1 et Rac1 est nécessaire à l’activité de Rac1 au front de migration. Dans le projet 2, nous montrons que l’Exocyste interagit directement avec WRC, ce qui est un élément clé de la polymérisation de l'actine. Cette interaction est nécessaire à la localisation du complexe WRC au front de migration où il contrôle la formation de protrusions membranaires. Dans de nombreux carcinomes, la transition épithélio-mésenchymateuse (EMT) joue un rôle important dans la promotion de la migration, l’invasion et la formation des métastases. Le projet 3 a permis de mieux caractériser la plasticité de migration et l’invasion des cellules cancéreuses post-EMT et d’étudier la contribution de Ral dans l'invasion des cellules post-EMT. Nous montrons qu’après l’EMT les cellules envahissent la matrice individuellement ? en utilisant la contraction du cytosquelette d'acto-myosine. Nous montrons que RalB est nécessaire à l’invasion des cellules post-EMT, et à la contractilité cellulaire. Nous proposons que le rôle de RalB dans l'invasion passe par GEF-H1 qui est une protéine GEF (Guanine Nucleotide Exchange Factor) de Rho associée à l’Exocyste. Dans la dernière partie de ce manuscrit, nous présentons le logiciel « AVeMap » que nous avons développé afin d’automatiser la quantification des paramètres de la migration cellulaire.En résumé, dans ce travail de thèse nous montrons que la voie Ral/Exocyste est un organisateur moléculaire nécessaire à l’exécution à la fois de la motilité cellulaire contrôlée par Rac1 et à la motilité contrôlée par RhoMetastasis is a multistep process by which cancer cells migrate away from the primary neoplastic mass to give rise to secondary tumors at distant sites. Thus, the acquisition of motility and invasive traits by tumor cells is a crucial step for metastasis to occur. Depending on the cell type and the environment, cells can move collectively keeping stable cell-cell contacts or as individual cells, which translocate by exploiting either mesenchymal or amoeboid motility programs.Different molecules and pathways have been linked to the regulation of cell motility. Rho small GTPases (Rac1, Cdc42 and RhoA) control cell migration through their actions on actin assembly, actomyosin contractility and microtubules. Rac1 drives mesenchymal-type motility by promoting lamellipodia formation via the Wave Regulator Complex (WRC). On the contrary, amoeboid motility is governed by RhoA which promotes cell movement via the generation of actomyosin contractile force. Another family of small GTPases, the Ral proteins, was recently involved in the regulation of cell migration. RalB, through the mobilization of its main effector the Exocyst complex, was shown to play an essential role in cell motility. In this work of thesis we investigated the molecular mechanisms through which RalB/Exocyst pathway controls cell motility and invasion.In the first part of this manuscript we show that Exocyst interacts with the RacGAP SH3BP1 (project 1). In mesenchymal moving cells Exocyst/SH3BP1 interaction is required to organize membrane protrusion formation by spatially regulating the activity of Rac1 at the cellular front. In addition, in project 2, we show that the Exocyst binds to the wave regulator complex (WRC), a key promoter of actin polymerization. We provide evidences for Exocyst to be involved in driving the WRC to the leading edge of motile cells, where it can stimulate actin polymerization and membrane protrusions. Reactivation of a developmental program termed epithelial-mesenchymal transition (EMT) was recently shown to promote motility, invasion and metastasis of neoplastic cells. Tumor cells undergoing EMT loose cell-cell contacts acquire a fibroblastoid phenotype and invade the surrounding tissues as individual cells. In project 3 we characterized the invasion plasticity of cancer cells after EMT and we investigated the molecular contribution of Ral to post-EMT invasion. We showed that upon EMT cells disseminate individually in a Rho-driven fashion exploiting the generation of actomyosin force to deform the extracellular matrix. We document that RalB silencing severely impairs actomyosin contractility and dissemination of post-EMT cells. We hypothesize that RalB regulates invasion by controlling the dynamics of the Rho pathway via the Exocyst-associated RhoGEF GEF-H1 in post-EMT cells. Finally, in the last part of this thesis manuscript, we present the PIV-based “AVeMap” software which has been developed to quantify in a fully automated way cell migration and its parameters (Project 4).Taken together the results presented in this thesis manuscript point out the Ral/Exocyst pathway as a key molecular organizer of the execution of both Rac1- and Rho-driven motility programs
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Dean, Seema. "Does the cytoskeleton manipulate the auxin-induced changes in structure and motility of the endoplasmic reticulum?" Thesis, University of Canterbury. School of Biological Sciences, 2004. http://hdl.handle.net/10092/5036.
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The variations in ER structure and motility under different stages of cell development remain largely unexplored. Here, I observe ER structure and the changes that take place in this structure over time in growing and non-growing live epidermal cells of the pea tendril. The ER was labelled by green fluorescent protein, fused to the KDEL-ER retention signal and confocal scanning laser microscopy was used to
localize the fluorescent signal. I found both the structure and motility of growing cells to be different to non-growing cells. The growing cells had a more open arrangement of the cortical ER, fewer lamellae and showed greater tubular dynamics, while the non-growing cells had a denser arrangement of the cortical ER network, with more lamellae and less tubular dynamics. Furthermore, these differences in the cortical ER structure and dynamics were due to growth as, the ER in non-growing cells showed characteristics similar to those seen in growing cells when these cells were induced to grow by the exogenous application of auxin. These changes in ER structure and dynamics were dependant on both the microtubules and actin cytoskeleton networks.
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Tozluoglu, M. "Multiscale modelling of cancer cell motility." Thesis, University College London (University of London), 2013. http://discovery.ucl.ac.uk/1383588/.
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Cell motility is required for many biological processes, including cancer metastasis. The molecular requirements for migration and, the morphology of migrating cells, can vary considerably depending on matrix geometry. Therefore, predicting the optimal migration strategy or the effect of experimental perturbation is difficult. This thesis presents a computational model of single cell motility that encompasses flexible cell morphology, actin polymerisation based protrusions, cell cortex asymmetry, plasma membrane blebbing, local cortex heterogeneity at the protein level, cell–extracellular matrix adhesion, and varying extracellular matrix geometries. This computational model is used to explore the theoretical requirements for rapid migration in different matrix geometries. The analysis reveals that confinement of the cell within the extracellular matrix brings profound changes in the relationship between cortical contractility and cell velocity. In confined environments with discontinuity, the relationship between adhesion and cell velocity is fundamentally altered: adhesion becomes dispensable for a large range of gap sizes in between the extracellular matrix filaments. The utility of the model is shown by predicting cancer cell behaviour in vivo, in terms of both cell velocity and the morphology of the motile cell. Furthermore, the model is challenged to predict the effects of selected biochemical perturbations that alter i) cortical contractility, ii) cell-ECM adhesion, and iii) signalling between the cell-ECM adhesion sites and intracellular regulators of cell motility machinery. Multiphoton intravital imaging is used to verify bleb driven migration of melanoma, breast cancer cells, and, surprisingly, endothelial cells at tumour margins. Intravital imaging of melanoma verified model predictions on cell velocity, cell morphology, nucleus behaviour, and effects of anti-invasive interventions. The model succesfully predicted melanoma velocities in vitro and in vivo. Moreover, it successfully predicted the effects of anti-invasive interventions, showing all perturbations will result in significant reduction in cell velocity in vitro, whereas only perturbation of cortical contractility will affect cell velocity in vivo. The model also successfully predicted the interactions of the cell nucleus with the cell cortex and the cell morphology upon intervensions. Overall, from measure ment of rather simple variables in vitro, the model has been able to predict the in vivo response of three very different putative anti-invasive interventions.
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Rucka, Marta. "Metabolic regulation of tumour cell motility." Thesis, University of Southampton, 2013. https://eprints.soton.ac.uk/380962/.
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Di, Kaijun. "The role of Id-1 on the proliferation, motility and mitotic regulation of prostate epithelial cells." View the Table of Contents & Abstract, 2007. http://sunzi.lib.hku.hk/hkuto/record/B38588985.
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Hadjisavas, Michael. "Induction of mitogenesis and cell-cell adhesion by porcine seminal plasma." Title page, contents and abstract only, 1992. http://web4.library.adelaide.edu.au/theses/09PH/09phh1293.pdf.
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Includes list of publications by the author. Includes bibliographical references (leaves 103-123) Evaluates the nature of the interactions occurring between semen and cells of the uterus that occur following mating in pigs. Describes a novel ability of porcine seminal plasma to induce dose dependent cell-cell adhesion and mitogenesis amongst peripheral blood lymphocytes in vitro.
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Stakaitytė, Gabrielė. "Merkel cell polyomavirus small T antigen’s role in cell motility." Thesis, University of Leeds, 2016. http://etheses.whiterose.ac.uk/15538/.
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Merkel cell carcinoma (MCC) is an aggressive skin cancer of neuroendocrine origin with a high likelihood of recurrence and metastasis. In 2008, Merkel cell polyomavirus (MCPyV) was discovered monoclonally integrated within the host genome of at least 80% of MCC tumours. MCPyV transforms and maintains MCC tumours via the expression of the large and small tumour (LT and ST) antigens. Specifically, ST is thought to be the major transforming factor in the tumourigenesis of MCC. Since the discovery of MCPyV, a number of mechanisms have been suggested to account for replication and tu- mour formation, but to date, little is known about potential links between MCPyV T antigen expression and the highly metastatic nature of MCC. In this thesis, the link between MCPyV and MCC metastasis is explored by focusing on the role of MCPyV ST in promoting cell motility. Cell motility and migration is a complex, multi-step, and multi-component process, intrinsic in cancer progression and metastasis. Previous work in the Whitehouse laboratory has implicated the microtubule network in MCPyV ST-induced cell motility. This thesis builds upon those findings to show that MCPyV ST-induced cell motility is dependent on multiple factors, including the activity of integrin receptors, Rho-family GTPases and the actin cytoskeleton, and intracellular chloride channels. This thesis also further explores the MCPyV ST-PP4C interaction in MCPyV ST-induced cell motility and proposes a mechanism by which this interaction activates integrin receptors to promote cell motility, thereby contributing to the metastatic nature of MCC. Furthermore, the relocalisation of intracellular chloride channels CLIC1 and CLIC4 to the cell surface is shown to be important in MCPyV ST-induced cell motility. Overall, results presented herein describe a novel mechanism by which a tumour virus induces cell motility, ultimately leading to cancer metastasis. Therefore, there may be implications for the potential future therapeutic targets for disseminated MCC.
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Suranemi, Praveen K. "Arp2/3 complex in mammalian cell motility." Thesis, Open University, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.548065.
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Acton, S. E. "Mechanisms of cancer cell motility in vivo." Thesis, University College London (University of London), 2008. http://discovery.ucl.ac.uk/1387309/.
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Pinner, Sophie Elizabeth. "Mechanisms of cancer cell motility in vivo." Thesis, University College London (University of London), 2008. http://discovery.ucl.ac.uk/1444471/.
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This thesis describes investigations into mechanisms responsible for cancer cell motility in vivo. Chapters 1 and 2 provide a review of current literature in this field and also describe the techniques used to generate the following the results. Chapter 3 describes a candidate-based approach to investigate whether ROCK1 might be regulated by phosphorylation. Mutagenesis of ROCK1 was carried out at 3 chosen sites (T233 T380 T398) in the activation loop and the hydrophobic domain and the phenotypes of the mutants were analysed. Chapter 4 describes a parallel approach finding phosphorylation sites in ROCK1 by mass spectrometry. From these results T518 was chosen for further investigation and its possible function is investigated. Chapter 5 describes an siRNA screen designed to identify novel regulators of the cortical acto-myosin cytoskeleton. The read-out for this was based on the disruption of rounded blebbing morphology of A375 cells cultured on 3D gel matrices. The rounded morphology is similar to that observed in amoeboid cancer cell motility in vivo, therefore we hypothesised that genes required for contracted, rounded morphology might also be required for motility. Results identified PDK1 amongst other genes as a potential regulator of contractile forces in A375 cells and the role of PDK1 was investigated further. It was found that PDK1 was required both in vitro and in vivo for amoeboid cell motility. Chapters 6,7 and 8 detail the investigations into the mechanism of how PDK1 regulates the cytoskeleton and amoeboid cell motility. It was shown that PDK1 was responsible for the localisation of ROCK1 but not ROCK2 at the plasma membrane. This regulation was achieved by the direct binding of ROCK1 to PDK1. It was further found that PDK1 was able to compete with and prevent RhoE, a negative regulator of ROCK1, from binding. Chapter 9 investigates the relationship between cell morphology, motility and pigment production. It was found that it was possible to image melanin containing vesicles using multiphoton excitation, and using this technique, the motile behaviour of pigmented melanoma cells was observed in vivo. It was found that motile invasive cells tended to contain less melanin than non-motile cells suggesting that they were less well differentiated. This chapter details investigations into what differences in signalling could be responsible for a switch to a de-differentiated, more invasive/metastatic phenotype. The final chapter discusses the findings contained within this thesis and the possible implications.
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Godeau, Amélie. "Cyclic contractions contribute to 3D cell motility." Thesis, Strasbourg, 2016. http://www.theses.fr/2016STRAF038/document.
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La motilité des cellules est un phénomène fondamental en biologie souvent étudié sur des surfaces planes, conditions peu physiologiques. Nous avons analysé la migration cellulaire dans une matrice cellulaire 3D contenant de la fibronectine fluorescente. Nous démontrons que les cellules y sont confinées, et déforment leur environnement de manière cyclique avec une période de ~14 min avec deux centres de contractions à l’avant et à l’arrière de la cellule qui contractent avec un déphasage de ~3.5 min. Une perturbation de ces cycles entraîne une réduction de la motilité. Par l’utilisation d’inhibiteurs spécifiques, nous avons identifié l’acto-myosine comme étant l’acteur principal de ce phénomène. En imposant des contractions-relaxations locales par ablations laser, nous avons déclenché la motilité cellulaire ce qui confirme notre hypothèse. L’ensemble de cette étude met en évidence un nouveau mécanisme fondamental de dynamique cellulaire impliqué dans le mouvement des cellulesCell motility is an important process in Biology. It is mainly studied on 2D planar surfaces, whereas cells experience a confining 3D environment in vivo. We prepared a 3D Cell Derived Matrix (CDM) labeled with fluorescently labeled fibronectin, and strikingly cells managed to deform the matrix with specific patterns : contractions occur cyclically with two contraction centers at the front and at the back of the cell, with a period of ~14 min and a phase shift of ~3.5 min. These cycles enable cells to optimally migrate through the CDM, as perturbation of cycles led to reduced motility. Acto-myosin was established to be the driving actor of these cycles, by using specific inhibitors. We were able to trigger cell motility externally with local laser ablations, which supports this framework of two alternating contractions involved in motion. Altogether, this study reveals a new mechanism of dynamic cellular behaviour linked to cell motility
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Lavi, Ido. "Physical modeling of cell motility and morphodynamics." Thesis, Sorbonne université, 2019. http://www.theses.fr/2019SORUS237.
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Cette thèse introduit un modèle hydrodynamique minimal de polarisation, migration et déformation d'une cellule vivante confinée entre deux surfaces parallèles. Le cytoplasme cellulaire, décrit comme une goutte visqueuse, est entraîné par une force active contrôlée par un soluté diffusif. Une analyse de stabilité linéaire révèle que l'activité du soluté déstabilise d'abord un mode global de polarisation et de translation, induisant une motilité cellulaire par rupture spontanée de symétrie. Pour une activité plus grande, le système traverse une série de bifurcations de Hopf conduisant à des oscillations couplées de la forme de la goutte et de la concentration de soluté. Nous trouvons également des solutions non linéaires de type onde progressive associées à des formes polarisées ressemblant à des observations expérimentales. De plus, nous avons développé des simulations numériques de ce problème basées sur la méthode des éléments finis. L'étude numérique a mis en évidence la stabilité des solutions de type onde progressive, l’existence d’attracteurs oscillants et l’apparition d’une singularité du bord à temps fini. En intégrant des interactions mécaniques avec l'environnement extérieur, nous avons exploré la diffusion cellulaire en présence de parois et d'obstacles stationnaires, la migration à travers des micro-géométries imposées et les collisions cellule-cellule. Ces simulations ont capturé une gamme de motifs non triviaux résultant de la mémoire intrinsèque et de la déformabilité de la cellule. Globalement, notre étude fournit un paradigme mathématique de systèmes actifs déformables qui couplent l'hydrodynamique de Stokes à des transducteurs de force diffusifsThis thesis introduces a minimal hydrodynamic model of polarization, migration, and deformation of a biological cell confined between two parallel surfaces. Our model describes the cell cytoplasm as a viscous droplet that is driven by an active cytoskeleton force, itself controlled by a diffusive cytoplasmic solute. A linear stability analysis of this two-dimensional system reveals that solute activity first destabilizes a global polarization-translation mode, prompting cell motility through spontaneous-symmetry-breaking. At higher activity, the system crosses a series of Hopf bifurcations leading to coupled oscillations of droplet shape and solute concentration profiles. At the nonlinear level, we find traveling-wave solutions associated with unique polarized shapes that resemble experimental observations. In addition, we developed a numerical simulation of our moving-boundary problem based on the finite element method. The numerical study demonstrated the stability of our traveling-wave solutions, the existence of sustained oscillatory attractors, and the emergence of a finite-time pinch-off singularity. By incorporating mechanical interactions with the external environment, we explored cell scattering from stationary walls and obstacles, migration through imposed micro-geometries, and cell-cell collisions. These exercises capture a range of nontrivial patterns resulting from the intrinsic memory and deformability of the cell. Altogether, our work offers a mathematical paradigm of active deformable systems in which Stokes hydrodynamics are coupled to diffusive force-transducers
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Suarez, Cristian. "ADF/cofiline, un facteur essentiel dans le contrôle de la dynamique de l'actine au cours de la motilité cellulaire." Thesis, Grenoble, 2011. http://www.theses.fr/2011GRENY033/document.
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Durant mon travail de thèse, j'ai étudié le rôle central de l'ADF/cofiline, une protéine qui se lie au cytosquelette d'actine, décore spécifiquement les parties ‘âgées' des filaments d'actine, diminue localement par un facteur 5 la rigidité du filament et provoque la fragmentation du filament à l'interface entre les sections nues et décorées. Dans ma première étude (Suarez et al., Current Biology, 2011), j'ai utilisé la microscopie à onde évanescente et une ADF/cofiline fluorescente pour démontrer que l'ADF/cofiline est un marqueur de l'état nucléotidique (ATP, ADP-Pi ou ADP) des sous-unités d'un filament d'actine en cours de polymérisation. De plus, l'ADF/cofiline, en accélérant la dissociation du phosphate inorganique (Pi), limite la taille du cap ATP/ADP-Pi du filament d'actine, sans toutefois le réduire à une taille zéro. Des analyses statistiques sur filaments isolés établissent une corrélation parfaite entre la densité de fixation de l'ADF/cofiline et son efficacité de fragmentation. Paradoxalement, l'efficacité de fragmentation est maximale pour une densité d'ADF/cofiline de 0.5. Ceci est confirmé par des analyses supplémentaires qui montrent que les sites de fragmentation du filament coïncident avec la position des frontières entre zones décorées et zones nues. Les conséquences de ce dernier résultat paradoxal sont l'objet de ma seconde étude (McCullough et al., 2011, Biophysical Journal). En combinant différentes sources d'ADF/cofilines (vertébré et levure) et d'actines (vertébré et levure), nous montrons, sur les quatre couples actine-ADF/cofiline possibles, qu'il existe une très forte corrélation entre (1) l'efficacité de fragmentation (qui dépend de la combinaison entre actine et ADF/cofiline) et (2) la déformation du filament, mesurée à la frontière entre zone décorée et zone nue. Au cours de ma troisième étude (Reymann et al., Molecular Biology of the Cell, 2011), nous montrons que le mécanisme de fragmentation ADF/cofiline-dépendant, établi à l'échelle d'un filament isolé, peut s'appliquer aussi à l'échelle d'une comète d'actine qui comporte un réseau complexe de filaments. Mon travail de thèse a montré que le mode d'action de l'ADF/cofiline se situe à l'intersection entre mécanismes microscopiques et macroscopiques, d'une part, et entre chimie et physique, d'autre part. Les caractéristiques microscopiques des interactions de cette protéine avec un filament d'actine isolé sont fondamentales pour expliquer des évènements macroscopiques, comme la fragmentation de filaments ou de structures complexes. D'autre part, nous avons montré comment les propriétés chimiques de l'ADF/cofiline modifient les propriétés physiques locales du filament et conduisent à la fragmentation. L'ADF/cofiline a un rôle central pour l'intégration de mécanismes physico-chimiques, à l'échelle microscopique, afin d'assurer un comportement cohérent à l'échelle de la celluleDuring my thesis, I have studied the pivotal role of ADF/cofilin, a protein that binds to the actin cytoskeleton, specifically decorates ‘old' actin filament parts, decreases by a factor of 5 the local filament rigidity and triggers filament fragmentation at boundaries between decorated and non-decorated filament sections. In my first study (Suarez et al., Current Biology, 2011), I have used evanescent wave microscopy and labeled ADF/cofilin to demonstrate that ADF/cofilin is a marker of the nucleotide state (i.e. ATP, ADP-Pi or ADP) associated with the actin sub-units in actively polymerizing filaments. In addition, because ADF/cofilin accelerates inorganic phosphate (Pi) release, the size of the ATP/ADP-Pi cap is diminished, although it cannot be reduced to zero. Fragmentation events frequency, determined from a thorough analysis of a population of single filaments decorated with labeled ADF/cofilin, is perfectly correlated with the binding density of ADF/cofilin on filaments. However, the maximal severing efficiency is obtained for half ADF/cofilin density. This paradoxical result is confirmed by analysis showing that severing sites are mainly associated with boundaries between decorated and bare actin filament sections. In consequence, in a second paper (McCullough et al., Biophysical Journal, 2011), I have took part in the study of actin filament deformation in relation with severing efficiency. Using different ADF/cofilin (vertebrate and yeast) and actin (vertebrate and yeast), we have shown that filament deformation at the boundary between bare and ADF/cofilin-decorated filament sections (which depends on the ADF/cofilin/actin combination) and severing are highly correlated. During my third study, (Reymann et al., Molecular Biology of the Cell, 2011), we established that stochastic dynamics, discovered at the molecular level for single filaments (or bundles of them), is also relevant to describe the macroscopic fragmentation of a comet tail consisting of hundreds of thousands filaments. I have shown that ADF/cofilin activity is at the crossroad between macroscopic and microscopic systems, on one hand, and physics and chemistry, on the other hand. The characteristics of microscopic interactions of ADF/cofilin with a single filament are fundamental to understand the macroscopic dynamics of a fragmenting comet. In addition, we have established how the binding of ADF/cofilin (chemistry) controls the mechanical properties of the filament (physics) before fragmentation. ADF/cofilin is essential in the integration of physical and chemical mechanisms at the microscopic level, to ensure consistent behavior at the cell scale
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Bratt, Anders. "The role of angiomotin in endothelial cell motility and cell-cell junction formation /." Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-479-1/.
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Ahmad, Omaima Farid. "The Role of Filamin A in Cell Motility, Adhesion and Invasion in Ovarian Cancer Cells." University of Toledo Honors Theses / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=uthonors1503407822068426.
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Adla, Shalini. "Characterization of the neural cell recognition molecule L1 in breast cancer cells and its role in breast cancer cell motility." Access to citation, abstract and download form provided by ProQuest Information and Learning Company; downloadable PDF file, 125 p, 2008. http://proquest.umi.com/pqdweb?did=1459905751&sid=5&Fmt=2&clientId=8331&RQT=309&VName=PQD.
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Wright, Adele Hart. "The role of integrins in the differential upregulation of tumor cell motility by endothelial extracellular matrix proteins." Diss., Georgia Institute of Technology, 1999. http://hdl.handle.net/1853/17352.
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Chon, John H. "Characterization of single-cell movement using a computer-aided fluorescence time-lapse videomicroscopy system : role of integrins in endothelial cell migration." Thesis, Georgia Institute of Technology, 1996. http://hdl.handle.net/1853/11171.
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Mrkonjić, Sanela 1983. "TRPV4 channel regulation and involvement in cell motility." Doctoral thesis, Universitat Pompeu Fabra, 2014. http://hdl.handle.net/10803/300754.
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The TRPV4 cation channel is expressed in a broad range of tissues where participates in the generation of a Ca2+ signal. TRPV4 participation in osmo- and mechanotransduction contributes to important functions such as cellular and systemic volume homeostasis, among others. TRPV4 also responds to temperature and 4α-phorbol 12,13-didecanoate (4αPDD) thus showing multiple modes of activation. Besides, dozens of TRPV4 mutations have been linked to osteoarticular and neuromuscular diseases. However, little is known about the domains relevant for TRPV4 activation by different stimuli. This Thesis research aims to elucidate the participation of the N-terminal cytosolic tail in the gating of TRPV4 by physiological stimuli and the channel implication in cell motility. I provide evidences that activation of TRPV4 by hypotonic shocks and temperature requires PIP2 binding within the sequence 121KRWRK125 of the N-terminus tail and rearrangement of the cytosolic tails. My results also point to the participation of TRPV4 in cell migration by modulating the dynamics of trailing adhesions, a function that may require the interplay of TRPV4 with other cation channels present at the focal adhesion sites.
Resumen
El canal TRPV4 es un canalEl canal TRPV4 es un canal catiónico capaz de generar señales intracelulares de Ca2+ en diversos tejidos. La participación del canal TRPV4 en procesos de mecano-osmotransducción le implica en funciones tan importantes como la regulación del volumen celular y sistémico. El TRPV4 también se activa en respuesta a calor y al agonista sintético 4αPDD, lo que implica la presencia de varios modos de activación. Además, existen numerosas mutaciones en el TRPV4 que se han encontrado en pacientes que sufren de patología osteoarticular y neuromuscular. Sin embargo, aún se desconocen aspectos de su función relacionados con los mecanismos de activación. Mi trabajo de Tesis doctoral aborda el estudio de la región N-terminal del TRPV4, su participación en la activación del canal por estímulos fisiológicos y la relevancia del canal en proceso de migración celular. Esta Tesis doctoral proporciona evidencias de que el TRPV4 necesita unir PIP2 a través de la secuencia 121KRWRK125 de la cola N-terminal y que las colas se reorganicen para que el canal se abra en respuesta a estímulos osmóticos y de calor. Mis estudios también sugieren que el canal TRPV4 participa en la modulación de la adherencia de la cola durante el proceso de la migración celular, posiblemente interaccionando con otros canales presentes en las adhesiones focales.
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Sroka, Thomas Charles. "Synthetic Peptide Ligand Mimetics and Tumor Cell Motility." Diss., Tucson, Arizona : University of Arizona, 2005. http://etd.library.arizona.edu/etd/GetFileServlet?file=file:///data1/pdf/etd/azu%5Fetd%5F1325%5F1%5Fm.pdf&type=application/pdf.
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Liu, Zhiwen. "Matrix metalloproteases and cell motility in malignant mesothelioma /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7140-061-3/.
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Kotha, Jayaprakash. "Molecular mechanism of tetraspanin CD9 mediated cell motility." View the abstract Download the full-text PDF version, 2007. http://etd.utmem.edu/ABSTRACTS/2007-010-Kotha-index.html.
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Thesis (Ph.D. )--University of Tennessee Health Science Center, 2007.Title from title page screen (viewed on July 16, 2007). Research advisor: Lisa K. Jennings, Ph.D. Document formatted into pages (xiv, 150 p. : ill.). Vita. Abstract. Includes bibliographical references (p.130-150).
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Fuhs, Thomas. "Intracellular polymer network as source od cell motility." Doctoral thesis, Universitätsbibliothek Leipzig, 2013. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-124097.
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Cell motility has been found to play a role in many important body functions as well
as the embryogenenis of mulitcellular organisms like vertebrates. From a physics
point of view the interesting questions behind every motion are: Why is it moving?
Where do the forces come from?
Today we know that the motility of many cells is dependent on an active polymer
network. Actin, one of the most abundant proteins in the body, is constantly polymerized,
being moved around and depolymerized in motile cells. Until now, only
forces outside the cell like traction forces could be measured. The direct measurement
of the force generated by polymerizing actin filaments has only been measured
by our lab and the lab of M. Radmacher. In these measurements fish keratocytes
were used. Whereas I did these experiments, for the first time, on mammalian cells.
To measure forward forces on neuronal growth cones I stabilized the SFM, as
measurement times went up from minutes to hours. Furthermore measurements
had to be performed at 37°C instead of room temerature, this induced drifts of the
substrate. I incorporated an optical trap into the microscope to track the motion
of the substrate. A feedback loop moved the SFM cantilever to minimize relative
motion of substrate and cantilever.
For keratocytes I directly measured the forces produced by actin polymerization
and, to my knowledge for the first time, the forces associated with the retrograde
actin flow using a SFM. The result was that both actin and myosin play important
but different roles in motility. For actin it turned out that considering just the polymerization
was not enough. Actin depolymerization and the resulting entropic forces
are a completely new physical effect in actin based cell motility. With this new force
in the force balance I can explain all effects observed in my experiments without introducing
any new biochemical feedback loops.
Finally I showed that neuronal growth cones are very soft and weak structures.
They are at least one order of magnitude softer and weaker as for example fibroblasts
or cells forming the blood vessel walls. As neurons are usually located in soft
environments this does not impede their normal outgrowth. It could even serve as a
safety mechanism that prevents cell from growing into wrong areas like breaching
the blood-brain-barrier, on a physical level. For a neuron the wall of a blood vessel
feels like a brick wall for us.
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Scott, Rebecca Wilson. "LIM kinase regulation of cell motility and invasion." Thesis, University of Glasgow, 2010. http://theses.gla.ac.uk/2247/.
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This thesis describes how both LIM Kinase 1 and LIM Kinase 2 are both important regulators of cell invasion. Chapter 3 presents data that shows that inhibition of LIMK function blocks the collective invasion of MDA MB 231 breast carcinoma cells in a three-dimensional matrix. Although LIMK was not required for cell motility in two dimensions, a novel role for LIMK in both extracellular matrix degradation and deformation activities was shown in three dimensions in Chapter 4. Consistent with matrix remodeling being a requirement for path generation by leading cells in collective invasion, LIMK activity was also shown to be required by leading cells in MDA MB 231 collective invasion. However, it was also discovered that LIMK activity was not required for path following MDA MB 231. The importance of Cofilin activity as a conduit of LIMK activity during invasion was investigated in Chapter 5, a well as potential novel protein interactions of Cofilin. The identification of novel substrates of LIMK was attempted in Chapter 6, leaving prospective routes of investigation to further elucidate the roles of LIMK1 and LIMK2 in cells. The main findings presented in this thesis reveal a requirement for LIMK activity in the path generation function of leading cells in collective invasion. Given that individual invading cells must generate their own paths, these results lend support to the continued development of LIMK inhibitors to counter tumor cell invasion and metastasis.
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Bochenek, Magdalena Ludmila. "Regulation of cell motility by ephrin-B2 signalling." Thesis, University of Bristol, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.492474.
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Ephrin ligands and their Eph receptor tyrosine kinases both are surface tethered proteins that control cell shape and movements through direct cell-cell contact. Their binding, and subsequent clustering, triggers bidirectional signalling pathways, with signals transduced from the receptor (forward) and the ligand (reverse), that regulate the behaviour of both Eph- and ephrin- expressing cells. Recent evidence suggests that reverse ephrin-B2 signalling controls endothelial cell sprout outgrowth and tip elongation, and smooth muscle cell shape changes and behaviour. In addition, misregulation of ephrin-B2 expression is observed in various tumour types and high expression of this ligand is correlated with increased tumour vascularisation and tendency to metastasise. To investigate how ephrin-B2 "reverse" signalling pathways direct changes during angiogenesis and how the expression level of ephrin ligands influences changes in cell behaviour and cell mot motility, I have used Human Umbilical Vein Endothelial Cells (HUVECs) overexpressing ephrin ligands as a model system.
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Kimpton, Laura Saranne. "On two-phase flow models for cell motility." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:93c3cc12-4aac-424d-83bf-3e695efb49fe.
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The ability of cells to move through their environment and spread on surfaces is fundamental to a host of biological processes; including wound healing, growth and immune surveillance. Controlling cell motion has wide-ranging potential for medical applications; including prevention of cancer metastasis and improved colonisation of clinical implants. The relevance of the topic coupled with the naturally arising interplay of biomechanical and biochemical mechanisms that control cell motility make it an exciting problem for mathematical modellers. Two-phase flow models have been widely used in the literature to model cell motility; however, little is known about the mathematical properties of this framework. The majority of this thesis is dedicated to improving our understanding of the two-phase flow framework. We first present the simplest biologically plausible two-phase model for a cell crawling on a flat surface. Stability analyses and a numerical study reveal a number of features relevant to modelling cell motility. That these features are present in such a stripped-down two-phase flow model is notable. We then proceed to investigate how these features are altered in a series of generalisations to the minimal model. We consider the effect of membrane-regulated polymerization of the cell's actin network, the effect of describing the network as viscoelastic, and the effect of explicitly modelling myosin, which drives contraction of the actin network. Validation of hydrodynamical models for cell crawling and spreading requires data on cell shape. The latter part of the thesis develops an image processing routine for extracting the three-dimensional shape of cells settling on a flat surface from confocal microscopy data. Models for cell and droplet settling available in the literature are reviewed and we demonstrate how these could be compared to our cell data. Finally, we summarise the key results and highlight directions for future work.
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Santiago, Joana Filipa Marques. "Modulation of sperm motility using cell-penetrating peptides." Master's thesis, Universidade de Aveiro, 2017. http://hdl.handle.net/10773/22325.
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Mestrado em Biologia Molecular e CelularThe large number of unintended pregnancies worldwide due to the non-use or failure of contraceptive methods and the fact that male contraceptives are limited to condom and vasectomy, highlight the urgent need for the development of new contraceptive methods. The mechanism of sperm motility acquisition in the epididymis constitutes an ideal target for new pharmacological male contraceptives since only the post-testicular sperm maturation is affected. It is known that protein phosphatase 1 subunit gamma 2 (PPP1CC2), a PPP1 isoform only present in testes and sperm, is essential for sperm motility acquisition. Protein-protein interactions (PPIs) have emerged as a promising class of drug targets and cell-penetrating peptides (CPPs) represents a recognized intracellular delivery system to target PPIs. The main goal of this work is to modulate PPP1CC2 complexes and, consequently, spermatozoa motility using peptides covalently coupled to CPPs. The results showed that both peptides tested could modulate sperm motility with a short incubation period, generally increasing the number of immotile spermatozoa. Additionally, we demonstrated that the peptide sequence that mimics the interaction interface between PPP1CC2 and a sperm-specific interactor – Akinase anchor protein 4 (AKAP4) – disrupted the PPP1CC2-AKAP4 interaction, resulting in arrest of sperm motility. The peptide that mimics the 22 amino-acid C-terminus of PPP1CC2 possible acts by disrupting the interaction between PPP1CC2 and isoform-specific interactors. Fifty putative isoform-specific interactors of PPP1CC2 C-terminus were identified by mass spectrometry and one of them was further validated (GPx4), suggesting new targets for similar contraceptive agents. In conclusion, this work confirmed the potential of CPPs to deliver peptide sequences that target unique PPIs in spermatozoa, clarified the mechanism of action of the peptides testes and identified other potential targets for new male contraceptives.
O elevado número de gravidezes indesejadas a nível mundial e o facto de os contracetivos masculinos estarem limitados ao preservativo e à vasectomia refletem a necessidade urgente de desenvolvimento de novos métodos contracetivos. O mecanismo de aquisição de mobilidade dos espermatozoides no epidídimo constitui um alvo perfeito para novos agentes contracetivos dado que apenas a maturação pós-testicular é afetada. Sabe-se que a proteína fosfatase 1 subunidade gama 2 (PPP1CC2), uma isoforma presente apenas nos testículos e espermatozoides, é essencial para a aquisição de mobilidade no epidídimo. As interações proteína-proteína (PPIs) têm surgido como uma promissora classe de alvos terapêuticos e os cell-penetrating peptides (CPPs) representam um reconhecido sistema de entrega intracelular de sequências peptídicas com o potencial de modular PPIs. Assim, o principal objetivo deste trabalho é modular complexos PPP1CC2 específicos de testículo e espermatozoide e, consequentemente, a mobilidade dos espermatozoides recorrendo a sequências peptídicas covalentemente ligadas a CPPs. Os resultados mostram que ambos os péptidos testados são capazes de modular a mobilidade dos espermatozoides, mesmo com curtos períodos de incubação, aumentando o número de espermatozoides imóveis. Adicionalmente, foi demonstrado que o péptido que mimetiza a interface de interação entre PPP1CC2 e uma a A-kinase anchor protein (AKAP4) – um interactor específico no espermatozoide – interfere com a interação PPP1CC2-AKAP4, resultando em espermatozoides imóveis. O péptido que mimetiza os 22 aminoácidos do C-terminal da PPP1CC2 atua disrompendo a interação entre a PPP1CC2 e interatores específicos desta isoforma. Cinquenta interatores específicos do Cterminal da PPP1CC2 foram identificados por espectrometria de massa, sugerindo novos potenciais alvos para futura modulação. Um desses interatores (GPx4) foi posteriormente validado. Concluindo, este trabalho confirmou o potencial dos CPPs na entrega de sequências peptídicas que têm como alvo PPIs únicas do espermatozoide, clarificou o mecanismo de ação dos péptidos testados e identificou potenciais alvos para novos contracetivos masculinos.
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Graham, Jason Michael. "Mathematical representations in musculoskeletal physiology and cell motility." Diss., University of Iowa, 2012. https://ir.uiowa.edu/etd/3305.
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Research in the biomedical sciences is incredibly diverse and often involves the interaction of specialists in a variety of fields. In particular, quantitative, mathematical, and computational methods are increasingly playing significant roles in studying problems arising in biomedical science. This is particularly exciting for mathematical modeling as the complexity of biological systems poses new challenges to modelers and leads to interesting mathematical problems. On the other hand mathematical modeling can provide considerable insight to laboratory and clinical researchers.
In this thesis we develop mathematical representations for three biological processes that are of current interest in biomedical science. A deeper understanding of these processes is desirable not only from the standpoint of basic science, but also because of the connections these processes have with certain diseases. The processes we consider are collective cell motility, bone remodeling, and injury response in articular cartilage. Our goals are to develop mathematical representations of these processes that can provide a conceptual framework for understanding the processes at a fundamental level, that make rigorous the intuition biological researchers have developed about these processes, and that help to translate theoretical and experimental work into information that can be used in clinical settings where the primary concern is in treating diseases associated with the process.
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Casanova, Morales Nathalie. "Contribution to the understanding of red blood cell invasion by Plasmodium Falciparum : study of parasites motility on rigid substrates." Thesis, Montpellier 2, 2012. http://www.theses.fr/2012MON20088/document.
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Le paludisme est causé par un parasite appelé Plasmodium falciparum, transmis lors de la piqûre d'un moustique. Au stade sanguin, ce parasite unicellulaire, de forme ovoïde, envahit les globules rouges, s'y multiplie avant d'être libéré pour une nouvelle invasion à la fin d'un cycle de 48 heures. Ce travail de thèse porte sur le mouvement du parasite au cours du processus d'invasion. L'étape préalable à la pénétration du parasite dans sa cellule hôte est le mouvement de réorientation permettant de mettre en contact son complexe apical avec la membrane de la cellule hôte. Afin de comprendre comment le parasite génère les mouvements nécessaires à cette réorientation sans l'aide de flagelle, de cil ou de déformation, notre approche est d'observer et de décrire le mouvement des parasites sur un substrat rigide, au travers d'une analyse détaillée des trajectoires du parasite. Nous observons que le parasite explore tous les degrés de liberté qui lui sont accessibles compte tenu de son attachement au substrat: translation et rotation dans le plan et réorientation de sa partie apicale. Nous avons identifié trois types de mouvement: confiné, dirigé et circulaire. Nous caractérisons ces trajectoires et mouvements en utilisant une analyse de corrélation et en discutant les mécanismes possibles à l'origine de ces trajectoires particulières. Enfin, nous examinons le rôle des constituants du cytosquelette sur le mouvement du parasite, en affectant spécifiquement les filaments d'actine et les microtubules. Les conséquences de la polymérisation de ces structures sur le mouvement du parasites sont discutéesMalaria is caused by a parasite called Plasmodium falciparum, transmitted via mosquito's bites. At the blood stage, these unicellular ovoidal parasites invade red blood cells (RBCs), multiply and are released at the end of a 48h cycle, ready for new invasions. This work is focused on the motion of the parasite during the invasion process. To penetrate into the host cell, the parasite reorient its apical part towards the RBC membrane. For this purpose, the parasite generates different movements that allow him to find the correct position to form a specific junction to invade the cell. To understand how the parasite is able to move and reorient without the aid of cilia, flagella or deformations, we performed a detailed analysis of the parasite trajectories and orientation on rigid substrate. We observe that the substrate-attached parasite explores all degrees of freedom with in-plane rotation, translation and flipping. Three types of motion have been identified: confined, directed circular . We characterize these trajectories and motions using correlation analysis and we discuss the possible mechanisms that could explain these peculiar trajectories. Finally, to determine the role of the cytoskeleton components in the parasite motion, specific structures such as the actin filaments and the microtubules have been specifically affected. We will describe and discuss the consequences of depolymerizing or stabilizing these structures
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Blazakis, Konstantinos N. "Computational methods for investigating cell motility with applications to neutrophil cell migration." Thesis, University of Sussex, 2015. http://sro.sussex.ac.uk/id/eprint/56990/.
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Cell motility is closely linked to many important physiological and pathological events such as the immune response, wound healing, tissue differentiation, embryogenesis, in ammation, tumour invasion and metastasis. Understanding the ability of cells to alter their shape, deform and migrate is of vital importance in many biological studies. The rapid development in microscopy and imaging techniques has generated a huge amount of discrete data on migrating cells in vivo and in vitro. A key challenge is the use of discrete experimental observations to develop novel methods and algorithms that track cells and construct continuous trajectories of their motion as well as characterising key geometric quantities associated with cell migration. Therefore, in this work using robust numerical tools we focus on proposing and implementing mathematical methodologies for cell movement and apply them to model neutrophil cell migration. We derive and implement a computational framework that encompasses modelling of cell motility and cell tracking based on phase field and optimal control theory. The cell membrane is represented by an evolving curve and approximated by a diffuse interface; while the motion of the cell is driven by a force balance acting normal on the cell membrane. This approach allows us to characterise the locus of the centroid cell-surface position. In addition, we describe a surface partial differential equation framework that can be coupled with the phase-field framework, thereby offering a wholistic approach for modelling biochemical processes and biomechanics properties associated with cell migration.
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Maghzal, Nadim. "The epithelial cell adhesion molecule (EpCAM) regulates cell motility and cell-cell adhesion by inhibiting PKC signaling." Thesis, McGill University, 2013. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=114215.
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Tissue cohesion is achieved in part by a large family of plasma membrane-bound cell adhesion molecules (CAMs). During morphogenesis, CAM-mediated interactions provide adhesive forces required for cells to aggregate and form tissues. CAM-mediated adhesions in developing cells are highly dynamic, which provides the fluidity required for cellular movements that drive morphogenesis. Xenopus laevis gastrulation is an established model to study morphogenetic movements. During this phase of development, the mesoderm moves inside the embryo through involution, and migrates along the inner surface of the ectoderm while remaining separated from this tissue. Members of the Fagotto lab have identified the Xenopus orthologue of the Epithelial Cell Adhesion Molecule (EpCAM) in a gain-of-function screen to find gene products that cause aberrant ectoderm/mesoderm tissue mixing in the gastrula. EpCAM is a well known tumor-associated antigen that is specifically expressed in epithelial tissues, where its overexpression often correlates with malignancy. The initial aim of this thesis was to understand the molecular mechanism through which EpCAM promotes ectoderm/mesoderm tissue mixing. Overexpression of EpCAM in cells at the boundary increases their "invasive" behavior via a signaling property of its cytoplasmic domain (EpTAIL) that inhibits PKC signaling to promote cell motility. The most important findings of this thesis are that 1) EpTAIL inhibits PKC activity to promote cell motility and cell-cell adhesion by acting as a PKC pseudosubstrate domain that binds the enzyme on its catalytic site, and 2) this previously unknown mode of PKC inhibition is not specific to EpCAM as other PKC pseudosubstrate-mimicking plasma membrane proteins were identified and could potentially play important roles in the regulation of PKC activity. The data presented in this thesis further our understanding of EpCAM biology and unravel a new mode of PKC regulation that is valuable as PKCs are one of the major families of cytoplasmic kinases in cells.Les mécanismes de liaison cellulaire sont établis en partie par une vaste famille de protéines d'adhésion cellulaire ou CAMs. Lors de la morphogenèse, les interactions induites par les CAMs créent des forces d'adhésion nécessaires afin que les cellules puissent s'agréger et former des tissues. Les adhésions induites par les CAMs dans les cellules en développement sont très dynamiques et offrent ainsi la fluidité nécessaire aux mouvements cellulaires qui régissent la morphogenèse. La gastrulation chez la grenouille Xenopus laevis sert de modèle d'étude des mouvements morphogéniques. Durant ce stade de développement, le mésoderme se déplace vers l'intérieur de l'embryon via un mouvement d'involution et migre le long de la paroi interne de l'ectoderme tout en maintenant une séparation des deux tissues. Des membres du laboratoire de Dr. Fagotto ont réussi à identifier un orthologue de la protéine «Epithelial Cell Adhesion Molecule (EpCAM) » chez Xenopus dans un tri de gain de fonction permettent d'identifier des protéines pouvant être à l'origine d'aberrations au niveau du maintien de la séparation de l'ectoderme et du mésoderme durant la gastrulation. EpCAM est un antigène associé aux tumeurs exprimé dans les cellules épithéliales et dont la surexpression corrèle avec des tumeurs malignes. L'objectif initial de cette thèse était de découvrir les mécanismes moléculaires pouvant expliquer l'effet de EpCAM sur les aberrations entre la séparation des tissues de l'ectoderme et du mésoderme. Une surexpression de EpCAM dans les cellules à la bordure de l'ectoderme et du mésoderme cause une augmentation du comportement « invasif » entre les deux tissues, via la fonction de transduction du signal de son domaine cytoplasmique (EpTAIL), qui inhibe le signal de la protéine PKC afin de promouvoir le mouvement cellulaire. Les principales contributions de cette thèse ont été 1) EpTAIL inhibe l'activité de PKC en jouant le rôle d'un pseudosubstrat de PKC en interagissant avec le site catalytique de l'enzyme, et 2) ce mécanisme d'inhibition jusqu'à présent inconnu pour PKC n'est pas seulement spécifique à EpCAM, car d'autres protéines membranaires possède également cette capacité à imiter le pseudosubstrat de PKC et pourraient potentiellement avoir un rôle important à jouer au niveau de la régulation de l'activité de PKC. Les donnée présentées dans cette thèse contribuent à approfondir davantage notre connaissance d'EpCAM et dévoilent un nouveau mécanisme de régulation de PKC qui pourrait être important puisque les molécules PKC forment l'une des plus importantes familles de kinases cytoplasmiques dans les cellules.
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Loitto, Vesa-Matti. "Towards a Refined Model of Neutrophil Motility." Doctoral thesis, Linköping : Univ, 2001. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-5142.
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Magder, Ilana. "The importance of a radial spoke protein in flagellar motility /." Thesis, McGill University, 2000. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=31266.
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The aim of our investigation was to gain insight on the regulation of flagellar movement, at the axonemal level. In our laboratory a panel of monoclonal antibodies (MoAbs) has been produced against the axoneme of the biflagellated algae, Chlamydomonas reinhardtii, a well-characterized model for the study of flagellar movement. Of these MoAbs, L2H12 has been selected, because it has a potent inhibitory effect on the motility of de membranated-reactivated flagella of Chlamydomonas cells. Using video micrography, we demonstrated that low concentrations of L2H12 cause a progressive decrease in the wave amplitude and beat frequency of the flagella. Results of Western blotting of the axonemal proteins indicates that L2H12 recognizes a 105 kDa protein. Analysis of Chlamydomonas radial spoke mutants deficient in one or more radial spoke proteins (RSPs) suggests that this protein is RSP2. Immunoprecipitation of this protein was performed to further characterize it.
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MITONAKA, Tomoaki, Yoshiyuki MURAMATSU, Shin SUGIYAMA, Tomoaki MIZUNO, and Yasuyoshi NISHIDA. "Essential roles of myosin phosphatase in the maintenance of epithelial cell integrity of Drosophila imaginal disc cells." Elsevier, 2007. http://hdl.handle.net/2237/9388.
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Idoux-Gillet, Ysia. "Implication des voies de différenciation épithéliale précoce dans la morphogenèse mammaire et la progression des cancers du sein." Thesis, Montpellier 1, 2013. http://www.theses.fr/2013MON1T008.
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La morphogenèse de la glande mammaire résulte de la coordination de différentes voies, incluant l'apoptose, la prolifération, la différenciation et la dynamique des cellules souches/progénitrices. La transition épithéliale-mésenchymateuse (EMT) semble être impliquée dans ces voies de signalisation. Ainsi, nous nous sommes concentrés sur le facteur de transcription Slug, un gène clé régulant l'EMT, et son implication dans la morphogenèse de la glande mammaire. Dans un premier temps, en utilisant un modèle de souris transgéniques Slug-Lacz, nous avons localisé Slug dans une sous-population couvrant 10 à 20% des cellules basales du tubule et des cap cells du bourgeons terminal, coexprimant les marqueurs P-cadhérine, CK5, CD49f. Ensuite, nous avons montré par des expériences in vitro de perte et de gain de fonction, que Slug régulait la différenciation et la prolifération des cellules épithéliales mammaires. De plus, nous avons trouvé que Slug inhibait l'apoptose, promouvait la motilité cellulaire, et permettait l'émergence et la croissance de mammosphères clonales. Ce dernier point montre l'implication de Slug dans les cellules souches, qui est renforcé par le fait que des cellules primaires déficientes pour Slug étaient incapables de donner des mammosphères secondaires. Par ailleurs, nous avons pu observer in vivo que les souris déficientes pour Slug présentaient un retard de développement de la glande mammaire, possédant moins de cellules en prolifération, et une surexpression des marqueurs des cellules luminale CK8/18, GATA3 et ER. D'autres gènes régulant l'EMT sont retrouvés surexprimés, suggérant un mécanisme de compensation, qui peut expliquer le fait que le retard de développement de la glande mammaire est rattrapé à l'âge adulte. Les glandes mammaires Slug-knockout présentaient également des branchements excessifs, évoquant une différenciation précoce, similaire aux glandes mammaires de souris déficientes pour la P-cadhérine, exprimée dans les cellules basales. Sachant cela, nous avons constaté que la P-cadhérine était diminuée dans les glandes mammaires Slug-knockout, et dans les cellules CommaDβ traitées par siRNA ciblant Slug. Nous avons alors trouvé que Slug se liait directement au promoteur de la P-cadhérine et l'activait, et que cette dernière intervenait dans certains effets fonctionnels de Slug, tels que la croissance de mammosphères, la différenciation et la migration cellulaire. Ainsi, nous avons montré l'importance d'une nouvelle voie de signalisation Slug/P-cadhérine dans les capacités souches/progénitrices des cellules épithéliales mammaires, intégrant la différenciation et la motilité cellulaire, et nous avons maintenant une meilleure compréhension de son rôle dans l'agressivité de certains cancers du seinMammary gland morphogenesis results from the coordination of different pathways, including apoptosis, proliferation, differentiation, and stem/progenitor cell dynamics. Epithelial-mesenchymal transition (EMT) appears to be involved in these signalling pathways. Thus, we focused on transcription factor Slug, a key gene regulating EMT, and its involvement in mammary gland morphogenesis. First, using a Slug–LacZ transgenic mice model, we located Slug in a subpopulation covering about 10–20% basal duct cells and cap cells of terminal end bud, coexpressed with basal markers P-cadherin, CK5 and CD49f. Then, we have shown by in vitro experiments of loss and gain of function that Slug regulated the differentiation and proliferation of mammary epithelial cells. Moreover, we found that Slug inhibited apoptosis, promoted cell motility, and allowed the emergence and growth of clonal mammospheres. This last point shows the involvement of Slug in stem cells, which is reinforced by the fact that primary cells deficient for Slug were unable to give secondary mammospheres. Furthermore, we observed in vivo that mice deficient for Slug showed delayed development of the mammary gland, with less proliferating cells, and overexpression of markers of luminal cells CK8/18, GATA3 and ER. Other genes regulating EMT are found overexpressed, suggesting a compensatory mechanism, which can explain the fact that the delayed development of the mammary gland is caught up in adulthood. The Slug-knockout mammary glands also showed overbranching, evoking an early differentiation, similar to the mammary glands of mice deficient in P-cadherin, expressed in the basal cells. Knowing this, we found that P-cadherin was decreased in Slug-knockout mammary glands, and in CommaDβ cells treated with siRNA targeting Slug. We then found that Slug binds directly to the promoter of the P-cadherin and activated it, and that P-cadherin was involved in some functional effects of Slug, such as mammospheres growth, differentiation and cell migration. Thus, we have shown the importance of a new signalling pathway Slug/P-cadherin in the capacity of mammary epithelial stem/progenitor cells, integrating differentiation and cell motility, and we now have a better understanding of its role in the aggressiveness of some breast cancers
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Karlsson, Thommie. "Water Fluxes and Cell Migration : How Aquaporin 9 Controls Cell Shape and Motility." Doctoral thesis, Linköpings universitet, Medicinsk mikrobiologi, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-90024.
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Prerequisites for all modes of cell migration are cell-substratum interactions that require a sophisticated interplay of membrane dynamics and cytoskeletal rearrangement. Generally, a migrating cell is polarized with a distinct rear and front, from which it extends a wide and thin membrane protrusion- lamellipodium, small fingerlike projections- filopodia, and membrane blisters- blebs. The development of these structures is primarily driven by cytoskeletal contractions and actin polymerization, which are under regulation of several actin-binding proteins and the small GTPases Cdc42, Rac and Rho. Lamellipodia and filopodia are assumed to arise from polymerizing actin, pushing the membrane forward through a Brownian-ratchet mechanism. However, other models based on shifts in the local hydrostatic pressure have also been suggested since blebs are initially void of actin. Recently, fluxes of water through membrane-anchored water channels, aquaporins (AQPs), have been implicated in cell motility, while they appeared to localize to lamellipodia and facilitate cell locomotion. Indeed, expression of AQP9 was shown to induce filopodia in fibroblasts. Here, we have focused on the effects of AQP9 on cell morphology and motility. By using primarily live cell imaging of GFP-AQP9 and other cytoskeletal components we found that AQP9: (i) enhances cell polarization and migration in a Rac1 and serine11 phosphorylation-dependent manner in neutrophils, (ii) induces and accumulates in filopodia, before actin polymerization, (iii) locally deforms the membrane upon rapid reductions osmolarity, (iv) accumulates in the cell membrane underlying bleb development, (v) induces multiple protrusions and thereby impairs the intrinsic directionality, and (vi) facilitates epithelial wound closure through a mechanism involving swelling and expansion of the monolayer. Based on these findings, we have presented models for how water fluxes through AQPs aids actin polymerization in the formation of membrane protrusions. In summary, these models rely on localized accumulation of ion and water channels that control the influx of water and thereby the buildup of a hydrostatic pressure between the membrane and the cytoskeleton. Upon reaching a critical pressure, it will dislocate the membrane from the cytoskeleton and force it to protrude outwards. Moreover, this will promote a local cytoplasmic gel-to-sol transformation, which facilitates diffusion of cytoskeletal reactants. Hereby, we can furthermore assign to filopodia a role as osmo-sensors, protecting the cell from different osmotic loads. In addition, we have postulated a novel model for wound healing involving force generation by cell swelling. Taken together, this thesis provides the field of cell migration with solid evidence for pivotal roles of water fluxes through AQP9 in particular, but most likely AQPs in general, during cell locomotion and localized volume control.
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Browne, Cecille D. "Molecular mechanisms of B cell tolerance, proliferation and motility." Diss., [La Jolla, Calif.] : University of California, San Diego, 2010. http://wwwlib.umi.com/cr/ucsd/fullcit?p3397169.
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Thesis (Ph. D.)--University of California, San Diego, 2010.Title from first page of PDF file (viewed March 29, 2010). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references.
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Liu, Chenli, and 刘陈立. "Formation of novel biological patterns by controlling cell motility." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B46541913.
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The Best PhD Thesis in the Faculties of Dentistry, Engineering, Medicine and Science (University of Hong Kong), Li Ka Shing Prize,2010-11published_or_final_version
Biochemistry
Doctoral
Doctor of Philosophy
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Sahni, Kritika [Verfasser]. "Migration component dynamics in epithelial cell motility / Kritika Sahni." Bonn : Universitäts- und Landesbibliothek Bonn, 2019. http://d-nb.info/1194464858/34.
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Mele, Silvia. "Role of CD38 in chronic lymphocytic leukaemia cell motility." Thesis, King's College London (University of London), 2015. https://kclpure.kcl.ac.uk/portal/en/theses/role-of-cd38-in-chronic-lymphocytic-leukaemia-cell-motility(b1abad03-7b14-4c05-ae59-99d7d8f21e68).html.
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Chronic lymphocytic leukaemia (CLL) is characterised by the proliferation of malignant B cells that progressively accumulate into lymphoid tissues and peripheral blood. Whereas CLL cells in the peripheral blood are mainly resting, proliferative and survival signals are provided to CLL cells within the lymphoid tissues in specific structures known as proliferation centres. Understanding the molecular basis for CLL cell migration and retention within lymphoid tissues is therefore essential to devise new treatment strategies for CLL. Expression of the surface molecule CD38 on CLL cells is a marker of poor prognosis. CD38 is a transmembrane ectoenzyme involved in Ca2+ mobilization, and although CD38 expression in CLL cells has been linked to cell migration, the underlying molecular mechanisms are unknown. In this study, the role of CD38 in cell motility was investigated using a CD38 stably transfected CLL-derived cell line (MEC1) and primary CLL cell samples with different CD38 expression levels. CD38 expression markedly enhanced MEC1 cell basal migration and chemotaxis towards the chemokine CCL21. Additionally, CD38 expression increased MEC1 cell spreading on VCAM-1 and reduced their ability to crawl on and transmigrate through an endothelial cell monolayer. These results correlated with increased Rap1 GTPase activity observed in cells expressing CD38 compared to control cells, both in resting conditions and after CCL21 stimulation. An important finding was that CD38 expression increased intracellular basal Ca2+ levels in MEC1 cells. Knockdown and localisation studies in CD38-expressing MEC1 cells revealed that RasGRP2, a Ca2+-regulated guanine nucleotide exchange factor for Rap1, may act as a critical signalling molecule in regulating the CD38-dependent migratory phenotype observed. Data obtained with primary CLL samples indicate that a similar mechanism could be responsible for the increased migration linked to CD38 expression in CLL cells. In conclusion, this study reveals a link between CD38 and a RasGRP2-Rap1 signalling axis, which could contribute to our understanding of the role of CD38 in CLL cell motility and disease progression.
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Volakis, Leonithas I. "Effect of Myoferlin Depletion on Breast Cancer Cell Motility." The Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1316453651.
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Marth, Wieland. "Hydrodynamic Diffuse Interface Models for Cell Morphology and Motility." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2016. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-204651.
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In this thesis, we study mathematical models that describe the morphology of a generalized biological cell in equilibrium or under the influence of external forces. Within these models, the cell is considered as a thermodynamic system, where streaming effects in the cell bulk and the surrounding are coupled with a Helfrich-type model for the cell membrane. The governing evolution equations for the cell given in a continuum formulation are derived using an energy variation approach. Such two-phase flow problems that combine streaming effects with a free boundary problem that accounts for bending and surface tension can be described effectively by a diffuse interface approach. An advantage of the diffuse interface approach is that models for e.g. different biophysical processes can easily be combined. That makes this method suitable to describe complex phenomena such as cell motility and multi-cell dynamics. Within the first model for cell motility, we combine a biological network for GTPases with the hydrodynamic Helfrich-type model. This model allows to account for cell motility driven by membrane protrusion as a result of actin polymerization. Within the second model, we moreover extend the Helfrich-type model by an active gel theory to account for the actin filaments in the cell bulk. Caused by contractile stress within the actin-myosin solution, a spontaneous symmetry breaking event occurs that lead to cell motility. In this thesis, we further study the dynamics of multiple cells which is of wide interest since it reveals rich non-linear behavior. To apply the diffuse interface framework, we introduce several phase field variables to account for several cells that are coupled by a local interaction potential. In a first application, we study white blood cell margination, a biological phenomenon that results from the complex relation between collisions, different mechanical properties and lift forces of red blood cells and white blood cells within the vascular system. Here, it is shown that inertial effects, which can become of relevance in various parts of the cardiovascular system, lead to a decreasing tendency for margination with increasing Reynolds number. Finally, we combine the active polar gel theory and the multi-cell approach that is capable of studying collective migration of cells. This hydrodynamic approach predicts that collective migration emerges spontaneously forming coherently-moving clusters as a result of the mutual alignment of the velocity vectors during inelastic collisions. We further observe that hydrodynamics heavily influence those systems. However, a complete suppression of the onset of collective migration cannot be confirmed. Moreover, we give a brief insight how such highly coupled systems can be treated numerically using finite elements and how the numerical costs can be limited using operator splitting approaches and problem parallelization with OPENMPDiese Dissertation beschäftigt sich mit mathematischen Modellen zur Beschreibung von Gleichgewichts- und dynamischen Zuständen von verallgemeinerten biologischen Zellen. Die Zellen werden dabei als thermodynamisches System aufgefasst, bei dem Strömungseffekte innerhalb und außerhalb der Zelle zusammen mit einem Helfrich-Modell für Zellmembranen kombiniert werden. Schließlich werden durch einen Energie-Variations-Ansatz die Evolutionsgleichungen für die Zelle hergeleitet. Es ergeben sie dabei Mehrphasen-Systeme, die Strömungseffekte mit einem freien Randwertproblem, das zusätzlich physikalischen Einflüssen wie Biegung und Oberflächenspannung unterliegt, vereinen. Um solche Probleme effizient zu lösen, wird in dieser Arbeit die Diffuse-Interface-Methode verwendet. Ein Vorteil dieser Methode ist, dass es sehr einfach möglich ist, Modelle, die verschiedenste Prozesse beschreiben, miteinander zu vereinen. Dies erlaubt es, komplexe biologische Phänomene, wie zum Beispiel Zellmotilität oder auch die kollektive Bewegung von Zellen, zu beschreiben. In den Modellen für Zellmotilität wird ein biologisches Netzwerk-Modell für GTPasen oder auch ein Active-Polar-Gel-Modell, das die Aktinfilamente im Inneren der Zellen als Flüssigkristall auffasst, mit dem Multi-Phasen-Modell kombiniert. Beide Modelle erlauben es, komplexe Vorgänge bei der selbst hervorgerufenen Bewegung von Zellen, wie das Vorantreiben der Zellmembran durch Aktinpolymerisierung oder auch die Kontraktionsbewegung des Zellkörpers durch kontraktile Spannungen innerhalb des Zytoskelets der Zelle, zu verstehen. Weiterhin ist die kollektive Bewegung von vielen Zellen von großem Interesse, da sich hier viele nichtlineare Phänomene zeigen. Um das Diffuse-Interface-Modell für eine Zelle auf die Beschreibung mehrerer Zellen zu übertragen, werden mehrere Phasenfelder eingeführt, die die Zellen jeweils kennzeichnen. Schließlich werden die Zellen durch ein lokales Abstoßungspotential gekoppelt. Das Modell wird angewendet, um White blood cell margination, das die Annäherung von Leukozyten an die Blutgefäßwand bezeichnet, zu verstehen. Dieser Prozess wird dabei bestimmt durch den komplexen Zusammenhang zwischen Kollisionen, den jeweiligen mechanischen Eigenschaften der Zellen, sowie deren Auftriebskraft innerhalb der Adern. Die Simulationen zeigen, dass diese Annäherung sich in bestimmten Gebieten des kardiovaskulären Systems stark vermindert, in denen die Blutströmung das Stokes-Regime verlässt. Schließlich wird das Active-Polar-Gel-Modell mit dem Modell für die kollektive Bewegung vom Zellen kombiniert. Dies macht es möglich, die kollektive Bewegung der Zellen und den Einfluss von Hydrodynamik auf diese Bewegung zu untersuchen. Es zeigt sich dabei, dass der Zustand der kollektiven gerichteten Bewegung sich spontan aus der Neuausrichtung der jeweiligen Zellen durch inelastische Kollisionen ergibt. Obwohl die Hydrodynamik einen großen Einfluss auf solche Systeme hat, deuten die Simulationen nicht daraufhin, dass Hydrodynamik die kollektive Bewegung vollständig unterdrückt. Weiterhin wird in dieser Arbeit gezeigt, wie die stark gekoppelten Systeme numerisch gelöst werden können mit Hilfe der Finiten-Elemente-Methode und wie die Effizienz der Methode gesteigert werden kann durch die Anwendung von Operator-Splitting-Techniken und Problemparallelisierung mittels OPENMP
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Messent, Anthea Jane. "Novel roles for matix metalloproteinases in cell-matrix interactions." Thesis, Open University, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.242514.
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Di, Kaijun, and 狄凱軍. "The role of Id-1 on the proliferation, motility and mitotic regulationof prostate epithelial cells." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2007. http://hub.hku.hk/bib/B38944704.
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Challa, Anil Kumar. "Identification and functional analysis of Zebrafish orthologs of genes." Connect to this title online, 2003. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1061302731.
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Thesis (Ph. D.)--Ohio State University, 2003.Document formatted into pages; contains 119 p. Includes bibliographical references. Abstract available online via OhioLINK's ETD Center; full text release delayed at author's request until 2005 Aug. 19.
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Daher, Jalil. "Exposure of endothelial cells to physiological levels of myeloperoxidase modified LDL delays pericellular fibrinolysis and reduces cell motility." Doctoral thesis, Universite Libre de Bruxelles, 2014. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/209337.
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Cardiovascular diseases are considered the first cause of death in westernized societies. They are directly linked to atherosclerosis, a clinical condition characterized by a thickening of the arterial wall. Atherosclerosis is in his turn linked to various genetic and environmental factors; among those factors are high oxidized LDL levels and endothelial dysfunction. In the present study, we have analyzed in vitro the effect of myeloperoxidase oxidized LDL on endothelial cells at the level of fibrinolysis and cell motility.In the first part of the work, we measured fibrinolysis in real time at the surface of endothelial cells. Our results suggest that myeloperoxidase oxidized LDL interferes with the regulation of fibrinolysis by endothelial cells by decreasing their pro-fibrinolytic activity. This effect was not related to a modification in expression of major regulators of fibrinolysis such as PAI-1 and t-PA. Our data link the current favorite hypothesis that oxidized LDL has a causal role in atheroma plaque formation with an old suggestion that fibrin may also play a causal role. A model that best explains our results would be as follows: oxidized LDL increases fibrin deposition on endothelial cells which will increase their permeability resulting in more oxidized LDL infiltration into the subendothelial space of the arterial wall initiating atherogenesis.
In the second part of the work, we investigated the effect of myeloperoxidase oxidized LDL at the level of endothelial cell motility. We have shown that oxidized LDL is able to decrease cell migration, wound healing and tubulogenesis in endothelial cells. Those effects were not associated with any alteration at the level of neither cell viability nor proliferation. Subsequent gene expression analyses enabled us to link the oxidized LDL induced phenotypical changes in the cells to a change in expression of both microRNA-22 and Heme Oxygenase 1 genes. Our observations suggest a novel role of oxidized LDL not only as an important factor in the initiation of atheromatous lesions, but also as a potential player in the progression of the atherosclerosis disease by impeding blood vessel repair and wound healing at the sites of lesions.
Doctorat en Sciences
info:eu-repo/semantics/nonPublished
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McCorkle, Joseph Robert. "NM23-H1 BLOCKS CELL MOTILITY INDEPENDENTLY OF ITS KNOWN ENZYMATIC ACTIVITIES IN A COHORT OF HUMAN MELANOMA CELLS." UKnowledge, 2010. http://uknowledge.uky.edu/gradschool_diss/84.
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The metastasis suppressor gene NM23-H1 has been shown to possess three enzymatic activities including nucleoside diphosphate kinase, histidine-dependent protein kinase and 3’-5’ exonuclease activity. While these properties have been demonstrated in vitro using recombinant proteins, the contribution of these activities to suppression of metastatic dissemination is unknown. Site-directed mutagenesis studies were used to identify amino acid residues which are required for proper function of each enzymatic activity associated with H1, providing a platform for studying the importance of each function on an individual basis. To assess the relevance of these activities to melanoma progression, a panel of mutants harboring selective lesions disrupting the enzymatic activities of H1 were overexpressed using stable transfection in two melanoma cell lines, WM793 (isolated from a vertical growth phase human melanoma), and the metastatic derivative cell line 1205LU. In vitro correlates of metastasis measuring motility and invasion were used in an attempt to identify the mechanism mediating H1-dependent motility suppression of cancer cells. Surprisingly, all mutants studied retained full motility suppression in this setting, suggesting that the enzymatic functions associated with H1 are not required for inhibiting cell migration. Instead, gene expression analyses conducted on the panel of stable transfectants indicate that differences in steady-state mRNA levels of genes involved in mitogen-activated protein kinase (MAPK) signaling showed significant correlations with H1 expression and motility suppression. RNAi studies have confirmed that H1-dependent modulation of the expression of two genes in particular, BRAP and IQGAP2, contribute to the observed phenotype, suggesting a novel mechanism used by NM23 to control cellular migration in human melanoma.