Dissertations / Theses on the topic 'Ephrin'
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Tosch, Paul. "Investigations of ephrin ligands during development." Title page, abstract and table of contents only, 2002. http://web4.library.adelaide.edu.au/theses/09PH/09pht713.pdf.
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"May 2002." Addendum inside back cover. Bibliography: p. 139-157. Aims to isolate ephrin ligands from Drosophila melanogaster and analyse their involvement in Drosophila deveopment. Also investigates the potential of ephrin B-1 as a causative gene in the human condition Aicardi's syndrome.
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Brodie, James Cameron. "Investigation of ephrin regulation during hindbrain segmentation." Thesis, University College London (University of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.249431.
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Eberhart, Johann. "EphA4/Ephrin interactions in motor axon guidance /." free to MU campus, to others for purchase, 2002. http://wwwlib.umi.com/cr/mo/fullcit?p3060095.
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Schmidt, Tim Sebastian. "Ephrin-B2 overexpression in the vascular endothelium." Thesis, University College London (University of London), 2006. http://discovery.ucl.ac.uk/1446088/.
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Previous work has established that Eph family receptor tyrosine kinases and ephrin ligands control a wide range of morphogenetic processes in vertebrate embryos through cell-contact dependent signalling interactions. In the developing cardiovascular system, ephrin-B2, a transmembrane protein is expressed by arterial endothelial cells (ECs) whereas the cognate receptor EphB4 is predominantly found on the venous endothelium. Gene targeting studies in mice have demonstrated that both molecules are critically required for angiogenic remodelling of embryonic blood vessels and survival beyond midgestation. To gain more insight into the role of ephrin-B2 in vascular development and its arterial expression, I have used the tetracycline-controlled expression systems to overexpress the ligand in the endothelium of all vascular beds (i.e. in arteries, veins and microvessels) of transgenic mice. In the course of this study, I have employed several different transgenic EC-specific driver lines in combination with tetracycline-controlled (tTA, Tet-OFF) and reverse tetracycline-controlled (rtTA, Tet-ON) transactivators. Ephrin-B2 overexpression triggers enhanced activation of EphB receptors particularly in the venous endothelium. This leads to severe vascular malformations such as oedema and haemorrhaging. Induction of ephrin-B2 expression at different stages of embryonic development controls not only vascular patterning and the recruitment of supporting pericytes and vascular smooth muscle cells but it can also trigger tissue-specific responses. In summary, my work has established that ephrin-B2 is an important regulator of blood vessel morphogenesis throughout embryonic development. Some results suggest that the ligand may also be involved in pathological conditions such as fibrosis as ectopic expression of ephrin-B2 in the embryonic liver triggers the activation of hepatic stellate cells. The resulting increase in matrix deposition around hepatic blood vessels could represent early signs of a fibrotic phenotype.
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Zimmer, Manuel. "Mechanisms of Eph, ephrin mediated cell-cell communication." Diss., [S.l.] : [s.n.], 2003. http://edoc.ub.uni-muenchen.de/archive/00001547.
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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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Khan, Taslima. "Isolation and functional analysis of Xenopus Ephrin-A3." Thesis, University College London (University of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.399711.
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Koch, William Tyler. "Elucidating Mechanisms of Canonical Wnt - ephrin-B Crosstalk." Thesis, West Virginia University, 2016. http://pqdtopen.proquest.com/#viewpdf?dispub=10146608.
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Throughout development, canonical Wnt signaling contributes to the formation and maintenance of a wide array of cells, tissues, and organs. Dys-regulated Wnt signaling during embryonic development is implicated in developmental defects known as neurochristopathies, including craniofacial and heart defects, as well as defects in neural development. Due to its roles in stem cell maintenance and self-renewal, tissue homeostasis, and regeneration, aberrant Wnt signaling in adult tissues can result in various forms of cancer, including colorectal cancer, breast cancer, lung cancer, and gastro-intestinal cancer, among others. Dys-regulated Wnt signaling is also implicated in other pathologies including bone disease, and metabolic diseases, such as Type II diabetes. Our lab has previously identified a novel crosstalk between canonical Wnt signaling and ephrin signaling. Ephrin signaling occurs through the interaction of ephrin ligands and Eph receptor tyrosine kinases, and is bidirectional. Due to the roles of ephrin signaling in tissue development and maintenance, aberrant ephrin signaling is implicated in many diseases including bone remodeling diseases, diabetes, and cancer. The molecular mechanism of the crosstalk between canonical Wnt signaling and ephrin-B signaling remains unknown. β-catenin is a key intracellular effector of canonical Wnt signaling that transduces the signal to the nucleus, where β-catenin interacts with the TCF/LEF transcription factors and activates transcription of target genes. Due to its central role in transducing the canonical Wnt signal to the nucleus, we predict that ephrin-B signaling antagonizes canonical Wnt signaling by affecting the stability and/or sub-cellular localization of β-catenin, or the interaction between β-catenin and TCF/LEF transcription factors. By employing mouse ephrin-B constructs in human cell lines, we show that the canonical Wnt - ephrin-B crosstalk is conserved between frogs and mammals. We also found that ephrin-B antagonism of canonical Wnt signaling is likely independent of ubiquitin proteasome system (UPS)-mediated degradation of β-catenin. Furthermore, confocal immunofluorescence microscopy revealed that overexpression of ephrin-B in HEK293T cells treated with lithium chloride (LiCl) seems to promote membrane localization of β-catenin, particularly at the apical Z sections. These results suggests that re-localization of β-catenin to the cell membrane may contribute to the ephrin-B antagonism of canonical Wnt signaling.
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Gregory, L. G. L. "Eph-ephrin signalling in cell sorting and directional migration." Thesis, University College London (University of London), 2011. http://discovery.ucl.ac.uk/1318081/.
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An important problem in developmental biology is to understand how precise patterns of cell types are maintained during development. Eph receptor tyrosine kinases and ephrins have key roles in stabilising these patterns of cell organisation and segregation during development and can restrict the movement of cells by promoting cell repulsion. Previous work by Alexei Poliakov in the Wilkinson lab has shown that Eph-ephrin signalling leads to directional persistence of migration, and modelling suggests that this can contribute to cell segregation. In order to test experimentally the contribution of directional persistence in cell segregation, I have used and developed in vitro assays to dissect the roles of EphB2-ephrinB1 signalling in cell segregation, boundary sharpening and directional persistence. In these assays, stable HEK293 cell lines expressing EphB2 or ephrinB1 are mixed in cell culture and this leads to segregation of the two cell populations. Plating these cells either side of a removable barrier and allowing migration of cells towards each other leads to the formation of a sharp boundary on interaction. Analysis of cell behaviour shows EphB2 cells to move more persistently after interaction with ephrinB1 cells. To analyse how EphB2-ephrinB1 interactions lead to directional persistence of migration, my studies have focussed on the role of components potentially involved in directional persistence that act downstream of EphB2-ephrinB1 signalling, including the planar cell polarity (PCP) pathway (Dishevelled and Daam1) and core polarity components such as the PAR proteins (PAR-3 and PAR-6B). The PCP and PAR components were all found to have roles in cell segregation, as siRNA-mediated knockdown of each of these components disrupted EphB2-ephrinB1 mediated cell segregation and boundary sharpening. However, cell behaviour studies showed that only Dishevelled and PAR-6B have roles in EphB2-ephrinB1 mediated directional persistence, whilst Daam1 knockdown has no effect on the migratory response of cells. PAR-3 knockdown affects the basal ability of cells to migrate, potentially due to its role in establishing front-rear polarity. Taken together, these findings can be explained by a model in which Dishevelled and PAR-6B have a role in EphB2-ephrinB1 mediated directional persistence required for cell segregation and boundary sharpening. I propose that Daam1 may function in the contact inhibition of locomotion between cells also required for segregation.
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Harbott, Lene Karen. "Signalling pathways mediating ephrin-A-induced growth cone collapse." Thesis, University College London (University of London), 2004. http://discovery.ucl.ac.uk/1446636/.
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The ephrin-A family of axon guidance cues, which activate the EphA family of receptor tyrosine kinases, guide the axons of many types of neuron to the correct target during embryonic development. One particularly well-studied example is the projection of RGC processes to precise positions in the midbrain target that reflect the position of the RGC in the retina. Ephrin-As are membrane-tethered molecules expressed in a gradient in the midbrain, and they govern the formation of the retinotectal map by differential, contact-mediated repulsion of Eph-A-expressing RGC axons. In order to identify signalling molecules that mediate ephrin-A induced repulsion of RGCs, I have developed a novel co-culture assay in which contact with a single non-neuronal cell that expresses endogenous levels of ephrin-A induces rapid loss of RGC growth cone lamella, followed by axon retraction. I have confirmed that these cellular responses are mediated by neuronal EphA receptor signalling and, in combination with the traditional soluble collapse assay, have used this physiologically relevant co-culture assay to identify a more specific role for the Rho effector ROCK in ephrin-A-induced RGC responses than has previously been published. Specifically ROCK activity mediates ephrin-A-induced RGC axon retraction, but not loss of growth cone lamella. I have also identified the non-receptor tyrosine kinase Abl as having a major role in the ephrin-A-induced RGC repulsive response, as the Abl kinase inhibitor STI571 prevents both the ephrin-A-induced loss of RGC lamella and axon retraction. I have demonstrated the existence of a protein complex containing active Eph receptors, Abl and Mena, and shown that disruption of this complex correlates with STI571-dependent inhibition of the ephrin-A-induced RGC repulsive responses. These results comprise the first evidence that Abl plays a role in mediating Eph receptor signals, and is involved in the cytoskeletal rearrangements that underlie ephrin-A-induced growth cone collapse in vitro, and thus both complement and extend the published evidence demonstrating a role for Abl in mediating axon guidance in vivo.
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Dickinson, Sarah. "Regulation of the actin cytoskeleton by ephrin-B signalling." Thesis, University College London (University of London), 2006. http://discovery.ucl.ac.uk/1445415/.
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Ephrin ligands and their Eph receptors play an essential role in angiogenesis during development. Both ephrins and Eph receptors are membrane-tethered proteins and their interaction at sites of cell-cell contact triggers bi-directional signalling, with signals transduced from the receptor (forward signalling) and ligand (reverse signalling). I have used two model systems to study ephrin-B2 signalling: Swiss 3T3 fibroblasts expressing exogenous ephrin-B2 and Human Umbilical Arterial Endothelial Cells (HUAECs) endogenously expressing ephrin-Bs. Stimulation of ephrin-B2 with soluble EphB receptors, has enabled the characterisation of the cellular responses, and signalling pathways, triggered by ephrin-B2 activation. I have shown that clustering of expressed ephrin-B2 in cultured fibroblasts induces a loss of cell-cell contact, dependent on the presence of serum factors and independent of actin-myosin contractility. The intracellular domain of ephrin-B2 is essential: tyrosine phosphorylation of the ligand via Src, and binding of the adaptor protein Grb4 are required for loss of cell-cell contact. Stimulation of endogenous ephrin-B2 in cultured endothelial cells results in dramatic cell retraction, and in a proportion of cells membrane blebbing. I have shown that the small GTPase Rho and activation of its downstream effector ROCK are essential for membrane retraction to occur, which is driven by an actin-myosin contraction event. In addition, I find that the c-Jun amino terminal kinase (JNK) is required for retraction, acting upstream of Rho/ROCK, and retraction occurs independently of Grb4. The cell contraction response to ephrin-B2 activation is rapid and transient with cells recovering to re-spread lamellipodia within minutes. Re-spreading is coupled to a loss of actin stress fibres and concomitant with down regulation of Rho and ROCK activity.
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Langlais, Valentin. "Contrôle de l'activité des récepteurs NMDA par la D-sérine : rôle des récepteurs astrocytaires EphB3 et CB1." Thesis, Bordeaux, 2016. http://www.theses.fr/2016BORD0211/document.
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Les astrocytes sont des partenaires clés des neurones. Dans l’hippocampe, et tout particulièrement au niveau des synapses CA3-CA1, en libérant la D-sérine, ces cellules gliales régulent l’activité des récepteurs glutamatergiques de type N-methyl-D-aspartate (NMDA) et de ce fait la mémoire synaptique, aussi connue sous le nom de plasticité synaptique à long terme. Cependant, le signal synaptique à l’origine de la libération de la D-sérine par les astrocytes reste à ce jour méconnu. De par des données rapportées dans la littérature nous nous sommes tout particulièrement intéressés aux récepteurs astrocytaires aux ephrins de type B3 (EphB3) et aux endocannabinoïdes de type 1 (CB1). Pour ce faire nous avons principalement utilisé une approche électrophysiologique sur des tranches aiguës d’hippocampe de souris adulte. Dans une première étude, nos données indiquent que l’activation des récepteurs EphB3 augmente la présence de D-sérine synaptique et en conséquence l’activité des récepteurs NMDA synaptiques. A l’inverse, leur inhibition diminue à la fois l’activité des récepteurs NMDA synaptiques et la potentialisation à long-terme qui en dépend (LTP ; une forme de plasticité synaptique à long terme). L’interaction EphB3-ephrinB3 contrôle donc la LTP en contrôlant la disponibilité en D-sérine synaptique. Dans une seconde étude, nous avons utilisé un modèle transgénique permettant d’inhiber l’expression des récepteurs CB1 astrocytaires (souris GFAP-CB1-KO). Nous avons découvert que la suppression de ces récepteurs diminue la disponibilité en D-sérine synaptique. De plus, nos travaux montrent que les récepteurs CB1 astrocytaires sont nécessaires à l’induction de la LTP via la D-serine. En conclusion, ces travaux de Thèse révèlent que les récepteurs astrocytaires EphB3 et CB1 régulent les fonctions dépendantes des récepteurs NMDA via le contrôle qu’ils exercent sur la disponibilité en D-sérineAstrocytes are key partners of neurons. In the hippocampus, and more particularly at CA3-CA1 synapses, by releasing D-serine, these glial cells regulate the activity of synaptic Nmethyl-D-aspartate (NMDA) receptors and thus synaptic memory, also known as long-term synaptic plasticity. Yet, the synaptic signal inducing D-serine release by astrocytes is still unknown. Based on interesting data from the literature we have investigated the role of the astrocytic receptors for ephrinB3 (EphB3) and endocannabinoids (CB1). To this end we used electrophysiological approaches on acute hippocampal slices of adult mice. In a first study, our data indicate on one hand that the activation of EphB3 receptors increases synaptic D-serine availability and in consequences the activity of synaptic NMDA receptor activity. On the other hand, inhibition of EphB3 receptors induces a decrease of synaptic NMDA receptor activity as well as the induction of the long-term potentiation (LTP; a form of long-term plasticity). Thus, EphB3-ephrinB3 interaction controls LTP induction through the availability of synaptic D-serine. In a second study, we used a transgenic model allowing the inhibition of CB1 receptors expression in astrocytes (GFAP-CB1-KO mice). We discovered that their deletion reduced synaptic D-serine availability. Our work shows that astrocytic CB1 receptors are necessary for LTP induction via this D-serine. All together, this PhD work reveals that astrocytic EphB3 and CB1 receptors regulate synaptic NMDA receptor functions through the control of D-serine availability
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Holmberg, Johan. "Ephrins off the beaten path /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-720-7.
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Zarbalis, Konstantinos. "Molekulare und funktionale Analyse des Ephrin-A5-Gens der Maus." [S.l. : s.n.], 2000. http://deposit.ddb.de/cgi-bin/dokserv?idn=960645179.
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Batson, Jennifer. "Regulation of contact inhibition of locomotion by Eph-ephrin signalling." Thesis, University of Bristol, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.627947.
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Metastatic prostate cancer cells display EphB receptor-mediated attraction when they contact stromal fibroblasts but EphA-driven repulsion and contact inhibition of locomotion (CIL) when they contact one another. The impact of these social interactions between cells during cancer cell invasion and the signalling mechanisms downstream of Eph receptors are unclear. Here, I show that EphA receptors drive prostate cancer cell dissemination in a 20 dispersal assay and a 3D cancer cell" spheroid assay by activating repulsive interactions and CIL between contacting prostate cancer cells. I show that EphA receptors interact with the exchange factor Vav2 to activate RhoA, and that both Vav2 and RhoA are required for prostate cancer cell-cell repulsion. Using pharmacological inhibitors I show actomyosin contractility is not a key driver of CIL. I find instead that microtubule dynamics are important for generating the front-rear polarity switch required during CIL, and that EphA2/EphA4, Vav2 and RhoA affect microtubule stability in prostate cancer cells. Furthermore, I find that in EphA2/EphA4, Vav2 or RhoA knockdown cells, contact repulsion can be restored by partial microtubule destabilisation. I propose that EphAVav2- RhoA-mediated repulsion between contacting cancer cells at the tumour edge could enhance their local metastatic invasion and dissemination from the primary tumour. Subsequently, EphB-mediated attractive migration and failure of CIL, between prostate cancer cells contacting ephrin-B2· expressing fibroblasts, could facilitate cancer cell invasion through the surrounding stroma. Stimulation of prostate cancer cells with ephrin-B2lFc leads to filopodia formation and activation of Cdc42. I show that Cdc42-silenced PC-3 cells have significantly impaired migration towards surface coated ephrin-B2 compared with control siRNA-treated cells. Furthermore, Cdc42 is required for attractive migration and defective CIL during collisions b~tween advanced prostate cancer cells and ephrin-B2-expressing fibroblasts. Using organotypic 3D gel invasion assays, I show that ephrin-B2 expressing fibroblasts enhance prostate cancer cell invasion. These data suggest that EphB-Cdc42-mediated attractive interactions with fibroblasts and defective CIL might facilitate prostate cancer cell invasion through the surrounding stroma.
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Finkelmeier, Fabian [Verfasser]. "Die Rolle des Eph/Ephrin Systems bei Hirntumoren / Fabian Finkelmeier." Gießen : Universitätsbibliothek, 2011. http://d-nb.info/1063111358/34.
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Fujii, Haruko. "Eph-ephrin A system regulates murine blastocyst attachment and spreading." Kyoto University, 2010. http://hdl.handle.net/2433/97940.
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Fero, Daniel James. "The role of PI3K in Ephrin-A1 induced cell retraction." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2008. http://wwwlib.umi.com/cr/ucsd/fullcit?p3315045.
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Thesis (Ph. D.)--University of California, San Diego, 2008.Title from first page of PDF file (viewed August 4, 2008). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 104-113).
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Fabes, J. "Investigating the role of ephrin signalling in spinal cord injury." Thesis, University College London (University of London), 2006. http://discovery.ucl.ac.uk/1445432/.
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Spinal cord injury in adult mammals commonly leads to the permanent loss of motor and sensory function in regions of the body below the level of injury. The inability of the central nervous system to regenerate is, in part, due to the presence of growth-inhibitory agents surrounding the lesion site. This thesis presents a previously unreported, inhibitory interaction between ephrinB2 expressed on reactive astrocytes and the EphA4 receptor present on lesioned corticospinal tract axons. This interaction appears to mediate the unusually large retraction of the corticospinal tract away from spinal cord injury sites. An attempt to interfere with this interaction by implanting a cell line secreting the ephrinA5 receptor binding domain is reported. While this approach induced improvements in regenerative sprouting from the corticospinal tract, complications with immune rejection and cell proliferation stopped further investigation. A second intervention using a small peptide with high affinity and specificity for the EphA4 receptor is also reported. Intrathecal infusion of this peptide for 14 or 28 days after injury reversed the retraction of the corticospinal tract and induced improvements in regenerative sprouting from corticospinal and rubrospinal tracts following dorsal or lateral white matter transection injuries. Sprouts were seen to migrate long distances, often to the astrocyte margin of the lesion cavity. Astrocyte behaviour following injury was also altered with the formation of astrocytic 'bridges' into the lesion cavity along which regenerating axons grew. Functional recovery was also enhanced with improvements in the paw reaching assay within 10 days of a unilateral dorsal column lesion with a 30% recovery of function at 28 days post-operation. The simplicity of this intervention and direct translation to human application make it a promising candidate for use in combinatorial approaches to human spinal cord injury treatment.
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Hirsch, Karmela [Verfasser]. "Expression von Ephrin-Rezeptoren und Ephrin-Liganden in mit Ammoniak behandelten, kultivierten Rattenastrozyten und in post mortem Hirnproben von Leberzirrhosepatienten mit hepatischer Enzephalopathie / Karmela Hirsch." Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2019. http://d-nb.info/1180023609/34.
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McCarron, Jennifer Kylie. "The role of the Eph and ephrin proteins in prostate cancer." Thesis, Queensland University of Technology, 2011. https://eprints.qut.edu.au/67918/1/Jennifer_McCarron_Thesis.pdf.
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Prostate cancer is the most commonly diagnosed malignancy and the second leading cause of cancer related deaths in Australian men. Treatment in the early stages of the disease involves surgery, radiation and/or hormone therapy. However, in late stages of the disease these treatments are no longer effective and only palliative care is available. Therefore, there is a focus on exploration of novel therapies to increase survival and treatment efficacy. Advanced prostate cancer is characterised by bone or other distant metastasis. Spreading of the primary tumour to a secondary location is a complex process requiring an initial loss in cell-cell adhesion followed by increased cell migration and invasion. One gene family that has been known to affect cell-to-cell contact in other model systems are the Eph receptor tyrosine kinases. They are the largest family of receptor tyrosine kinases made up of 14 vertebrate Eph receptors that bind to nine cell membrane bound ephrin ligands. Eph-ephrin interaction is crucial in regulating cell behaviour in developmental processes and it is now thought that the underlying mechanisms involved in development may also be involved in cancer. Aberrant expression has been reported in many human malignancies including prostate cancer. Furthermore, expression has been linked with metastasis and poor prognosis in other tumour models. This study explores the potential role of the Eph receptor family in prostate cancer, in particular the roles of EphA2, EphA3 and ephrin-A5.
Gene expression profiles were established for the Eph family in a series of prostate cancer cell lines using quantitative real time RT-PCR. A smaller subset of the most prominently expressed genes was chosen to screen a cohort of clinical samples. Elevated levels of EphA2, EphA3 and their ligands, ephrin-A1 and ephrin-A5 were observed in individual cell lines. Interestingly high EphA3 expression was observed in the androgen responsive cell lines while EphA2 was more prominent in the androgen independent cell lines. However, studies using 5-dihydrotestosterone suggest that EphA3 expression in not regulated by androgen. Cells expressing EphA2 showed a greater ability for migration and invasion while cells expressing EphA3 showed poor migration and invasion. Forced expression of EphA2 in the LNCaP cell line resulted in a more invasive phenotype while forced expression of EphA3 in the PC-3 cell line suggests a possible negative effect for EphA3 on cell migration and invasion.
Cell signalling studies show activation of EphA2 decreases activity of proteins thought to be involved in pathways regulating cell movement including Akt, Src and FAK. Changes to the activation status of Rho family members, including RhoA and Rac1, associated with reorganisation of the actin cytoskeleton, an important part of cell migration was also observed. As a result, activation of EphA2 in PC-3 cells resulted in a less invasive phenotype. A novel finding in this study was the discovery of a combination of two EphA2 Mabs able to activate EphA2. Preliminary results show a potential for this antibody combination to reduce prostate cancer invasion in vitro.
A unique aspect of Eph-ephrin interaction is the resulting bi-directional signalling that occurs through both the receptor and ligand. In this study a potential role for ephrin-A5 mediated signalling in prostate cancer was observed. LNCaP cells express high levels of EphA3 and its high affinity ligand ephrin-A5. In stripe assays, used to study guidance cues, LNCaP cells show strong attraction/migration to EphA3-Fc stripes but not ephrin-A5-Fc stripes suggesting ephrin-A5 mediated reverse cell signalling is involved. Knockdown of ephrin-A5 using shRNA resulted in a decrease in attraction/migration to EphA3-Fc stripes. Furthermore a reduction in proliferation was also observed in vitro. A subcutaneous xenograft model using ephrin-A5 shRNA cells versus controls showed a decrease in tumour formation.
This study demonstrates a difference in EphA2 and EphA3 function in prostate cancer migration/invasion and a potential role for ephrin-A5 in prostate cancer cell adhesion and growth.
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Betschart, Andreas. "Der Einfluss der EphB4 und Ephrin-B2 Expression auf die Tumorangiogenese /." [S.l.] : [s.n.], 2009. http://www.ub.unibe.ch/content/bibliotheken_sammlungen/sondersammlungen/dissen_bestellformular/index_ger.html.
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Rodríguez, Franco Pilar. "Mechanics of boundary formation in epithelial monolayers by Eph-ephrin interactions." Doctoral thesis, Universitat de Barcelona, 2017. http://hdl.handle.net/10803/461913.
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For an organism to develop and maintain homeostasis, cell types with distinct functions must often be separated by physical boundaries. The formation and maintenance of such boundaries is commonly attributed to local mechanisms restricted to the cells lining the boundary. Here we show that, besides these local subcellular mechanisms, the formation and maintenance of tissue boundaries involves long-lived, long-ranged mechanical patterns. We analyzed the formation of repulsive epithelial boundaries between two epithelial monolayers, one expressing the receptor tyrosine kinase EphB2 and one expressing its ligand ephrinB1. Upon contact, both monolayers exhibited oscillatory patterns of traction forces and intercellular stresses that spanned several cell rows and tended to pull cell-matrix adhesions away from the boundary. With time, monolayers jammed and supracellular mechanical patterns became long-lived, thereby permanently contributing to sustain tissue segregation. Jamming was paralleled by the emergence of soliton-like deformation waves that propagated away from the boundary. This phenomenon was not specific to EphB2-ephrinB1 repulsion but was also present during the formation of boundaries with an inert interface. Our findings thus unveil a global physical mechanism that sustains tissue separation independently of the biochemical and mechanical features of the local tissue boundary.Para que un organismo desarrolle y mantenga la homeostasis, a menudo los tipos celulares con distintas funciones deben estar separados por barreras físicas. La formación y mantenimiento de dichas barreras se suele atribuir a mecanismos locales restringidos a las células que las bordean. En este trabajo mostramos que, además de estos mecanismos subcelulares locales, la formación y el mantenimiento de las barreras físicas entre tejidos implica patrones mecánicos de largo alcance y larga duración. En particular, hemos analizado la formación de barreras epiteliales repulsivas entre dos monocapas epiteliales, una que expresa el receptor tirosina quinasa EphB2 y otra que expresa su ligando ephrinB1. Tras el contacto, ambas monocapas exhibieron patrones oscilatorios de fuerzas de tracción y tensiones intercelulares que involucraban varias hileras de células y que tendían a retirar las adhesiones célula-matriz hacia fuera de la barrera. Con el paso del tiempo, las monocapas se densificaron y los patrones mecánicos supracelulares se volvieron estables, contribuyendo así a mantener la segregación tisular permanentemente. La aglomeración de células fue acompañada por la aparición de ondas de deformación, similares a solitones, que se propagaron hasta más allá del campo de visión. Este fenómeno no es específico de las barreras repulsivas controladas por el par EphB2-ephrinB1, sino que también aparecen cuando una única monocapa interfiere con una interfaz inerte. Nuestros hallazgos revelan un mecanismo físico global que mantiene la separación entre tejidos independientemente de las características bioquímicas y mecánicas del límite tisular local.
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Campbell, Jessica. "The regulation of cell migration and invasion by Eph-ephrin signalling." Thesis, University of Bristol, 2015. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.688221.
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Cell migration and invasion are essential aspects of normal cellular behaviour, however abnormal cell migration can lead to defects in essential cell processes, such as wound healing, or can also promote diseases such as cancer. Cell migration can be regulated by many factors and, importantly, can depend upon a cells interaction with its surrounding cellular microenvironment. Eph receptors are the largest family of receptor tyrosine kinases and are essential in transmitting signals between cells as, uniquely to this family, the ephrin ligands are cell surface bound, therefore signalling is cell-cell contact dependent. Although Eph and ephrin functions have been studied for many years, much of the mechanisms by which they signal are still unclear. In this thesis, I have investigated the role of Eph-ephrin signalling in regulating different aspects of cell migration and invasion in prostate cancer cells and during keratinocyte cell wound healing. I find that the activity of EphB4 is regulated by the expression of PTEN phosphatase both in DU145 and PC-3 prostate cancer cells. This regulation leads to altered heterotypic cell contact inhibition of locomotion, in a co-culture assay between DU145 cells and fibroblasts. I also find that PTEN expression regulates the number of DU145 cells invading from a tumour cell spheroid, towards fibroblasts, in a 3D collagen gel. I suggest these cell behaviours may be as a consequence of altered Rac activity, downstream of EphB4 and PTEN signalling. I also use SILAC based phosphoproteomics to investigate some of the proteins regulated downstream of PTEN expression ilnd EphB4 activity. Furthermore I find that Ephrin-Bs are essential in regulating keratinocyte cell reepithelialisation during tissue culture wound healing, by regulating the actin cytoskeleton structure and E-cadherin processing. Finally, I have attempted to investigate the role of EphB2 in regulating prostate cancer cell migration and invasion, and find that EphB2 depletion does not alter PC-3 cell migration velocity in two dimensions.
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Wild, Corinne. "Involvement of the ephrin-B2 ligand in spleen development and function /." [S.l.] : [s.n.], 2008. http://opac.nebis.ch/cgi-bin/showAbstract.pl?sys=000277025.
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Reißenweber, Bettina. "Der Einfluss der Hypoxie auf die Expression und Synthese verschiedener Eph-Rezeptoren und Ephrin-Liganden beim malignen Melanom." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2013. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-101756.
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Das maligne Melanom ist die aggressivste Form von Hautkrebs und verschiedene Familien von Rezeptortyrosinkinasen sind an der Entwicklung und der verstärkten Malignität beteiligt. Eph-Rezeptoren stellen die größte Klasse der Rezeptortyrosinkinasen dar und spielen eine wichtige Rolle bei der Tumorangiogenese und -progression. Die Genexpression und Proteinsynthese verschiedener Eph-Rezeptoren und Ephrin-Liganden ist bei vielen Tumorentitäten erhöht. Aus diesem Grund sollten sie sich als Zielproteine für die Entwicklung neuer Radiopharmaka eignen. Zudem zeigen Literaturbefunde einen Einfluss der hypoxischen Zellumgebung auf die Genexpression und die Proteinsynthese verschiedener Eph-Rezeptoren und Ephrin-Liganden.
Das Ziel dieser Arbeit war es, Regulationsmechanismen bei verschiedenen Eph-Rezeptoren und Ephrin-Liganden aufzuklären, welche durch ein hypoxisches Umfeld hervorgerufen werden. Dazu wurde neben einem extrinsischen Hypoxiemodell an Monolayerzellkulturen auch ein intrinsisches Hypoxiemodell in Form von Tumorsphäroiden untersucht. Da die Genexpression und die Proteinsynthese von EphA2, EphB4, EphrinA1 und EphrinB2 laut Literatur vom Malignitätsgrad abhängig sind, wurden die metastatischen Melanomzelllinien A375, A2058 und MeWo und die prämetastatische Melanomzelllinie MEL-JUSO verwendet. Die Verifizierung der experimentellen Hypoxie erfolgte durch den etablierten Hypoxiemarker [18F]Fluormisonidazol, sowie dem Nachweis der VEGF-Genexpression unter den verwendeten Kulturbedingungen. Damit konnte die Eignung der hypoxischen Systeme gezeigt werden. Unabhängig vom Hypoxiemodell war in keiner der untersuchten Zelllinien ein Einfluss der Hypoxie auf die Genexpression und Proteinsynthese von EphA2, EphB4, EphrinA1 und EphrinB2 nachweisbar. Ein gesteigerter EphA2-Gehalt in Melanomzellen ist laut Literatur mit einer Erhöhung des Metastasierungspotentials verbunden. Um diesen Einfluss innerhalb einer Zelllinie zu untersuchen, wurden transgene A375-Zellen generiert. Mit dieser Zelllinie fanden Untersuchungen zu verschiedenen Metastasierungseigenschaften statt. Dabei wurde festgestellt, dass sich die Migration der Zellen durch den erhöhten EphA2-Gehalt verringerte, dabei war die hypoxische Umgebung ohne Einfluss. Weiterhin wurde festgestellt, dass der EphA2-Rezeptor das Adhäsionsverhalten von A375-Zellen nicht beeinflusst. Auch ein Einfluss auf das invasive Verhalten konnte nicht festgestellt werden. Eine hypoxische Umgebung war in beiden Fällen nicht von Bedeutung.
Aus den Ergebnissen der vorliegenden Arbeit kann geschlussfolgert werden, dass bei den untersuchten Melanomzelllinien keine Regulation der Eph-Rezeptoren und Ephrin-Liganden durch ein hypoxisches Umfeld erfolgt. Durch die ausführliche Charakterisierung des EphA2-Rezeptors in der Arbeit kann jedoch geschlussfolgert werden, dass sich der Rezeptor als potentielles Zielmolekül für die Entwicklung neuer Radiotherapeutika und Radiodiagnostika eignet, nicht jedoch für die Detektion hypoxischer Bereiche in Tumoren. Durch die nunmehr etablierte Generierung von Sphäroiden und einer Zelllinie, welche den Rezeptor verstärkt exprimiert und synthetisiert, stehen nun Zellmodelle für die weiterführende Charakterisierung und Analyse neuer Radiodiagnostika und Radiotherapeutika auf der Basis von Inhibitoren und Antikörper gegen EphA2 zur Verfügung.
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Depner, Cornelia [Verfasser]. "Die Rolle von Ephrin-B2 in der Invasion maligner Gliome / Cornelia Depner." Mainz : Universitätsbibliothek Mainz, 2012. http://d-nb.info/1019192461/34.
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Turner, Christopher John. "Ephrin-B2 controls cell motility and adhesion during blood vessel wall assembly." Thesis, University College London (University of London), 2008. http://discovery.ucl.ac.uk/16746/.
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Eph receptor tyrosine kinases and their ligands, the ephrins, are versatile regulators of cell migration and tissue morphogenesis. Previous studies have shown that endothelial expression of EphB4 and its ligand ephrin-B2 are essential for angiogenic remodelling of blood vessels in the early embryo. However, ephrin-B2 is also expressed on mural cells (vascular smooth muscle cells and pericytes), which wrap around the endothelium to form stable and functional vessels. To gain further insight into the role of ephrin-B2 on mural cells, I have analysed tissue-specific mutant mice that lack ephrin-B2 on both vascular smooth muscle cells (vSMCs) and pericytes. This has revealed that ephrin-B2 is essential for the proper association of mural cells with endothelium. Using ephrin-B2-deficient (Δephrin-B2) and control immortalised vSMCs, I have found that loss of ephrin-B2 leads to striking changes in cell morphology. Ephrin-B2-deficient cells appear elongated and insufficiently spread, show numerous lamellipodial protrusions, and have problems detaching at the rear. Live video microscopy has revealed that Δephrin-B2 cells are unable to stabilise their lamellipodia despite forming functional focal adhesions and move in an erratic nonpolarised fashion. To further investigate the mechanism by which the loss of ephrin-B2 leads to defects in vSMCs, I’ve carried out affymetrix chip microarray. This has revealed that control and ephrin-B2 deficient cells display distinct expression profiles and identified differentially expressed genes involved in cell adhesion, matrix deposition, and Rho GTPase Activity. Most interesting is the finding that Tiam1 (T-lymphoma invasion and metastasis), a specific guanine-exchange factor (GEF) for Rac1, is down-regulated 49-fold in cells lacking ephrin-B2.
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Vicente, A. "Role of ephrin-B2 signalling in the developing and mature lymphatic vasculature." Thesis, University College London (University of London), 2014. http://discovery.ucl.ac.uk/1418702/.
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The formation of the lymphatic vasculature takes place in two main steps. The first step establishes the lymphatic endothelial cell fate and primitive vascular network during the early stages of development and is controlled by the transcription factor PROX-1. In the second step at late embryonic and postnatal stages the initial lymphatic plexus is remodelled into a hierarchical mature lymphatic network. A key regulator of this process is the transmembrane protein ephrin-B2, a ligand for the Eph family of receptor tyrosine kinases. With the research depicted in this thesis I have focused on understanding the role ephrin-B2 and its receptor EphB4 play during lymphatic development and the underlying molecular mechanisms. Ephrin-B2 and the signalling mediated via its PDZ-binding motif were previously described to be required for lymphatic development. Using constitutive and inducible tissue-specific loss-of-function mouse models I have shown that ephrin-B2 and its PDZ-related signalling are required not only to initiate the process of lymphatic remodelling but also for the maintenance of a mature lymphatic network. Loss of either of them results in immature lymphatic vessels that lack intraluminal valves. In vitro and in vivo experiments suggest that this is due to defects in the regulation of lymphatic endothelial cell cytoskeleton and cell-cell adhesion. Similarly, EphB4 is required for the initial steps of lymphatic remodelling; however, it is dispensable for the maintenance of adult lymphatic network. Finally, I demonstrated that ephrin-B2 and EphB4 are essential regulators of lymphatic sprouting, but this process is not dependent on ephrin-B2 PDZ-binding motif. These data show that ephrin-B2 signalling is required all through lymphatic development but the underlying molecular mechanisms differ between different developmental stages and processes. While the experimental evidence points towards a synergistic role of ephrin-B2 and EphB4 during lymphatic sprouting and initial remodelling, the role of ephrin-B2 in lymphatic maintenance is EphB4- independent. In addition, lymphatic sprouting is, to our knowledge, the first lymphangiogenic process where ephrin-B2 is required in a PDZ-independent manner. To study the lymphatic-specific deletion of ephrin-B2 and EphB4 I used a novel mouse line that drives Cre recombinase expression under the control of Prox1 promoter. While characterising the line, I described a previously unreported expression of Prox1 in the mesenteric veins. This expression was associated with the appearance of Prox1-positive sprouts from the veins and lympho-venous connections that I further analysed by micro computed tomography.
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Krusche, Benjamin. "Ephrin-B2 is a glioblastoma oncogene that drives perivascular invasion and proliferation." Thesis, Imperial College London, 2015. http://hdl.handle.net/10044/1/49785.
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Glioblastoma multiforme (GBM) are the most aggressive and devastating tumours of the brain and are essentially incurable. They are defined by diffuse invasion of the surrounding brain parenchyma along preexisting structures like the vasculature. Glioma stem cells (GSC) are thought to be largely responsible for tumour recurrence following treatment due to their high resistance to therapy, their ability to recapitulate tumours from single cells and their marked invasive potential. Here we show, that normal neural stem cell in the subventricular zone are compartmentalised by endothelial ephrinB2 and their proliferation limited through activation of p53 in an Eph signalling dependent manner. GSCs however evade both compartmentalisation and proliferation inhibition and are able to invade perivascularly. Intravital imaging, coupled with mechanistic studies in vitro revealed that upregulation of ephrinB2 in highly aggressive, mesenchymal GSCs enables escape from endothelial compartmentalisation through homotypic forward signalling. Surprisingly we also find that that ephrinB2 reverse signalling promotes tumourigenesis by mediating anchorage-independent cytokinesis through activation of RhoA. In preclinical models using human GSCs we show, that inhibition of ephrinB2 by RNA silencing or with ephrinB2-blocking antibodies strongly suppresses tumourigenesis of established glioblastoma by inducing cell-cycle arrest and blocking GBM/vascular interactions. Thus, ephrinB2 is an oncogene and represents an attractive candidate for anti-GBM therapies aimed at eradicating the GSC compartment by targeting both glioma invasion and proliferation.
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Stanforth, Hannah Amy. "Transcriptional targets of Eph receptor and ephrin signalling in the zebrafish hindbrain." Thesis, University College London (University of London), 2018. http://discovery.ucl.ac.uk/10053620/.
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In vertebrates, there is a large family of Eph receptor tyrosine kinases and their ephrin ligands, which have complex and varied roles during development and in adult homeostasis. The most researched role of Eph receptors and ephrins is in control of cell migration through the regulation of the actin cytoskeleton and cell adhesion. More recently, it has been found that in some tissues Eph-ephrin signalling also leads to changes in gene transcription, for example to control cell differentiation. In the zebrafish hindbrain, Eph receptors and ephrins are expressed segmentally in the rhombomeres in a complementary pattern with respect to their binding partner. Signalling via this pathway induces a unique cell population to arise at rhombomere borders, known as the boundary cells. In order to understand more about Eph receptor and ephrin function in the hindbrain, RNA-sequencing was carried out on dissected hindbrains of zebrafish with endogenous Eph-ephrin signalling and fish that lack Eph-ephrin signalling. The transcriptional profiles were then compared to identify potential downstream targets, which were verified using RT-qPCR and in situ hybridisation. This identified four genes regulated downstream of Eph-ephrin signalling that are markers of progenitor cells and neural differentiation. When Eph-ephrin signalling is disrupted the expression of these genes alters, and the expression pattern of one gene, mdka, was consistent with loss of hindbrain boundary cells. To investigate this observation further, the expression of progenitor and neurogenic markers was determined when Eph-ephrin signalling was disrupted. This supported previous studies which found that Eph-ephrin signalling is required for formation of boundary cells and that boundary cell loss results in ectopic neurogenesis. In addition, it was found that ectopic neurogenesis was accompanied by the depletion of nestin-expressing neural progenitor cells at later stages of development. Together these findings support previous work showing that hindbrain boundary cells are essential for restricting neurogenesis to neurogenic zones adjacent to the boundaries.
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Chennakesava, Cuddapah Sunku. "Involvement of EphB4 receptor and ephrin-B2 ligand expression in human placentation /." [S.l.] : [s.n.], 2005. http://www.zb.unibe.ch/download/eldiss/05chennakesava_cs.pdf.
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Lisle, Jessica E. "Proteolytic regulation of the EphB4-Ephrin-B2 signalling axis in prostate cancer." Thesis, Queensland University of Technology, 2016. https://eprints.qut.edu.au/101573/1/Jessica_Lisle_Thesis.pdf.
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EphB4 is a receptor protein over-expressed by many different cancers. This study explored the regulation of EphB4 and its binding partner, the ephrin-B2 ligand, in prostate cancer cells. This work showed that both EphB4 and ephrin-B2 can be cleaved by an important prostate cancer associated protease, KLK4 and this regulates the interaction between EphB4 and ephrin-B2 to activate different biological responses which could contribute to the initiation and progression of prostate cancer. This is a novel mechanism, that with further investigation, may provide new options for the development of anti-cancer therapies.
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Eulenburg, Volker. "Funktionelle Charakterisierung der Interaktion der Protein-Tyrosin-Phosphatase PTP-BL mit Ephrin Bs." [S.l.] : [s.n.], 2001. http://deposit.ddb.de/cgi-bin/dokserv?idn=964429713.
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Dolce, Luca. "A DNA-Microarray screening: δ-Catenin, a new mediator of Eph-ephrin signaling." Diss., lmu, 2005. http://nbn-resolving.de/urn:nbn:de:bvb:19-42383.
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Bowden, Thomas Alexander. "Ephrin signalling and henipavirus attachment : A structural basis for receptor and viral specificity." Thesis, University of Oxford, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.509897.
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Rohani, Larijani Nazanin. "Characterizing the role of Ephrin Eph signaling on tissue separation in Xenopus Laevis." Thesis, McGill University, 2014. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=123100.
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As they acquire distinct fates, embryonic cell populations become separated bysharp boundaries. Several theories have been proposed to explain this astonishingphenomenon, which remains very poorly understood. This study investigatestissue separation at the cellular and molecular level, using the gastrulatingXenopus embryo as a model. At this developmental stage, boundaries divide theembryo into its basic body structures, starting with separation of the germ layers,followed by the separation of presomitic mesoderm from notochord. Live cellmicroscopy at these boundaries revealed a contact-mediated repulsion mechanismthat is controlled by a combination of several Eph receptors and their ephrinligands. Loss and gain of function approaches suggest that ephrin-Ephs interactselectively and not promiscuously. They are expressed in a partiallycomplementary pattern on both sides of the boundary. Integration of signals fromthose pairs reaches maximum intensity at the tissue interface. This phenomenonwas simulated computationally based on relative ephrin and Eph concentrations aswell as binding affinities. Despite differences in the expression profile of ephrinsand Ephs at various boundaries, our model holds true. The underlying cytoskeletalmechanism downstream of ephrin-Eph-mediated cell contraction was investigatedfurther. We found that repulsive events and membrane contraction made the cellmembranes less permissive to form stable adhesive bonds, resulting in a state ofloose adhesion – as indicated by the smooth appearance of Cadherins at theboundary. This thesis provides a novel understanding of ephrin-Eph control oftissue boundaries. It also has a direct impact on deciphering their intricate role intumor cell metastasis and invasion.Au cours du développement embryonnaire, la différenciation cellulaire entraîne lamise en place de frontières nettes afin de séparer les différentes populations decellules qui se dessinent. Plusieurs théories ont tenté d'expliquer ce phénomènefascinant, qui demeure mal compris. La présente étude s'appuie sur la gastrula deXénope afin d'examiner le processus de séparation des tissus aux niveauxcellulaire et moléculaire. A ce stade du développement, des frontières divisentd'abord l'embryon en trois couches de feuillets embryonnaires, puis séparent lanotocorde du mésoderme présomitique. L'imagerie de ces frontières sur descellules vivantes a révélé un mécanisme de répulsion cellulaire, qui serait contrôlépar une combinaison de plusieurs types de récepteurs Eph et de leurs ligands, leséphrines. Nous montrons à la fois par perte et par gain de fonction que leséphrines interagissent avec les récepteurs Eph de manière sélective, et non pasaléatoire. L'expression de ces protéines de part et d'autre des frontières suit unschéma de complémentarité partielle. L'intégration des signaux générés par lespaires d'éphrine-Eph produit une réaction d'amplitude maximale aux interfacesentre les tissus. Nous proposons une simulation numérique de ce phénomène designalisation intégrée, sur la base des concentrations relatives d'éphrines etd'Ephs, ainsi que de leurs affinités de liaison. Cette simulation semble valide pourmodéliser de nombreuses frontières embryonnaires, et ce malgré la variabilité desprofils d'expression des éphrines et Ephs à ces différentes frontières. Nous avonségalement étudié les modifications du cytosquelette en aval de la voie designalisation éphrine-Eph, qui entraîne la contraction cellulaire. Nos résultatsindiquent que les instances de répulsions cellulaires, en conjonction avec lacontraction membrannaire, entravent la formation de liaisons adhésives stablesentre les cellules. Ceci engendre un état d'adhérance faible, se traduisant parl'apparance lisse des Cadhérines le long des frontières embryonnaires. Laprésente thèse apporte une compréhension nouvelle du rôle de la voie designalisation éphrine-Eph dans la régulation des frontières entre différents tissus.Ces trouvailles promettent également d'éclairer l'étude du rôle de ces moléculesdans l'invasion et la métastase de tumeurs.
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Wang, Y. "Regulation of the angiogenic growth of blood and lymphatic vessels by Ephrin-B2." Thesis, University College London (University of London), 2009. http://discovery.ucl.ac.uk/16161/.
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The angiogenic growth of blood vessels and lymphatic vessels plays important roles during embryonic development as well as in disease conditions such as cancer. Previous work has shown that ephrin-B2, a transmembrane protein and ligand for Eph family receptor tyrosin kinases, regulates the growth of these endothelial networks. In mice, inactivation of ephrin-B2 in endothelial cells (ECs) results in similar vascular defects and embryonic lethality as in global Efnb2 knockouts, indicating that the main function of ephrin-B2 is in the endothelium. Despite its importance, the functional roles of ephrin-B2 in vascular endothelium are incompletely understood. To gain further insight into the function of ephrin-B2 in ECs in mice, I have used EC-specific and temporally controlled loss-of-function and gain-of-function genetic approaches, and analysed the function of ephrin-B2 in different vascular beds. My data show that ephrin-B2 has two distinct functional roles in the blood vasculature. In arteries, the domain with the highest expression of ephrin-B2, the ligand is critical for arterial remodelling. Outside arteries, in the microvessels of capillary beds, ephrin-B2 is essential for endothelial motility and invasiveness during angiogenic sprouting. Furthermore, ephrin-B2 is an important regulator of angiogenic lymphatic endothelial cell (LEC) behaviour, which may be associated with VEGFR3-mediated signalling. In addition, ephrin-B2 is essential for the maintenance of LEC differentiation and, at least during embryonic development, normal Prox1 expression. Moreover, my data indicates that ephrin-B2 is critical for the postnatal remodeling of the primary dermal lymphatic plexus, which appears to be mainly mediated through ephrin-B2 reverse signalling. The sum of my findings demonstrates that ephrin-B2 is a key regulator of EC motility during the angiogenic growth of blood vessels and lymphatic vessels. Ephrin-B2 plays multiple indispensable and vascular domain-specific roles in the angiogenic growth of endothelial networks.
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Vogt, Noora Raya. "Der Einfluss des ephrin-B2 Liganden auf die Entwicklung und Funktion der Milz /." [S.l.] : [s.n.], 2008. http://opac.nebis.ch/cgi-bin/showAbstract.pl?sys=000277036.
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Falivelli, Giulia <1985>. "Attenuation of Eph Receptor Kinase Activation in Cancer Cells by Coexpressed Ephrin Ligands." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2014. http://amsdottorato.unibo.it/6264/1/Falivelli_Giulia_tesi.pdf.
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The Eph receptor tyrosine kinases mediate juxtacrine signals by interacting “in trans” with ligands anchored to the surface of neighboring cells via a GPI-anchor (ephrin-As) or a transmembrane segment (ephrin-Bs), which leads to receptor clustering and increased kinase activity. Additionally, soluble forms of the ephrin-A ligands released from the cell surface by matrix metalloproteases can also activate EphA receptor signaling. Besides these trans interactions, recent studies have revealed that Eph receptors and ephrins coexpressed in neurons can also engage in lateral “cis” associations that attenuate receptor activation by ephrins in trans with critical functional consequences. Despite the importance of the Eph/ephrin system in tumorigenesis, Eph receptor-ephrin cis interactions have not been previously investigated in cancer cells. Here we show that in cancer cells, coexpressed ephrin-A3 can inhibit the ability of EphA2 and EphA3 to bind ephrins in trans and become activated, while ephrin-B2 can inhibit not only EphB4 but also EphA3. The cis-inhibition of EphA3 by ephrin-B2 implies that in some cases ephrins that cannot activate a particular Eph receptor in trans can nevertheless inhibit its signaling ability through cis association. We also found that an EphA3 mutation identified in lung cancer enhances cis interaction with ephrin-A3. These results suggest a novel mechanism that may contribute to cancer pathogenesis by attenuating the tumor suppressing effects of Eph receptor signaling pathways activated by ephrins in trans (Falivelli et al. 2013).
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Falivelli, Giulia <1985>. "Attenuation of Eph Receptor Kinase Activation in Cancer Cells by Coexpressed Ephrin Ligands." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2014. http://amsdottorato.unibo.it/6264/.
Full textAbstract:
The Eph receptor tyrosine kinases mediate juxtacrine signals by interacting “in trans” with ligands anchored to the surface of neighboring cells via a GPI-anchor (ephrin-As) or a transmembrane segment (ephrin-Bs), which leads to receptor clustering and increased kinase activity. Additionally, soluble forms of the ephrin-A ligands released from the cell surface by matrix metalloproteases can also activate EphA receptor signaling. Besides these trans interactions, recent studies have revealed that Eph receptors and ephrins coexpressed in neurons can also engage in lateral “cis” associations that attenuate receptor activation by ephrins in trans with critical functional consequences. Despite the importance of the Eph/ephrin system in tumorigenesis, Eph receptor-ephrin cis interactions have not been previously investigated in cancer cells. Here we show that in cancer cells, coexpressed ephrin-A3 can inhibit the ability of EphA2 and EphA3 to bind ephrins in trans and become activated, while ephrin-B2 can inhibit not only EphB4 but also EphA3. The cis-inhibition of EphA3 by ephrin-B2 implies that in some cases ephrins that cannot activate a particular Eph receptor in trans can nevertheless inhibit its signaling ability through cis association. We also found that an EphA3 mutation identified in lung cancer enhances cis interaction with ephrin-A3. These results suggest a novel mechanism that may contribute to cancer pathogenesis by attenuating the tumor suppressing effects of Eph receptor signaling pathways activated by ephrins in trans (Falivelli et al. 2013).
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Egawa, Miho. "Ephrin B1 is expressed on human luteinizing granulosa cells in corpora lutea of the early luteal phase : the possible involvement of the B-class Eph-ephrin system during corpus luteum formation." Kyoto University, 2005. http://hdl.handle.net/2433/144492.
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Piffko, Andras [Verfasser]. "Ephrin-B2 - EphB4 interaction as a therapeutic target in spinal metastasis formation / Andras Piffko." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2019. http://d-nb.info/1202042872/34.
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Parks, Michael. "The role of syntenin-1 in modulating ephrin-b2 pathways in breast epithelial cells." Thesis, University of Birmingham, 2014. http://etheses.bham.ac.uk//id/eprint/5062/.
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Eph receptor tyrosine kinases and their ligands ephrins are involved in many physiological processes, including tissue homeostasis, vascularisation and development. They are also involved in promoting angiogenesis and metastasis in many cancers, including breast, colon and lung. Upon interaction with EphB receptors, ephrinB ligands signal through SH2- and PDZ-interacting cytoplasmic adaptors. To date, little is known on PDZ-mediated ephrinB signalling. The aim of our study was to determine the role of PDZ domain-containing proteins in modulating ephrinB2 signalling and trafficking pathways in the context of epithelial breast cancer cells, with a specific focus on the scaffolding protein syntenin-1. We also endeavoured to determine whether the ephrinB2 – syntenin-1 axis affects breast cancer tumourigenesis. Our findings demonstrate that syntenin-1 modulates ephrinB2 internalization upon receptor-induced stimulation and that this affects ephrinB signalling. Furthermore, we found that phospho-Tyr330 on ephrinB2 increases binding to the PDZ domain-containing proteins syntenin-1 and PAR3. Finally, we report that ephrinB2 drives MCF7 colony growth in 3D cultures and that syntenin-1 is involved in boundary formation between ephrinB2 and EphB4 expressing cells. These findings describe, for the first time, the role of syntenin-1 in ephrinB2 signalling and the functional relevance of the ephrinB2 – syntenin-1 axis in epithelial breast cancer pathways.
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McLennan, Rebecca. "Expression and function of EphA4 and ephrin-As in avian trunk neural crest migration /." free to MU campus, to others for purchase, 2004. http://wwwlib.umi.com/cr/mo/fullcit?p3144440.
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Kenmuir, Cynthia L. "The Role of ephrin-A Ligands and EphA Receptors in the Development and Maintenance of Somatosensory Connectivity." University of Toledo Health Science Campus / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=mco1269537701.
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Köhler, Jenny. "Imaging of the dynamics of Eph receptors and their ephrin ligands in mature hippocampal neurons." Diss., lmu, 2005. http://nbn-resolving.de/urn:nbn:de:bvb:19-42068.
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Dimidschstein, Jordane. "Ephrin-B1 controls the spatial distribution of cortical pyramidal neurons by restricting their tangential migration." Doctoral thesis, Universite Libre de Bruxelles, 2012. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/209658.
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During development of the cerebral cortex, the various neuronal subtypes have to reach their correct final position in the post mitotic compartment where they complete their maturation and eventually establish functional networks. Precise positioning of individual neurons is acquired through tight regulation of the multiple transitions that neurons undergo on their way to the cortical plate. Neurons of the cerebral cortex are organized in layers and columns. Although several molecular mechanisms have been identified that control the final position of neurons along the radial dimension of the cortex (i.e. layer specificity), much less is known about how their final tangential, or mediolateral, distribution is controlled. However this may have a direct impact on the structural and functional organization of cortical columns, since sister neurons derived from the same progenitor display selective patterns of connectivity with each other and/or share similar functional properties. Here we studied the role of B-ephrins in the control of migration of cortical pyramidal neurons. Gain of function experiments using in utero electroporation of ephrin-B1 revealed a striking alteration of the tangential distribution of pyramidal neurons during the multipolar stage of radial migration, resulting in clustering of the pyramidal neurons in the cortical plate. Conversely, clonal analysis of migrating neurons in ephrin-B1 knockout mice showed a wider mediolateral dispersion of cortical neurons. Static and dynamic analyses of migrating neurons revealed that ephrin-B1 modulates the morphology of pyramidal neurons during their multipolar phase, thereby restricting their tangential migration at that stage. Our results demonstrate that ephrin-B1 is a specific inhibitor of non-radial migration of pyramidal neurons, thereby controlling the pattern of cortical columns. These data shed new light on this important aspect of pyramidal neuronal migration, and illustrate how alterations of patterns of migration can affect cortical column organization.Doctorat en Sciences biomédicales et pharmaceutiques
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Neuber, Christin. "Eph-Rezeptoren und Ephrin-Liganden als molekulare Schnittstelle zwischen Melanomzellen und Tumor-assoziierten inflammatorischen Zellen." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2013. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-115913.
Full textAbstract:
EINLEITUNG
Das maligne Melanom stellt aufgrund seiner frühen Metastasierung und der Resistenz gegenüber den bisher bekannten Therapieansätzen eine der aggressivsten Tumorentitäten dar. Allerdings handelt es sich beim Melanom um einen antigenen und immunogenen Tumor. Dies schürt die Hoffnung, dass durch das bessere Verständnis der Mechanismen, die der Metastasierung, aber auch der Dysregulation des Immunsystems zugrunde liegen, Rückschlüsse auf neue Therapieansätze, beispielsweise unter Einbeziehung der Immunabwehr, gezogen werden können. Darüber hinaus würde die Entwicklung von Radiotracern, die eine frühzeitige Diagnose und möglicherweise auch die Auswahl von Patienten für eine personalisierte Tumortherapie ermöglichen, die Heilungschancen des malignen Melanoms wesentlich verbessern. Das Eph-Ephrin-System wiederum stellt ein vielfältiges Zellkommunikations-System dar, das sowohl in lebenswichtige als auch in pathologische Prozesse involviert ist. Beispielsweise nehmen Eph-Rezeptoren und Ephrine Einfluss auf die gerichtete Bewegung von neuronalen, endothelialen und inflammatorischen Zellen. Zudem beeinflussen sie die Bewegung von Tumorzellen und tragen so zur Tumorprogression bei.
Ausgehend von diesem Hintergrund wurde die Hypothese formuliert, dass die Eph-Ephrin-vermittelte Interaktion von Melanomzellen und Tumor-assoziierten inflammatorischen Zellen die Progression und Metastasierung des malignen Melanoms beeinflusst. Im Speziellen sollte im Rahmen der vorliegenden Arbeit geprüft werden, ob die Rezeptor-Tyrosinkinase EphB4 im Zusammenspiel mit seinem Liganden EphrinB2 die Progression und Metastasierung des malignen Melanoms fördert. Darüber hinaus sollte getestet werden, ob der Rezeptor EphB6, der ebenfalls zur Bindung von EphrinB2 fähig ist, aber über eine mutierte und damit funktionsunfähige Kinasedomäne verfügt, eine regulative Rolle übernimmt und antitumorigen wirkt. Aufbauend auf den Erkenntnissen zur Bedeutung von EphB4, EphB6 und EphrinB2 beim malignen Melanom sollten zudem verschiedene Ansätze zur Bildgebung der oben genannten Eph-Rezeptoren und Ephrine mittels PET etabliert und geprüft werden.
ERGEBNISSE UND DISKUSSION
Im Rahmen der vorliegenden Arbeit wurde erstmalig gezeigt, dass die Membranproteine EphB4, EphB6 und EphrinB2 bei den ausgewählten humanen Melanomzellen und den inflammatorischen Zellen exprimiert werden und somit potentielle Interaktionsmöglichkeiten dieser Zellen darstellen. Infolge der Kokultur mit HL-60(M)-Zellen, die als Modell für Tumor-assoziierte Makrophagen dienten, kam es zu einer verminderten Adhäsion und/oder Migration der Melanomzellen sowie im Falle der A375- und A2058-Melanomzellen zu einer verstärkten Sekretion des proinflammatorischen Zytokins IL-6. Aufgrund der breiten Wirkung von IL-6 ergeben sich daraus vielfältige Einflussmöglichkeiten auf das Tumormikromilieu. Diese wurden im Rahmen der vorliegenden Arbeit jedoch nicht näher charakterisiert, da erste Ergebnisse eine Beteiligung des Eph-Ephrin-Systems ausschlossen.
Während die Überexpression von EphB6 keinen Einfluss auf die Metastasierungs-relevanten Eigenschaften der A375-Melanomzellen hatte, führte die erhöhte Proteinbiosynthese von EphB4 zu einer verminderten Migration der Zellen im intakten Zellverband. Des Weiteren bewirkte EphB4 eine verstärkte Adhäsion der A375-Zellen an das Extrazellularmatrix-Protein Fibronektin, wodurch die Migration dieser Melanomzellen, im Sinne einer Metastasierung, zusätzlich beeinträchtigt wird. Die erhöhte mRNA-Expression des Liganden EphrinB2 in den A375-Melanomzellen führte zu einer verminderten chemotaktischen Migration der Zellen.
Um den Einfluss von EphB4 auf die Tumorprogression und Tumorangiogenese beim malignen Melanom in vivo untersuchen zu können, wurde im Rahmen der vorliegenden Arbeit ein murines Xenograft-Modell mit subkutanen A375 pIRES- bzw. A375 EphB4-Tumoren etabliert. Die Auswertung der Tumorvolumina sowie der [18F]FDG-, [18F]FMISO- und Hoechst 33342-Anreicherung in den Tumoren ergab, dass die erhöhte EphB4-Proteinbiosynthese zu tendenziell kleineren Tumoren führte. Diese waren zudem signifikant schwächer perfundiert und wiesen im Inneren größere hypoxische Areale auf als die A375 pIRES-Tumoren. Somit zeigte EphB4 neben seiner antimetastasischen Wirkung in vitro auch eine antitumorigene Wirkung in vivo, wobei letztere möglicherweise auf eine Störung der Gefäßbildung zurückzuführen ist. Da eine adäquate Blutversorgung der Tumoren für die Metastasierung von Tumorzellen von Bedeutung ist, könnte dies auch auf eine antimetastatische Wirkung in vivo hinweisen.
Des Weiteren wurde im Rahmen der vorliegenden Arbeit ein neuer, 18F-markierter EphB4 Kinaseinhibitor (Verbindung [18F]2) getestet. Dieser zeigte im A375-pIRES/EphB4-Tumor-Xenograft-Modell eine geringe Tumoranreicherung, die von der EphB4-Proteinbiosynthese in den Tumoren unabhängig war. Darüber hinaus kam es zur schnellen hepatobiliären Ausscheidung von Verbindung [18F]2, was deren radiopharmazeutischer Anwendung im Wege steht.
SCHLUSSFOLGERUNG UND AUSBLICK
Insbesondere die erhöhte Proteinbiosynthese von EphB4 hatte im Falle der untersuchten A375-Melanomzellen zu einer verminderten Migration und zu einer erhöhten Adhäsion der Zellen geführt. Somit konnte im Rahmen der vorliegenden Arbeit gezeigt werden, dass EphB4 die Metastasierungs-relevanten Eigenschaften dieser Zellen in vitro beeinträchtigt. Darüber hinaus deuteten Untersuchungen am A375-pIRES/EphB4-Tumor-Xenograft-Modell auf eine antitumorigene Wirkung des EphB4-Rezeptors in vivo hin. Aufgrund dessen muss der anfänglich formulierten Hypothese, dass EphB4 im Zusammenspiel mit seinem Liganden EphrinB2 die Progression und Metastasierung des malignen Melanoms fördert, widersprochen werden. Eine regulative Beteiligung des Kinase-defizienten Rezeptors EphB6, der ebenfalls zur Bindung von EphrinB2 fähig ist, konnte im Rahmen der vorliegenden Arbeit nicht sicher nachgewiesen werden.
Allerdings ergeben sich aufgrund der Expression der Rezeptoren EphB4 und EphB6 sowie deren Ligand EphrinB2 sowohl auf den untersuchten Melanomzellen als auch auf den verschiedenen Tumor-assoziierten inflammatorischen Zellen interessante Interaktionsmöglichkeiten dieser Zellen. Deren Einfluss auf die Progression und Metastasierung des malignen Melanoms sollte in weiterführenden Experimenten untersucht werden.
Das im Rahmen der vorliegenden Arbeit etablierte A375-pIRES/EphB4-Tumor-Xenograft-Modell ermöglicht die In vivo-Charakterisierung von Radiotracer, die gegen Rezeptor-Tyrosinkinasen im Allgemeinen oder aber selektiv gegen EphB4 gerichtet sind. Da Verbindung [18F]2 eine ungünstige Pharmakokinetik zeigte, was wahrscheinlich auf die hohe Lipophilie des Radiotracers zurückzuführen ist, sollten sich zukünftige Untersuchungen mit der chemischen Modifikation dieser Verbindung beschäftigen, mit dem Ziel die Lipophilie und damit die biologische Halbwertszeit des Radiotracers zu verbessern. Zusätzlich sollte die Entwicklung von Radiotracern auf der Basis von löslichen Eph-Rezeptoren und Ephrinen (sEph bzw. sEphrin) weiter vorangetrieben werden.
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Addison, M. E. "Investigating the roles of cell identity regulation and Eph/ephrin signalling in early hindbrain segmentation." Thesis, University College London (University of London), 2017. http://discovery.ucl.ac.uk/1559130/.
Full textAbstract:
During development of the vertebrate hindbrain, the neuroepithelium becomes subdivided into seven morphological units, known as rhombomeres. It is necessary that rhombomeres have sharp, well-defined boundaries, which are established from initially rough gene expression domains during early hindbrain segmentation. The mechanisms involved in early hindbrain segmentation that create sharp segment borders are not well understood. There is evidence to suggest that both regulation of cell identity and Eph/ephrin-mediated cell sorting are required for establishing sharp interfaces between rhombomeres. This thesis investigates the extent to which identity regulation contributes to hindbrain border sharpening in zebrafish. I created a new zebrafish reporter line by CRISPR/Cas9-mediated reporter integration at the egr2b locus, which enables cell identity and cell intermingling to be visualised in live embryos during border sharpening. This new reporter line indicates a contribution of cell identity regulation to border sharpening. I also demonstrate that the contribution of cell identity switching to border refinement is greater in cases where cell intermingling is increased by perturbed Eph/ephrin signalling. To help study the role of Eph/ephrin signalling in border sharpening, I have also created a novel EphrinB3b mutant. The thesis also investigates the mechanisms of identity regulation by community effects and discusses their contribution to border refinement by identity respecification; community effects are suspected to help overcome noise in early gene induction through spatial averaging and thus help establish regions of homogeneous gene expression. The ability of candidate genes to non cell-autonomously regulate the identity of neighbouring cells in the hindbrain is investigated. Of particular focus is the potential involvement of retinoic acid (a morphogen involved in specification of anteroposterior identity) and segmentally-expressed Cyp26 enzymes involved in its metabolism. Analysis of mosaic embryos is used to compare the ability of isolated cells and clustered groups of cells to maintain a different identity to their surroundings. Results presented here are consistent with segmental regulation of retinoic acid signalling contributing to border sharpening.