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1
Tuzi, Nadia Lucia. "The Eph growth factor receptor." Thesis, Open University, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.294878.
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Bovenkamp, Diane Elizabeth. "Eph receptor tyrosine kinases, nervous system development and angiogenesis, cloning and characterization of Eph receptors from zebrafish and mice." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0021/NQ54056.pdf.
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Soskis, Michael. "A Chemical-Genetic Study of EphB Receptor Tyrosine Kinase Signaling in the Developing Nervous System." Thesis, Harvard University, 2012. http://dissertations.umi.com/gsas.harvard:10525.
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EphB receptor tyrosine kinases regulate cell-cell contacts throughout nervous system development, mediating processes as diverse as axon guidance, topographic mapping, neuronal migration and synapse formation. EphBs bind to a group of ligands, ephrin-Bs, which span the plasma membrane, thus allowing for bidirectional signaling between cells. Since EphBs are capable of multiple modes of signaling, and since they regulate numerous interdependent stages of development, it has been challenging to define which signaling functions of EphBs mediate particular developmental events. To overcome this hurdle, we developed an approach combining chemical biology with genetic engineering to reversibly inhibit EphB receptors in vivo. By mutating a residue in the receptor’s ATP-binding pocket, we rendered its kinase activity sensitive to reversible inhibition by PP1 analogs that do not inhibit wild type receptors. We engineered triple knockin mice bearing this mutation in which the kinase activity of EphB1, EphB2, and EphB3 can be rapidly, reversibly, and specifically blocked. Since we are able to block the kinase activity of EphBs while leaving their scaffolding and reverse signaling capabilities intact, we can precisely isolate the role of the kinase domain. In addition, acute inhibition can circumvent the developmental compensation that may occur after genetic mutations and can even allow the controlled study of EphBs in the mature brain and in disease models. Using these mice, termed analog-sensitive EphB triple knockin (AS-EphB TKI) mice, we demonstrate a requirement for the kinase-dependent signaling of EphBs in the collapse of retinal ganglion cell growth cones in vitro and the guidance of retinal axons at the optic chiasm in vivo. In addition, we show that the formation of several cortical axon tracts, including the corpus callosum, requires EphB tyrosine kinase signaling. In contrast, we find that steps in synapse development that are thought to be EphB-dependent occur normally when the kinase activity of EphBs is inhibited. We conclude that a cardinal in vivo function of EphB signaling, the ability to mediate axon guidance via growth cone repulsion, requires the tyrosine kinase activity of EphBs, while the development of functional excitatory synapses is independent of EphB tyrosine kinase activity.
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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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Scully, Audra L. "Isolation and characterization of Dek, a Drosophila Eph receptor protein tyrosine kinase /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 1998. http://wwwlib.umi.com/cr/ucsd/fullcit?p9904821.
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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/.
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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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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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Schaupp, Andreas. "Eph receptor clustering is the central integrator in eliciting graded Kinase-dependent signaling responses." Diss., lmu, 2012. http://nbn-resolving.de/urn:nbn:de:bvb:19-147651.
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Karam, Sana. "Mechanisms of pattern formation in the developing cerebellum : role for Eph receptor gene family /." Thesis, Connect to this title online; UW restricted, 2001. http://hdl.handle.net/1773/10557.
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Sabet, Ola [Verfasser], Philippe [Akademischer Betreuer] Bastiaens, and Roland [Akademischer Betreuer] Winter. "The spatial organization of EPH receptor tyrosine kinase activity / Ola Sabet. Betreuer: Philippe Bastiaens. Gutachter: Roland Winter." Dortmund : Universitätsbibliothek Dortmund, 2013. http://d-nb.info/1100168591/34.
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Schaupp, Andreas [Verfasser], and Rüdiger [Akademischer Betreuer] Klein. "Eph receptor clustering is the central integrator in eliciting graded Kinase-dependent signaling responses / Andreas Schaupp. Betreuer: Rüdiger Klein." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2012. http://d-nb.info/1025635159/34.
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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.
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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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Kaneko, Megumi. "Cloning and characterization of an Eph receptor and its ligand ephrin in the developing primary olfactory pathway of the moth Manduca sexta." Diss., The University of Arizona, 2003. http://hdl.handle.net/10150/280361.
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This dissertation investigates possible roles of the Eph family receptor tyrosine kinases and their ligand ephrins in the developing primary olfactory pathway in the moth Manduca sexta. The Manduca homologs of the Eph receptor (MsEph) and ephrin ligand (MsEphrin) are most closely related to Drosophila Eph and ephrin, respectively, and biochemical assays establishes MsEphrin as a functional ligand for MsEph. In situ labeling with Fc-fusion probes in which IgG Fc was linked to the extracellular domain of MsEph and MsEphrin reveals that both Eph receptors and ephrins are expressed on olfactory receptor cell (ORC) axons during their ingrowth to the primary brain center, the antennal lobe (AL). Eph receptors and ephrins are differentially distributed among identifiable glomeruli such that glomeruli with high receptor staining show little ligand staining and vice versa, indicating a complementary Eph/ephrin expression on subsets of ORC axons innervating particular set of glomeruli. Their expression appears upregulated once ORC axons reach the region where axon sorting occurs. In contrast, neither Eph receptors nor ephrins are detectable in intrinsic components of the AL. In vitro, MsEph and MsEphrin proteins, when present homogeneously in the substratum, inhibit neurite outgrowth from olfactory epithelial explants. Moreover, in patterned substrata, neurites growing on the standard substratum avoid extending onto the substratum containing MsEphrin proteins, with behaviors characterized by turning or stopping at the border. These in vitro observations indicate that MsEphrin can act as an inhibitory/repulsive cue for ORC axons. Based on these in situ and in vitro results, I hypothesize that Eph-ephrin signaling mediates segregation of Eph-positive axons from ephrin-positive axons through repulsive inter-axonal interactions. Simultaneous labeling of ALs for Eph/ephrin and fasciclin II, a homophilic cell adhesion molecule, reveals that fasciclin-positive glomeruli are distributed in a partially overlapping pattern with Eph- or ephrin-positive glomeruli. Thus, Eph receptors and ephrins, together with fasciclin II and other adhesive/repulsive cues, might constitute a combinatorial molecular system in which sorting of ORC axons is determined by the balance of adhesive and repulsive forces.
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Segura, Castell Mónica. "Peripheral blood biomarkers in Psychiatric Diseases." Doctoral thesis, Universitat Internacional de Catalunya, 2012. http://hdl.handle.net/10803/83727.
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Actually, there is a strong incidence of psychiatric diseases, representing a 13% of total burden diseases and 450 million of people affected. The etiology of psychiatric diseases remains unknown. However, scientific evidences suggest a maldevelopment of nervous system (NS). The diagnosis is inaccurate, and international manuals (ICD-10 and DSM-IV) identify pathologies according to a list of symptoms but no underlying biological cause of disease. The aim of the thesis is to identify potential biomarkers -related to the development of NS- in peripheral blood of psychiatric patients diagnosed as different mental diseases, such as autism spectrum disorders (ASD), schizophrenia and bipolar disorders. It is intended to contribute with the improvement of diagnostic, prognostic and treatment of subjects.
The thesis is divided into 4 chapters: 1) study of neurotrophins in ASD, where the results show the relationship of this family of molecules with the disease, 2) study of Latrophilin-3 (LPHN3) in the TEA, which was obtained in association with lower cognitive level of ASD, 3) study of the Eph-receptor A4 in the pathology of schizophrenia and bipolar disorder, results of which show no association, and finally 4) study of Ankyrin-3 (ANK3) in schizophrenia and bipolar disorder, which shown a relationship with bipolar disorder but not with schizophrenia.Actualment, hi ha una forta incidència de les patologies psiquiàtriques, representant un 13% del total de les malalties i 450 milions de persones afectades. L’etiologia de les patologies psiquiàtriques és desconeguda. Tot i així, evidències científiques suggereixen un mal desenvolupament del sistema nerviós (SN). El diagnòstic és poc precís, i els manuals internacionals (ICD-10 i DSM-IV) identifiquen les patologies d’acord a un llistat de símptomes, però sense cap causa biològica subjacent de la patologia. L’objectiu de la tesi és la identificació de biomarcadors potencials –relacionats en el desenvolupament del SN- en sang perifèrica de pacients diagnosticats amb diferents patologies mentals, com ara els trastorns de l’espectre autista (TEA), esquizofrènia i desordres bipolars. És pretén contribuir amb la millora del diagnòstic, el pronòstic i el tractament de les persones que les pateixen. La tesi s’estructura en 4 capítols: 1) estudi de les neurotrofines en els TEA, on els resultats evidencien la relació d’aquesta família de molècules amb la patologia, 2) estudi de la Latrofilina-3 (LPHN3) en els TEA, on s’ha obtingut associació amb el nivell cognitiu més baix dels TEA, 3) estudi del receptor EPH A4 en les patologies d’esquizofrènia i desordres bipolars, resultats del qual no mostren associació i, per últim 4) estudi de la Ankirina-3 (ANK3) en l’esquizofrènia i els desordres bipolars, en el qual si que es troba una relació amb els desordres bipolars, però no amb l’esquizofrènia.
Actualmente, hay una fuerte incidencia de las patologías psiquiátricas, representando un 13% del total de las enfermedades y 450 millones de personas afectadas. La etiología de las patologías psiquiátricas es desconocida. Aún así, evidencias científicas sugieren un mal desarrollo del sistema nervioso (NS). El diagnóstico es poco preciso, y los manuales internacionales (ICD-10 y DSM-IV) identifican las patologías de acuerdo a un listado de síntomas, pero sin ninguna causa biológica subyacente de la patología. El objetivo de la tesis es la identificación de biomarcadores potenciales –relacionados con el desarrollo del SN- en sangre periférica de pacientes diagnosticados con diferentes patologías mentales, como son los trastornos del espectro autista (TEA), esquizofrenia y desordenes bipolares. Se pretende contribuir en la mejora del diagnóstico, el pronóstico i el tratamiento de las personas que las padecen. La tesis se estructura en 4 capítulos: 1) estudio de las neurotrofinas en los trastornos del espectro autista (TEA), en el cual los resultados evidencian la relación de esta familia de moléculas con la patología, 2) estudio de la Latrofilina-3 (LPHN3) en los TEA, donde se ha obtenido una asociación con el nivel cognitivo más bajo de los TEA, 3) estudio del receptor EPH A4 en las patologías de la esquizofrenia y los desordenes bipolares, resultados del cual no muestran asociación y, por último 4) estudio de la Ankirina-3 (ANK3) en la esquizofrenia y los desordenes bipolares, en el cual si que se ha encontrado una relación con los desordenes bipolares, pero no con la esquizofrenia.
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Eriksson, Oskar. "Studies on Tissue Factor with Focus on Cell Signaling and Cancer." Doctoral thesis, Uppsala universitet, Koagulation och inflammationsvetenskap, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-245807.
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This thesis have explored the functions of the protein Tissue Factor (TF), which together with its ligand coagulation factor VII/VIIa (FVII/FVIIa) forms a proteolytic complex that functions in initiation of blood coagulation and activation of cell signaling. In paper I, the mechanisms behind the observation that TF/FVIIa signaling protects cells from apoptosis were further investigated. Using cell culture models, we found that antiapoptotic signaling by TF/FVIIa requires signaling by the Insulin-like growth factor I receptor (IGF-1R), as synthetic IGF-1R inhibitors and IGF1-R siRNA knock-down abolished the antiapoptotic effect of FVIIa. Furthermore, the IGF-1R translocated to the cell nucleus after FVIIa stimulation, implying a role in regulation of gene expression. Papers II and III describe the discovery that the Eph tyrosine kinase receptors EphB2 and EphA2 are proteolytically cleaved directly by TF/FVIIa. By using mass spectrometry and N-terminal Edman sequencing, the exact cleavage site was identified after a conserved arginine residue in the EphA2/EphB2 ligand binding domains, in agreement with the cleavage preferences of FVIIa. TF and EphA2/EphB2 co-localized in cancer cell lines and FVIIa potentiated ligand-dependent Eph signaling by increasing cytoskeletal remodeling and cell repulsion, demonstrating a novel proteolytical event that modulates Eph receptor signaling. In paper IV, expression of TF was investigated in colorectal cancer in both the stromal and tumor cell compartments by immunohistochemistry using an anti-TF-antibody developed and validated by the Human Protein Atlas project. In normal large intestine, TF was strongly expressed in the innermost pericryptal sheath cell layer lining the epithelium, in a cell population distinct from intestinal pericryptal myofibroblasts. We evaluated TF expression in two colorectal cancer materials, and found that TF was variably present in both the stromal and tumor cell compartments. TF expressed by pericryptal sheath cells was progressively lost after the adenoma-to-carcinoma transition and was a strong predictor of survival in rectal but not colon cancer patients independently of disease stage, histological tumor grade and age. In summary, this thesis demonstrates novel signaling mechanisms for the TF/FVIIa complex, and provides evidence of a hitherto unknown role of TF expressed by a specific population of stromal cells in colorectal cancer.
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Danielson, Kathryn, and Sean Ustic. "Characterization of the Signaling Properties of FLAG Tagged EP2 and EP4 Prostanoid Receptors." The University of Arizona, 2009. http://hdl.handle.net/10150/623990.
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Class of 2009 AbstractOBJECTIVES: To develop a novel characterization system utilizing immunofluorescent FLAG tagged EP2 and EP4 receptors to assist in the explanation of their unique cell signaling properties for exploitation in future drug development design. METHODS: Plasmids were obtained and isolated that contained cDNAs encoding FLAG-tagged EP2 and EP4 receptors for transient expression in HEK-293 cells. The sequences of these plasmids were confirmed by restriction enzyme analysis and DNA sequencing. Transfected cells were treated with vehicle, PGE2 or forskolin to assess appropriate receptor functionality based on cAMP induction. RESULTS: The two PGE2 receptor subtypes, EP2 and EP4, are similar in their activation of adenylyl cyclase (AC) and subsequent up regulation of cAMP production. These receptors differ, however, in that EP2 more efficiently stimulates cAMP production and EP4 signaling involves the activation of phosphatidylinositol 3-kinase (PI3K) and extracellular signal related kinases (ERKs). The PGE2- treated cells responded as predicted with intracellular production of cAMP, with the EP2 receptor responding more efficiently than the EP4 receptor. CONCLUSIONS: The intent is for these cells to be used as a novel assay system for the development of future selective EP2 and EP4 agonists. This research could potentially benefit in selectively targeting EP2 or EP4 pathways linked to prevalent ailments such as pain, fever, inflammation, possibly cancer or bone growth.
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Rodenas-Ruano, Alma Ileana. "EphrinB3 and Eph Receptors Regulate Hippocampal Synaptic Function." Scholarly Repository, 2008. http://scholarlyrepository.miami.edu/oa_dissertations/34.
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EphrinB ligands and their Eph receptor tyrosine kinases are known to regulate excitatory synaptic functions in the hippocampus. In the CA3-CA1 synapse, ephrinB ligands are localized to the post-synaptic membrane, while their cognate Eph receptors can be expressed in both pre-and post-synaptic membranes. Previous studies show that interaction of ephrinB molecules with Eph receptors leads to changes in long-term potentiation (LTP), suggesting that reverse signaling through postsynaptic ephrinBs may be required for learning and memory. Our collaborative studies demonstrate that the cytoplasmic domain of ephrinB3, and hence reverse signaling, is not required for ephrinB-dependent learning and memory tasks or for LTP of these synapses. We demonstrate that ephrinB3 null mutants show changes in several synaptic proteins including reduced levels of NMDA receptor subunits. These abnormalities are not observed in ephrinB3lacZ reverse signaling mutants, supporting an Eph receptor forward signaling role for ephrinB3 in these processes. NMDA receptors are important in regulating synaptic functions and plasticity in the adult hippocampus, and Eph receptors have been shown to cluster NMDA receptors to the cell membrane. These studies show that ephrinB3 interacts with EphA4 to regulate plasma membrane levels of NR1 in Cos-1 cells and primary hippocampal neurons. In the absence of ephrinB3, NR1 levels are decreased in synaptosomal membranes, increased in microsomal tissues, but not changed in total extracts. This suggests that ephrinB3 regulates NR1 levels through protein trafficking and not gene transcription. Analysis of protein trafficking confirmed that ephrinB3 specifically interacts with EphA4 receptor to regulate NR1 exocytosis but not endocytosis in both transfected Cos-1 cells and primary hippocampal neurons. We postulate that ephrin-Eph receptor interactions are important mediators of synaptic formation and function, in part, through their regulation of NMDA receptors in the hippocampal synapse. In addition, we find that both ephrinB3KO and ephrinB3lacZ mice show an increased number of excitatory synapses, demonstrating a cytoplasmic-dependent reverse signaling role of ephrinB3 in regulating synapse number. Together, these data suggest that ephrinB3 may act like a receptor to transduce reverse signals to regulate the number of synapses formed in the hippocampus, and that it likely acts to stimulate forward signaling through Eph receptors to modulate NMDA receptor trafficking, LTP and learning.
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Reschke, Cristina Ruedell. "RECEPTORES EP1 E EP3 MODULAM AS CRISES EPILÉPTICAS INDUZIDAS POR PENTILENOTETRAZOL E ÁCIDO CAÍNICO EM CAMUNDONGOS." Universidade Federal de Santa Maria, 2013. http://repositorio.ufsm.br/handle/1/3852.
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Coordenação de Aperfeiçoamento de Pessoal de Nível SuperiorEpilepsy is one of the most common neurologic disorders. It has been suggested that seizures may be facilitaded by inflammation. PGE2 is one of the most important inflammatory mediators, and facilitates pentylenetetrazol (PTZ)-induced seizures by stimulating EP1 and EP3 receptors. However, up to the present moment, no study has investigated whether EP1 and EP3 receptors blocking attenuate seizures induced by convulsants other than PTZ. It is also unknown whether Na+,K+-ATPase activity alterations are involved in such an effect. Therefore, in the current study we investigated whether EP1 and EP3 ligands (agonists and antagonists) modulate PTZ- and kainic acid (KA)-induced seizures, and whether alterations in Na+,K+-ATPase activity mediate such a protective effect, in mice. EP1 and EP3 antagonists (ONO-8713 and ONO-AE3-240, respectively, 10 Og/kg, s.c.) attenuated PTZ (60 mg/kg, i.p.)- and KA (20 mg/kg, i.p.)-induced seizures. The respective agonists (ONO-DI-004 and ONO-AE-248, 10 Og/kg, s.c.) facilitated seizures in both acute models, and at noneffective doses, prevented the protective effects of the antagonists. Animals injected with PTZ presented decreased Na+,K+-ATPase activity in the cerebral cortex and hippocampus. On the other hand, animals injected with KA presented increased Na+,K+-ATPase activity in the same cerebral structures at the end of the experiment. These divergent findings suggest that alterations in Na+,K+-ATPase activity in both acute models depends on the convulsant agent used and make difficult to establish a relationship between Na+,K+-ATPase activity and seizure development. Moreover, EP1 and EP3 antagonists administration abolished Na+,K+- ATPase activity alterations induced by PTZ and KA, in such a way that these alterations seem to be related more to the presence of ictal phenomenon itself than to the seizure induction mechanisms. Notwithstanding, the currrent results clearly show that EP1 and EP3 receptors might constitute novel targets for anticonvulsants development, since EP1 and EP3 decreased seizures, regardless of the convulsant agent used.
A epilepsia é uma das disfunções neurológicas mais comuns. Tem sido sugerido que as crises epilépticas podem ser facilitadas pela ocorrência de inflamação. A PGE2 é um dos mediadores inflamatórios mais importantes que, agindo por meio dos receptores EP1 e EP3, facilita as convulsões induzidas por pentilenotetrazol (PTZ). Contudo, até a presente data, nenhum estudo investigou, de maneira sistêmica, se a ativação ou bloqueio de receptores EP1 e EP3 facilitam as convulsões induzidas por outros agentes; tampouco se alterações na atividade da Na+,K+-ATPase estão envolvidas nesse efeito. Assim, no presente estudo, investigamos se ligantes (agonistas e antagonistas) de receptores EP1 e EP3 modificam as crises induzidas por PTZ e ácido caínico (KA), e se tais efeitos estão associados a alterações na atividade da enzima Na+,K+-ATPase, em camundongos. Os antagonistas EP1 e EP3 (ONO-8713 e ONO-AE3-240, respectivamente, 10 Og/Kg, s.c.) atenuaram as convulsões induzidas por PTZ (60 mg/Kg, i.p.) e KA (20 mg/Kg). Os seus respectivos agonistas (ONO-DI-004 e ONO-AE-248 de 10 Og/Kg, s.c.) facilitaram as convulsões em ambos modelos agudos de crises epilépticas e, em doses não efetivas para gerar crises, preveniram os efeitos dos antagonistas. Os animais submetidos à administração de PTZ apresentaram, ao final do experimento, a atividade Na+,K+-ATPásica diminuída no córtex cerebral e hipocampo. Por outro lado, animais tratados com KA apresentaram um aumento na atividade Na+,K+-ATPásica nestas mesmas estruturas, que se correlacionou positivamente com a vigência de status epilepticus no momento do sacrifício. Os achados divergentes no que diz respeito à alteração da atividade da Na+,K+-ATPase nos dois modelos de crises agudas sugere que tais alterações estejam relacionadas ao tipo de agente convulsivante utilizado, e dificultam estabelecer, de forma inequívoca, uma relação entre atividade desta ATPase e sensibilidade à crises agudas. Ademais, a administração de antagonistas EP1 e EP3 aboliu as alterações da atividade da Na+,K+-ATPase induzidas tanto por PTZ como por KA, de tal forma que estas parecem estar mais associadas com o fenômeno ictal em si, do que com os mecanismos de indução da crise. Contudo, os resultados mostram de forma clara que os receptores EP1 e EP3 podem se constituir possíveis novos alvos para o desenvolvimento de drogas antiepilépticas, pois antagonistas EP1 e EP3 diminuíram as crises, independente do agente convulsivante utilizado.
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Thibodeau, Jean-François. "Prostaglandin E2 Signaling Through Kidney EP1 and EP4 Receptors; Implications in Diabetes and Hypertension." Thesis, Université d'Ottawa / University of Ottawa, 2015. http://hdl.handle.net/10393/32749.
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Chronic kidney disease is defined as the appearance of kidney functional or structural injury. Cyclooxygenase and prostaglandin E2 have been implicated in the pathogenesis of diabetic nephropathy, the leading cause of chronic kidney disease. Beneficial in certain settings, inhibition of the cyclooxygenase pathway can however be detrimental in patients with compromised cardiac or renal function. Moreover, the quest for new therapies to treat diabetic nephropathy is hampered by the lack of appropriate rodent models. This doctoral thesis is a culmination of three studies, the first to determine the role of the prostaglandin E2 EP1 receptor in diabetic nephropathy, the second to elucidate the vascular prostaglandin E2 EP4 receptor’s role in hypertension and lastly to establish and characterise a novel mouse model of diabetic nephropathy. The goal being to uncover new therapeutic avenues for the treatment of CKD, its causes and/or complications.
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Plaza, Almolda Judith. "Validación preclínica del receptor EP2 mastocitario como diana terapéutica antiasmática." Doctoral thesis, Universitat Autònoma de Barcelona, 2016. http://hdl.handle.net/10803/385023.
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El asma es una enfermedad crónica de las vías respiratorias cuyo abordaje terapéutico actual no frena su progresión, y en ocasiones no revierte la sintomatología. El análisis de mecanismos endógenos de protección puede resultar en la identificación de nuevas dianas farmacológicas efectivas. Los estudios preclínicos realizados hasta ahora en nuestro laboratorio junto con evidencia clínica y básica de otros grupos, sugirieron la hipótesis de que la activación selectiva del receptor prostanoide EP2 de le la PGE2 inhibe la actividad mastocitaria, y consecuentemente reduce el proceso patológico respiratorio inducido en ratones por exposición a aeroalérgenos, lo cual puede suponer una estrategia terapéutica antiasmática sinérgica a la del bloqueo mastocitario por otros mecanismos. Con el fin de verificarla, se planteó el primer objetivo: evaluar la función selectiva del receptor prostanoide EP2 en la modulación de la actividad mastocitaria, y en la reactividad respiratoria a aeroalérgenos. Se observó en poblaciones mastocitarias fenotípicamente diversas la inhibición de los mastocitos mediante dos agonistas EP2 químicamente distintos. Inhibición que también se demostró in vivo en un modelo de asma en ratón expuesto a aeroalérgenos de ácaros del polvo. El efecto inhibitorio sobre los mastocitos se acompañó de la prevención de la hiperreactividad bronquial, y apuntaba hacia un posible control del proceso inflamatorio broncovascular. La naturaleza protectora del agonismo EP2 se confirmó al administrar antagonistas en modelos in vitro e in vivo. Estos desencadenaron una sobreactividad de los mastocitos que agravó la alteración respiratoria. Todo ello sugiere que el efecto beneficioso de la PGE2 descrito en estudios clínicos experimentales, es consecuencia de la mediación del receptor EP2 mastocitario. El segundo objetivo planteado fue el desarrollo de un ratón transgénico que sobreexpresase el receptor EP2 específicamente en los mastocitos con el fin de disponer de una herramienta experimental para evaluar la relevancia relativa del receptor EP2 en la protección inducida por PGE2. Se logró con éxito insertar el gen de EP2 y sobreexpresarlo, demostrándose en algunos ensayos in vitro que los mastocitos aislados de los ratones transgénicos EP2 respondían con un incremento en el bloqueo. Sin embargo no se pudo confirmar in vivo el efecto beneficioso atribuible a la presencia de un mayor número de receptores EP2, probablemente debido a las fluctuaciones compensatorias en la expresión de otros genes relacionados. El desarrollo de la colonia transgénica de EP2 requiere de una caracterización más exhaustiva para investigar la importancia del EP2 mastocitario en la prevención de la alteración respiratoria. Finalmente, en un tercer objetivo se planteó evaluar comparativamente la efectividad preclínica de la inhibición mastocitaria mediante agonismo EP2 y bloqueo de la IgE con anticuerpos monoclonales, en modelos de alergia in vivo e in vitro. Se demostró en un modelo de anafilaxia cutánea in vivo y en poblaciones mastocitarias in vitro que el agonismo EP2 y la neutralización de la IgE ejercen un bloqueo de los mastocitos cuantitativamente equiparable. Para posteriores estudios de la potencial sinergia o complementariedad terapéutica entre ambos mecanismos en las vías respiratorias de ratones sensibilizados, se desarrolló con éxito un innovador modelo de anafilaxia respiratoria pasiva (PRA) en ratones transgénicos que expresaban el receptor humano de la IgE. Los resultados obtenidos en esta tesis permiten concluir que la activación del eje “PGE2 - EP2 mastocitario – asma” supone un mecanismo endógeno de protección frente a la disfunción de las vías respiratorias inducida por aeroalérgenos. Los nuevos modelos experimentales in vivo desarrollados en este proyecto permitirán caracterizar el mecanismo antiasmático, y confirmar la condición de diana terapéutica del receptor EP2, o de otras moléculas que formen parte de ese eje.Asthma is a chronic disease of the airways whose therapeutic approach does stop progression, and occasionally does not revert the symptoms. Studying endogenous protective mechanisms may lead to the identification of newly effective pharmacological targets. Preclinical studies carried out in our laboratory together with clinical and basic evidence from other groups, suggested the following hypothesis: selective activation of the EP2 prostanoid receptor of PGE2 inhibits mast cell activity, and consequently reduces the pathological respiratory process induced in mice exposed to aeroallergens, and this may arise as an antiasthmatic therapeutic strategy synergic to mast cell blockade through other mechanisms. In order to check it, the first objective was to assess the selective function of the EP2 prostanoid receptor as a mast cell activity and aeroallergen-induced airways reactivity modulator. Phenotypically distinct mast cell populations were shown to be inhibited by means of chemically different agonists. Such inhibition was also seen in vivo in the asthma murine model induced through exposure to house dust mite aeroallergens. Mast cells inhibition was paralleled by a prevention of the airway hyperreactivity, and possibly a control of the bronchovascular inflammatory process. The protective nature of EP2 agonism was confirmed through the administration of antagonists in in vitro and in vivo models, where mast cells hyperreleasability and worsening of airways disorder were observed. All in all, this suggested that the described benefit of PGE2 in clinical experimental settings is mediated by the mast cells EP2 receptor. The second objective was to develop a transgenic mouse overexpressing the EP2 receptor specifically on the mast cells surface as an experimental tool to evaluate the relative relevance of EP2 in PGE2-driven protection. The EP2 gene was successfully inserted and overexpressed, owing to an increased blockade of the activity of mast cells isolated from transgenic mice. However, the beneficial effect attributable to a higher number of EP2 receptors could not be seen in vivo, possibly due to the compensatory fluctuation of related genes. The developed EP2 transgenic mice require a further characterization in order to investigate the role of mast cell EP2 in prevention of the respiratory dysfunction. Finally, the third objective was to compare the preclinical effectiveness of EP2 agonism versus anti-IgE using monoclonal antibodies, in allergy models in vivo and in vitro. Both, EP2 agonism and IgE neutralization exerted a quantitatively similar effect on mast cells population in vitro and in a model of cutaneous anaphylaxis in vivo. In order to further study the synergy or therapeutic complementarity between both mechanisms, an innovative model of passive respiratory anaphylaxis (PRA) was successfully established in transgenic mice expressing the human IgE receptor. The results of this thesis brought us to conclude that the “PGE2- mast cell EP2-asthma” axis is an endogenous protective mechanism against the airway dysfunction caused by aeroallergens. The new in vivo experimental models developed in this project, will allow to characterize the antiasthmatic mechanism, and confirm the EP2, or other molecules along the axis, as therapeutic targets.
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Milne, S. A. "Further characterisation of the EP4-receptor subtype." Thesis, University of Edinburgh, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.657821.
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The Rabbit Jugular vein (RJV) and Pig Saphenous vein (PSV) were used to further characterise the EP4-receptor. Organ bath studies with an array of EP-agonists and antagonists produced data which confirmed the PSV as an EP4-receptor containing preparation and that the RJV, after comparing agonist potency profiles, also contained the EP4-receptor subtype. The agonist potency profile obtained was PGF2 ≥ 11-deoxy PGE1 = 16, 16-dimethyl PGE2 > butaprost >> AH13205. The Chinese Hamster Ovary (CHO) cell line was used as an alternative to the smooth muscle cells to study the EP4-receptor subtype. Studies using the effects of EP-agonists and an EP-antagonist AH23848 on cyclic AMP production confirmed that the cell line expressed the EP4-receptor. Binding studies were attempted with CHO cell membranes but were inconclusive. Mononuclear phagocytic cells (monocytes) originate in the bone marrow, are resident in the blood and migrate to tissues where they differentiate into macrophages. Monocyte/macrophages are phagocytic cells which release many substances including reactive oxygen metabolites such as superoxide anion and cytokines such as IL-1α and IL-1β when stimulated. PGE2 has been shown to have an inhibitory effect on monocytes and the characterisation of the EP-receptor subtype(s) was attempted and the second messenger pathway was investigated. In human monocytes tested with an array of EP-agonists and antagonists, cAMP measurements indicated the involvement of the EP4 receptor giving a similar agonist potency profile as the smooth muscle studies. Further studies measuring IL-1α and IL-1β showed PGE2 to have an inhibitory effect but were unable to classify the receptor involved. Superoxide anion generation measurement from the human monocyte showed PGE2 to have an inhibitory effect in the human monocyte although it did not indicate which EP-receptor was involved. Second messenger studies using this preparation showed cAMP to be involved in PEG2 mediated inhibition of superoxide anion generation.
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Inazumi, Tomoaki. "Roles of Prostaglandin EP4 Receptor in Adipocytes." 京都大学 (Kyoto University), 2014. http://hdl.handle.net/2433/188727.
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Attwood, Benjamin Kenneth. "Investigating the role of Eph receptors and their molecular partners in anxiogenesis." Thesis, University of Leicester, 2016. http://hdl.handle.net/2381/37925.
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Psychological stress leads to the enhancement of anxiety and can trigger a variety of psychiatric disorders. The mechanisms by which stress regulates anxiety are unclear. Eph receptors and their ligands, Ephrins, are attractive candidates to consider due to their multifaceted functions and high expression in the limbic system. Eph/Ephrins have been shown to regulate both functional and structural neuronal plasticity as well as hippocampus-dependent behaviour in mice. Thus, the aim of this study was to investigate the roles of Eph/Ephrins in the hippocampus and the amygdala and their interaction with molecular partners upon stress. First, I found that plasmin, a stress-related protease, cleaves EphA4 with high specificity. Mass spectrometry and bioinformatic analyses revealed the cleavage site is located within the fibronectin-like repeats of EphA4. EphA4, highly expressed in the hippocampus, interacts with EphrinB2. Following stress their interaction increases, as does the expression of EphrinB2. Studies in mice in which EphrinB2 was conditionally deleted in forebrain neurons demonstrated that EphrinB2 signalling is critical to the formation of anxiety-like behaviour. Furthermore, EphrinB2 mediates stress-related potentiation of contextual fear conditioning. These findings implicate the EphrinB2/EphA4/plasmin pathway as a new player in hippocampal regulation of anxiety. Second, I found that in the amygdala an extracellular serine protease, neuropsin, cleaves EphB2 shortly after stress. This molecular event alters EphB2 membrane expression and promotes a dynamic interaction of EphB2 with NMDA receptors. Consistent with the role of EphB2 in the stress response, bilateral amygdala infusion of anti-EphB2 antibody before stress prevents the development of stress-induced anxiety. The anxiolytic phenotype of neuropsin-deficient mice is rescued by the infusion of neuropsin into the amygdala before stress, confirming the effect of neuropsin is acute and not developmental, and pointing to the amygdala as the locus of the neuropsin’s effect. Taken together these findings implicate the acute, stress related cleavage of EphB2 by neuropsin in the amygdala as a key event in the development of anxiety-related behaviour.
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Morley, R. H. "Investigation into the cellular mechanisms underlying cell sorting by Eph receptors and ephrins." Thesis, University College London (University of London), 2012. http://discovery.ucl.ac.uk/1353039/.
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The mechanisms that control the segregation of cells in the developing embryo are essential for normal development. Eph receptors and ephrins are responsible for cell segregation and the maintenance of sharp boundaries between regions of cells, such as those in the adult intestine or the compartments of the developing vertebrate hindbrain. The mechanisms through which they achieve this are not well understood. One widely discussed theory, based on the differential adhesion hypothesis, is that Eph receptors and ephrins influence the relative adhesion between cells in adjacent compartments. The other is that active migratory or repulsive mechanisms are responsible for segregation. Using in vitro assays that were established as part of this project, I have shown that N-cadherin is required for EphB2-ephrinB1 mediated cell sorting, consistent with an important role of cell-cell adhesion in this process. p120 and p0071, which are downstream targets of signalling through EphB2 and have established roles in regulating cadherin stability, are also required for cell segregation by EphB2 and ephrinB1. However, comparison with the segregation of cells expressing different cadherins suggests that differential adhesion is not the main mechanism driving sorting downstream of Eph-ephrins. Instead, I propose that repulsion is the main mechanism driving segregation mediated by EphB2 and ephrinB1 and that N-cadherin is required for general adhesion between all cells, which stabilises the formation of EphB2 cell clusters. Cell behaviour analyses indicate that N-cadherin is not required for the repulsion response of EphB2 cells after interactions with ephrinB1 cells, although it does play a contact-dependent role in cell migration. However, there is a cadherin-independent role of p120 in repulsion downstream of Eph-ephrins, which could contribute to cell sorting. These results support a model where Eph-ephrin mediated repulsion acts in combination with a basal level of cell-cell adhesion to drive cell segregation.
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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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Mendes, Shannon. "Multiple B-Class Ephrins and EPH Receptors Regulate Midline Axon Guidance in the Developing Mouse Forebrain." Scholarly Repository, 2006. http://scholarlyrepository.miami.edu/oa_dissertations/49.
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Ephrins and Eph receptors have been implicated in a number of developmental processes including axon growth and guidance. One important guidepost is the central nervous system midline, where ephrins and Eph receptors have been implicated. At the embryonic midline, axons either cross into the contralateral central nervous system (CNS) targeting appropriate partners on the opposite side or remain ipsilateral extending either rostrally or caudally. In these studies, we examine a major forebrain commissure called the corpus callosum (CC). Agenesis of the CC is a rare birth defect that occurs in isolated conditions and in combination with other developmental cerebral abnormalities. Recent identification of families of growth and guidance molecules has generated interest in the mechanisms that regulate callosal growth. One family, ephrins and Eph receptors, has been implicated in mediating midline pathfinding decisions; however, the complexity of these interactions has yet to be unraveled. This dissertation sheds light on which B-class ephrins and Eph receptors function to regulate CC midline growth, and how these molecules interact with important guideposts during development. We also show that multiple Eph receptors (B1, B2, B3, and A4) and B-class ephrins (B1, B2, and B3) are present and function in developing forebrain callosal fibers based on both spatial and temporal expression patterns and analysis of gene-targeted knockout mice. Defects are most pronounced in the combination double knockout mice, suggesting that compensatory mechanisms exist for several of these family members. Furthermore, these CC defects range from mild hypoplasia to complete agenesis and Probst's bundle formation. Further analysis of the ephrinB3 gene revealed that Probst's bundle formation may reflect aberrant glial formations which alter the normal architecture of midline glia resulting in one potential mechanism of this abnormal phenotype. Another potential mechanism we discovered is a role for EphB1 receptor in the altered sensitivity of CC axons to midline guidance cues. Removal of this receptor resulted in cortical axons responding to GW guidepost cells with increased sensitivity. Our results support a significant role for ephrins and Eph receptors in CC development and may provide insight to possible mechanisms involved in axon midline crossing as well how failed molecular and genetic mechanisms may contribute to human CC disorders. Lastly, we show that one fiber tract that remains ipsilateral in the forebrain may use distinct midline guideposts to regulate proper growth and guidance. These findings implicate additional ephrins and Eph receptors in CC midline guidance than previously known and reveal novel mechanisms in mice, which may be pertinent to human disease states that result in agenesis of the CC.
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Lee, Jinju. "IL-23 generates pathogenic Th17 cells by triggering T cell-intrinsic prostaglandin E2-EP2/4 signaling." Kyoto University, 2018. http://hdl.handle.net/2433/235123.
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Hirsch, Théo Z. "Voies de signalisation dépendantes de la protéine prion : de la physiologie à la pathologie." Thesis, Sorbonne Paris Cité, 2016. http://www.theses.fr/2016USPCB105.
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La conversion de la protéine prion cellulaire PrPC en une isoforme pathologique, la protéine prion scrapie PrPSc, est à l'origine d'un groupe de maladies neurodégénératives, les Encéphalopathies Spongiformes Transmissibles (EST). De nombreux travaux indiquent que la toxicité de la PrPSc implique une déviation de la fonction normale de la PrPC, cependant le rôle physiologique de la protéine prion n’est que partiellement compris. Dans ce travail, nous nous sommes attachés à identifier des voies de signalisation mobilisées par la PrPC qui pourraient à la fois rendre compte du rôle de cette protéine dans le développement du système nerveux et être impliquées dans la pathogénèse des EST. Nous montrons que la protéine prion contrôle l’activité de la voie Notch, une voie de signalisation qui joue un rôle majeur dans le développement mais également dans l’homéostasie du système nerveux central et la plasticité synaptique. Dans des modèles ex vivo et in vivo d’EST, nous mettons en évidence une diminution de l’activité de la voie Notch, ainsi que de l’expression des récepteurs de la famille Eph - connus pour leur implication dans l’activité synaptique. Cette diminution des Eph est retrouvée dans des cellules dépourvues de PrPC. Ainsi, l’observation d’un profil similaire entre la perte d’expression de la PrPC et l’infection par les prions renforce l’idée d’une déviation de la fonction normale de la PrPC par la PrPSc. Des inhibiteurs de l’activité histone désacétylase (HDAC) permettent de rétablir l’expression des acteurs de la voie Notch et des récepteurs Eph aussi bien dans les cellules déplétées en PrPC que dans celles infectées par les prions, suggérant que des mécanismes épigénétiques sont impliqués dans le contrôle transcriptionnel de ces gènes par la protéine prion. Ce travail fournit les bases pour évaluer un effet bénéfique des inhibiteurs de HDAC dans un modèle de souris infectées par les prions et ainsi déterminer si les HDAC pourraient constituer de nouvelles cibles thérapeutiques pour combattre les ESTThe conversion of the cellular prion protein PrPC into a pathogenic isoform, the scrapie prion protein PrPSc, lies at the root of a group of neurodegenerative disorders known as Transmissible Spongiform Encephalopathies (TSEs). Several lines of evidence indicate that PrPSc-mediated toxicity involves a subversion of PrPC normal function, however, our knowledge of PrPC physiological role is still far from complete. In this work, we sought to identify signalling pathways mobilized by PrPC that could accommodate both its role in central nervous system development and its implication in TSE pathogenesis. We show that the prion protein controls the activity of the Notch pathway, which plays an overriding role during embryonic development as well as central nervous system homeostasis and synaptic plasticity. In both ex vivo and in vivo models of TSE, we monitored a decrease in Notch activity, together with reduced expression of Eph receptors, which are key players in synaptic activity. The reduction in Eph is also found in PrPC-depleted cells. Hence, our observation of a similar signature of PrPC depletion and prion infection strengthens the view that PrPSc diverts PrPC function. We found a restoration of Notch and Eph effectors expression in response to histone deacetylase (HDAC) inhibitors, both in PrPC-depleted and prion-infected cells, suggesting that epigenetic mechanisms are involved in the PrP-dependent transcriptional control of these genes. This work provides a foundation for assessing a beneficial effect of HDAC inhibition in prion-infected mice and thereby defining whether HDAC could represent novel therapeutic targets to combat TSEs
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Peng, Lin [Verfasser], and Udo [Akademischer Betreuer] Jeschke. "The role of G-protein coupled prostaglandin E2 receptors (EP2 and EP3) in unexplained recurrent miscarriage and cervical cancer / Lin Peng ; Betreuer: Udo Jeschke." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2021. http://d-nb.info/1239049366/34.
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Furuyashiki, Miyako. "Facilitation of Th1-mediated immune response by prostaglandin E receptor EP1." Kyoto University, 2009. http://hdl.handle.net/2433/126454.
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Kunikata, Tomonori. "Suppression of allergic inflammation by the prostaglandin E receptor subtype EP3." Kyoto University, 2005. http://hdl.handle.net/2433/144482.
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Kyoto University (京都大学)0048
新制・課程博士
博士(医学)
甲第11827号
医博第2903号
新制||医||906(附属図書館)
23587
UT51-2005-K493
京都大学大学院医学研究科脳統御医科学系専攻
(主査)教授 坂口 志文, 教授 湊 長博, 教授 宮地 良樹
学位規則第4条第1項該当
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Fujikawa, Risako. "EP4 Receptor-Associated Protein in Microglia Promotes Inflammation in the Brain." 京都大学 (Kyoto University), 2017. http://hdl.handle.net/2433/225462.
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Kitaoka, Shiho. "Prostaglandin E2 acts on EP1 receptor and amplifies both dopamine D1 and D2 receptor signaling in the striatum." Kyoto University, 2008. http://hdl.handle.net/2433/135927.
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Jungas, Thomas. "Caractérisation du rôle de la signalisation Eph-éphrine dans la division cellulaire." Thesis, Toulouse 3, 2015. http://www.theses.fr/2015TOU30102/document.
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Au sein d'un organisme les cellules se divisent et assurent la croissance, la différentiation et l'homéostasie des tissus. Des travaux récents proposent qu'elles communiquent activement entre voisines au sein des organes solides pour coordonner leur propre division et la préservation de l'intégrité tissulaire. Nous proposons que la signalisation Eph-éphrine, acteur de la communication cellulaire locale, participe à cette coordination entre division cellulaire et cohésion du tissu. Au cours de ma thèse, j'ai démontré dans plusieurs modèles cellulaires que la signalisation Eph-éphrine contrôle la division cellulaire et peut induire des retards dans l'abscission et de la polyploïdie. J'ai prouvé par vidéomicrosocpie que ces défauts d'abscission dépendent du domaine catalytique du récepteur EphB2 et de l'activation de la protéine tyrosine kinase relais c-Src. En cascade, c-Src phosphoryle un régulateur clé de la stabilité du pont intercellulaire, la protéine citron kinase (CitK). J'ai également observé que CitK était anormalement localisé durant la cytocinése en aval de la voie Eph. Par des essais kinase in vitro, j'ai exclu une phosphorylation directe de CitK par le récepteur Eph et identifié c-Src comme capable de phosphoryler directement CitK. J'ai identifié les résidus tyrosines de CitK phosphorylés par c-Src, mutés deux d'entre eux et à l'aide d'analyses de sauvetage phénotypique, démontré que ces résidus étaient nécessaires et suffisants pour induire des défauts d'abscission. J'ai ensuite validé in vivo ce rôle original de la voie Eph-éphrine, dans le contexte du développement neuronal chez la souris. Plusieurs membres de la famille des Eph-éphrines sont exprimés dans les progéniteurs neuraux à l'origine des neurones corticaux et des auteurs ont montrés que CitK contrôle la cytocinèse de ces cellules. En utilisant un système Cre-lox, j'ai spécifiquement éteint la signalisation Eph dans ces progéniteurs et observé une modification de la ploïdie neuronale dans ces animaux. J'ai également observé dans les progéniteurs neuraux une co-localisation physiologique de résidus tyrosines phosphorylés et de la protéine CitK, qui adopte un enrichissement apical caractéristique. Ces résultats suggèrent notamment que la signalisation Eph-éphrine pourrait contrôler l'abscission des progéniteurs neuraux via la phosphorylation de CitK. La cytocinèse est aujourd'hui décrite comme un processus cellulaire autonome orchestré par la machinerie intracellulaire. Les résultats obtenus durant mon doctorat suggèrent que la cytocinèse est également régulée par l'environnement local de la cellule comme j'en ai fait la démonstration avec la signalisation Eph-éphrine. D'autre part, mes travaux suggèrent que la phosphorylation de CitK sert d'interrupteur moléculaire durant la progression à travers la division cellulaire et le contrôle de la ploïdie des neuronesCells within an organism successfully divide to ensure growth, differentiation and homeostasie. Recent work suggests that dividing cells actively communicate with neighbours thus spatially and temporally coordinating cell division while maintaining tissue cohesiveness. We hypothesized that Eph-ephrin signalling, a local cell-cell signalling pathway, could participate in coordinating cell division within a tissue. Using vertebrate and invertebrate cell culture models I showed that Eph-signalling controls cell division and induces delay in the abscission of nascent daughter cells as well as polyploidy. Using time-lapse imaging I proved that the Eph-mediated abscission failure depends on the catalytic activity of the receptor via the non receptor tyrosine kinase relay molecule c-Src. Downstream of Eph signalling c-Src phosphorylates the protein citron kinase (CitK) a well known regulator of intercellular bridge stability. I also observed that CitK was abnormally localized during cytokinesis when Eph signalling was active. Further, using in vitro kinase assays, I demonstrated that Eph does not directly phosphorylate CitK but that c-Src could do so. In addition, using Mass Spectrometry I mapped all tyrosine residues directly phosphorylated by c-Src. I mutated two of them located in the Rho binding domain of CitK and demonstrated that phosphorylation of those residues are necessary and sufficient to induce cytokinesis failure. I validated in vivo this novel role of Eph-ephrin signalling in a physiological context in the developing mouse neocortex. Members of the Eph/ephrin family are expressed in neural progenitors that give rise to neurons of the cortex upon neurogenic division. Importantly, CitK has been shown by others to control cytokinesis of these progenitor cells. Using the Cre-lox system, I specifically turned off Eph forward signalling in neural progenitor cells and observed an alteration of neuronal ploidy in these mutant animals. Further, I also observed that CitK which adopts a particular apical localisation in neural progenitors physiologically co-localized with phosphorylated tyrosine residues. Altogether, these results suggest that Eph-ephrin signalling controls abscission of neural progenitors by promoting phosphorylation of CitK. The textbook view of cytokinesis is that it is a cell autonomous event orchestrated by the intracellular machinery. Data obtained during my PhD suggest that cytokinesis is also regulated by local environment, here Eph/ephrin signalling, and that phosphorylation of CitK may represent a molecular switch in the normal progression of cell division and in the control of neuronal ploidy
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Tsoi, Lo-yan Luc, and 蔡露茵. "Morphological and metabolic alternations in adipose tissue of EP4 deficient mice." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2014. http://hdl.handle.net/10722/198799.
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Obesity is a rising global health burden. The accumulation of fat in the body is associated with metabolic syndrome, type 2 diabetes, cardiovascular disease, hypertension and cancer. Currently available anti-obesity medications are not effective and safe to meet the medical need for obesity management. Prostaglandin E receptor subtype 4 (EP4) is involved in the development of adipocytes, but the signaling in adipogenesis and the effect on the regulation of energy homeostasis is not clear to understand. Thus, EP4 receptor and its signaling pathway are interest for research. The purpose of this dissertation is to investigate the morphology and metabolic alteration in mice and to elucidate whether the lack of EP4 by administration of L-161,982, a selective EP4 antagonist, could influence lipid metabolism of the adipocytes in subcutaneous white adipose tissue. Our findings revealed that whether the mice were fed with normal or high-fat diet, EP4 has no significant influence on the adipocyte size in subcutaneous white adipose tissues. The lack of EP4 also showed no significant effect on the basal or stimulated lipolysis of subcutaneous white adipose tissue. However, EP4 deficiency reverses hepatic lipid storage in high-fat fed mice compared to those fed with normal diet. In conclusion, EP4 might be altered lipid metabolism in the liver, which is crucial in the management of obesity. Prospective studies are essential to investigate the effect of EP4 and its signaling pathway on adiposity and lipid metabolism in the liver.published_or_final_version
Pharmacology and Pharmacy
Master
Master of Medical Sciences
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Eckert, David. "The Prostaglandin E2 Receptor 1 (EP1) Antagonizes AngII in the Collecting Duct." Thesis, Université d'Ottawa / University of Ottawa, 2017. http://hdl.handle.net/10393/36196.
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Prostaglandin E2 (PGE2), a metabolite of arachidonic acid, plays a role in water and sodium reabsorption in the collecting duct of the kidney. The collecting duct is responsible for the fine tuning of water and electrolytes. Only a small fraction of the filtered water and sodium is reabsorbed in the collecting duct, a fraction crucial to the regulation of water and electrolyte balance. This current study addresses the role of EP1, one of four PGE2 receptors, in the collecting duct. It is well documented that PGE2 inhibits sodium and water reabsorption in the collecting duct, however the exact mechanism is still debated. To determine whether the EP1 receptor mitigates AngII renal effects, an in vivo study was performed with EP1-/- mice. Global EP1-/- knockout mice were crossed with a renin overexpressing mouse line (herein denoted as “Ren”) and subjected to a high salt (HS) and low salt (LS) diet. Ren mice displayed an 11mmHg increase in systolic blood pressure (BP) on a HS diet and a decrease in BP of 14mmHg on a LS diet compared to the normal salt (NS) diet. Ren EP1-/- mice did not display a significant increase or decrease in BP on a HS or LS diet. On a LS diet, Ren EP1-/- displayed a drop in urine osmolarity (1641 mOsm/ kgH2O) vs. wild type (WT) mice (2107 mOsm/ kgH2O), consistent with increased sodium reabsorption. Narrowing in on the collecting duct, Ren EP1-/- mice had enhanced αENaC levels compared to Ren mice. In ex vivo microperfusion experiments, EP1-/- tubules show no response to PGE2 in the presence of AVP, whereas PGE2 inhibits AVP induced water reabsorption in WT mice. An increase in αENaC membrane accumulation due to EP1 gene ablation results in increased sodium reabsorption subsequently leading to a rise in BP. This contributes to the lack of salt sensitivity in EP1-/- mice. Overall, the EP1 receptor in the collecting duct represents a potential therapeutic target for the treatment of hypertension.
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Hori, Ryusuke. "PROSTAGLANDIN E RECEPTOR SUBTYPE EP4 AGONIST PROTECTS COCHLEAE AGAINST NOISE-INDUCED TRAUMA." Kyoto University, 2010. http://hdl.handle.net/2433/120543.
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Nakatsuji, Masato. "EP4 receptor-associated protein in macrophages ameliorates colitis and colitis-associated tumorigenesis." Kyoto University, 2016. http://hdl.handle.net/2433/215397.
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Chandramouli, Anupama. "The Role of Prostaglandin E2/EP4 Prostanoid Receptor Signaling in Colorectal Carcinogenesis." Diss., The University of Arizona, 2009. http://hdl.handle.net/10150/195443.
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Colorectal cancer, among other tumors, is characterized by elevated levels of prostaglandins due to the up-regulation of cyclooxygenase -2 (COX-2), a key enzyme in the eicosanoid biosynthesis pathway. Prostaglandin E2 (PGE2) is an important prostaglandin that exerts its biological function via four transmembrane G protein coupled receptors (EP1-4), among which the EP4 receptor is the most important. The relevance of EP4 receptor to the carcinogenic process and the consequences of its interaction with PGE2 were explored in this dissertation.Despite the importance of the EP4 receptor in colon carcinogenesis, studies looking at the receptor expression during cancer progression have not been extensive. One study showed that the protein levels of EP4 receptor were elevated in colon cancer whereas another study indicated that mRNA levels were decreased in tumor compared to normal. We expanded these observations and now report that the elevated protein levels of EP4 receptor in cancer are due to increased translation of proteins.In addition, we identified S100P as a novel downstream target of the PGE2/EP4 receptor signaling pathway. S100P has been previously implicated in a number of gastro-intestinal cancers such as pancreatic, gastric and colon cancers. However, its regulation via the PGE2/EP4 receptor signaling pathway has never been investigated. Here, we show that PGE2 via the EP4 receptor signaling leads to the transcriptional activation of S100P and that this activation happens exclusively in the presence of CREB. In summary, this dissertation brings to light novel therapeutic targets which could be used as potential markers to stratify colon cancer patients as well as avenues for clinical intervention for the management of colon carcinogenesis.
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Israel, Davelene Davinah. "Differential Signaling and Gene Regulation Among Three Human EP3 Prostanoid Receptor Isoforms." Diss., The University of Arizona, 2008. http://hdl.handle.net/10150/196148.
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Prostaglandin E2 (PGE2) is a hormone derived from the metabolism of arachidonic acid whose functions include regulation of platelet aggregation, fever and smooth muscle contraction/relaxation. PGE2 mediates its physiological and pathophysiological effects through its binding to four G-protein coupled receptor subtypes, named EP1, EP2, EP3 and EP4. The EP3 prostanoid receptor is unique in that it has multiple isoforms generated by alternative mRNA splicing. These splice variants display differences in tissue expression, constitutive activity and regulation of signaling molecules. To date there are few reports identifying differential activities of EP3 receptor isoforms and their effects on gene regulation.We generated HEK 293 EBNA cell lines expressing the EP3-Ia, EP3-II, or EP3-III isoforms. After confirming the functional expression of each of these isoforms, we examined their activation of cellular signal transduction pathways.We found that each of these isoforms utilize distinct mechanisms to regulate ERK 1/2 phosphorylation and that these differences lead to unique regulation of the downstream effectors ELK-1 and AP-1. We also found MAPK dependent differences in regulation of cell proliferation. The EP3-III isoform increases cell proliferation in a MAPK dependent manner while the EP3-Ia dose dependently regulates cell proliferation via Gαi and not ERK 1/2. Activation of the EP3-II receptor had no effects on cell proliferation.To study differential gene regulation by these three EP3 receptor isoforms, we conducted microarray studies. Over 300 genes were differentially regulated by these isoforms. Quantitative real-time PCR analysis was used to validate 15 candidate genes. Five genes were chosen for further analysis of protein expression using immunoblotting, but only one of these, WT-1, was significantly increased following treatment with PGE2. WT-1, a transcription factor important for kidney and heart development, was strongly upregulated by PGE2 stimulation of the EP3-II receptor, but only weakly by the other isoforms.In conclusion, these studies show that the human EP3 prostanoid receptor isoforms are capable of distinct regulation of both signal transduction pathways and gene transcription. Elucidating the differential functions of EP3 receptor isoforms may allow for greater understanding of the diverse functions attributed to this receptor and their physiological functions.
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Wong, Chi-kin, and 黃志堅. "The role of prostaglandin E2 receptor EP4 subtype in energy balance and obesity." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hub.hku.hk/bib/B48334236.
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Obesity features increased accumulation of fat in the body and results in adverse health consequences, including type II diabetes mellitus and cardiovascular diseases. The global epidemic of obesity and lack of effective treatments call for the search of new anti-obesity medication. Activation of prostaglandin receptor subtype 4 (EP4) had been shown to produce potent anti-inflammatory effect and possibly induce brite adipocytes to increase energy expenditure, both of which can potentially ameliorate obesity. The purpose of this dissertation is to characterize the metabolic phenotypes of EP4 receptor in mice and to elucidate whether administration of CAY10580, a selective EP4 agonist, could protect against obesity and its related complications. The experiments were carried out on diet-induced obese mice and EP4 knockout mice. Anthropometric measurement, glucose and insulin tolerance test, indirect calorimetry, quantitative real-time PCR, plasma analytes measurement and histological studies were performed. The findings revealed that EP4 activation by CAY10580 prevented high-fat diet fed mice from becoming obese, but it did not exhibit a curative effect in reversing obesity in mice. Activation of EP4 by CAY10580 suppressed body weight gain and adiposity in high-fat diet fed mice by reducing the weight of epididymal, subcutaneous and peri-renal white adipose tissues, inter-scapular brown adipose tissue and liver. The lower adiposity resulted in improved glucose and insulin sensitivity and lower plasma leptin level. The cause of reduced adiposity by EP4 activation is not due to changes in energy intake, obligatory energy expenditure, locomotor activities, adaptive thermogenesis and lipolysis. EP4- mediated reduction in adiposity was characterized by smaller adipocyte size and greater proportion of small adipocytes in subcutaneous white adipose tissue. Furthermore, mice deficient in EP4 also showed reduced adiposity at epididymal, subcutaneous and peri-renal white adipose tissues, and inter-scapular brown adipose tissue. The reduced adiposity in EP4 deficient mice was associated with impaired cold intolerance. Taken together, EP4 activation is effective in preventing obesity and relieving obesity-associated glucose and insulin tolerance, and EP4 might play an essential role in adiposity maintenance through the modulation on adipocyte development.published_or_final_version
Pharmacology and Pharmacy
Master
Master of Medical Sciences
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Nakamura, Kazuhiro. "Physiological roles and molecular functions of prostaglandin EP3 receptor in the nervous system." 京都大学 (Kyoto University), 2002. http://hdl.handle.net/2433/150101.
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Nojima, Shingo. "Cryo-EM Structure of the Prostaglandin E Receptor EP4 Coupled to G Protein." Doctoral thesis, Kyoto University, 2021. http://hdl.handle.net/2433/263574.
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Sonoshita, Masahiro. "Acceleration of intestinal polyposis through prostaglandin receptor EP2 in Apc[Δ716] knockout mice." Kyoto University, 2004. http://hdl.handle.net/2433/147468.
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Yasui, Mika. "The Prostaglandin E2 Receptor EP4 Regulates ObesityーRelated Inflammation and Insulin Sensitivity." Kyoto University, 2016. http://hdl.handle.net/2433/215455.
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Genander, Maria. "No guts, no glory EphB mediated signaling in intestinal stem and progenitor cells /." Stockholm : Department of Cell and Molecular Biology, Karolinska Institutet, 2009. http://diss.kib.ki.se/2009/978-91-7409-735-1/.
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Nakamura, Yoshiko. "Direct pyrogenic input from prostaglandin EP3 receptor-expressing preoptic neurons to the dorsomedial hypothalamus." Kyoto University, 2007. http://hdl.handle.net/2433/135896.
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Seno, Hiroshi. "Cyclooxygenase 2- and prostaglandin E2 receptor EP2-dependent angiogenesis in ApcΔ716 mouse intestinal polyps." Kyoto University, 2002. http://hdl.handle.net/2433/149346.
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Wang, Li Racine Ronald J. "Expression of EphA receptors and ligands in rat brain following status epilepticus." *McMaster only, 2006.
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Franzén, Stephanie. "The role of hypoxia for the development of diabetic nephropathy : Temporal relationship and involvement of endothelin receptor signaling." Doctoral thesis, Linköpings universitet, Avdelningen för läkemedelsforskning, 2016. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-125522.
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Diabetic nephropathy is one of the most common causes of end stage renal disease and develops in approximately one third of all diabetes patients. Disease progression is characterized by deteriorating glomerular filtration rate and escalating urinary albumin/protein excretion; both are used as clinical markers for disease progression. Recently, it has been proposed that intrarenal hypoxia is a unifying mechanism for chronic kidney disease, including diabetic nephropathy. Several mechanistic pathways have been linked to the development of intrarenal hypoxia and diabetic nephropathy including increased angiotensin II signaling, oxidative stress and hyperglycemia per se. Furthermore, pathological endothelin signaling has recently immerged as a possible contributing factor for chronic kidney disease and diabetic nephropathy. The overall aims of this thesis were therefore to determine the temporal relationship between development of intrarenal hypoxia and kidney disease as well as elucidate the potential link between endothelin signaling, intrarenal hypoxia and kidney disease in experimental insulinopenic diabetes. It is well established that different mouse strains have different susceptibility for kidney and cardiovascular disease. The first step was therefore to compare four commonly used mouse strains with regards to development of kidney disease after onset of insulinopenic diabetes. From the results of this study, we concluded that the NMRI mouse strain has a disease progression closest to the human disease and this strain was chosen in the subsequent studies in mice. The next step was to adapt and optimize a suitable method for repetitive measurements of intrarenal oxygen tension during the course of disease development. Electron paramagnetic resonance (EPR) oximetry had previously been used in tumor biology and was now adapted and optimized for measurements of kidney oxygenation in our diabetic mouse model. EPR oximetry in normoglycemic control mice recorded cortical oxygen tension values similar to previous reports using invasive techniques. Surprisingly, intrarenal hypoxia developed already within the first 72h after induction of hyperglycemia and persisted throughout the two-week study period. Importantly, this was well before albuminuria developed. The final part of this thesis was to investigate the role of endothelin signaling for the intrarenal hypoxia in a diabetic rat model. Endothelin 1 signals via two distinctly different receptor-mediated pathways. In normal physiology, endothelin 1 binding to endothelin receptor type A (ETA) induces vasoconstriction, which can be blocked by the specific ETA antagonist BQ123, whereas endothelin 1 binding to endothelin receptor type B (ETB) induces nitric oxide-dependent vasodilation. ETB receptors can be selectively activated by Sarafotoxin 6c. The results from blocking ETA and activating ETB receptors demonstrated that endothelin 1 signaling via ETA receptors contributes to intrarenal hypoxia in the rat diabetic kidney, and that ETB stimulation significantly reduces the diabetes-induced intrarenal hypoxia. The beneficial effects on kidney oxygen availability in diabetes by ETA blockade or ETB stimulation were mainly linked to hemodynamic improvements rather than direct effects on kidney oxygen consumption or oxidative stress status. In conclusion, by applying EPR oximetry in a mouse model of insulinopenic diabetes mimicking the human disease, we demonstrated intrarenal hypoxia already within the first couple of days after the onset of hyperglycemia, which is well before detectable signs of kidney disease development. Furthermore, blockade of ETA or activation of ETB receptors significantly reduced intrarenal hypoxia in the diabetic kidney. These results demonstrate involvement of ETA receptor signaling in diabetes-induced intrarenal hypoxia and ETA blockade or ETB activation might provide new therapeutical targets to reduce kidney hypoxia and disease progression in diabetes.