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1
Nair, Prashant. "Signals involved in protein intracellular sorting /." Basel : [s.n.], 2005. http://edoc.unibas.ch/diss/DissB_6999.
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劉思恩 and See-yan Lau. "A study of intracellular signals of K-opioids in non-neuronal cells." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1997. http://hub.hku.hk/bib/B31214290.
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Lau, See-yan. "A study of intracellular signals of K-opioids in non-neuronal cells /." Hong Kong : University of Hong Kong, 1997. http://sunzi.lib.hku.hk/hkuto/record.jsp?B19667139.
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Liu, Ke, University of Western Sydney, of Science Technology and Environment College, and of Science Food and Horticulture School. "Role of second messengers in controlling growth patterns of corneal epithelial cells." THESIS_CSTE_SFH_Liu_K.xml, 2002. http://handle.uws.edu.au:8081/1959.7/387.
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The purpose of this thesis was to investigate mechanisms contolling the growth of corneal epithelial cells, particularly the intracellular signals involved with stratification compared with cellular migration and maturation. Buttons of epithelium were cultured in different culture media. The explants were monitored microscopically for their growth patterns and finally fixed and examined for cytokeratin, vimentin and actin. Different growth patterns were observed in the different media, indicating that different signalling patterns must be operating in these cells depending upon the media in which they were grown. To investigate the intracellular pathways controlling the different growth patterns, the protein phosphorylation of different cultures was investigated. The two proteins, p57 and p30, are strongly suggested to be associated with stratification of the epithelial cells. The possible involvement of the common serine kinase, PKC, in controlling the growth pattern of corneal epithelial cells were also investigated. The results suggested that an intracellular pathway involving PKC promotes the maturation and spread of the cells but is not involved in their stratification. These experiments taken together indicate that the different aspects of corneal epithelia cell growth are tightly controlled and may occur quite independently. Specific protein expression appears to be important for stratification, and phosphorylation of proteins by PKC appears to be involved with the maturation of epithelial cells from basal cells. It also indicates that the mature cells are capable of producing the extracellular matrix protein fibronectin which appears to have an important role in causing the spread as distinct from the stratification of the corneal epithelial cells.Doctor of Philosophy (Ph.D.)
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Levings, Megan K. "Biological and biochemical analyses of the distinctive intracellular signals activated by interleukin-4." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape8/PQDD_0025/NQ38928.pdf.
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Raraty, Michael Gordon Thomas. "Cytosolic calcium signals and intracellular enzyme activation in the pathogenesis of acute pancreatitis." Thesis, University of Liverpool, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.250238.
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Bradley, J. "Analysis of the mechanisms responsible for the generation and decoding of intracellular calcium signals." Thesis, University of Cambridge, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.596849.
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In many cells, including hepatocytes, receptors coupled to phosphoinositide hydrolysis stimulate oscillatory changes in cytosolic [Ca2+] ([Ca2+]i). I have used two methods to examine the means whereby such [Ca2+]i transients are linked to the stimulation of glycogenolysis. By perifusing rat hepatocytes prelabelled with [3H]-glucose, I showed that phenylephrine increases the rate of [3H]-glucose release by 2-3 fold, and confirmed this effect using a colorimetric assay for glucose. When cultured hepatocytes were loaded with Fura-2 and incubated with thapsigargin in a Ca2+-free medium, restoration of external Ca2+ caused Ca2+ entry. Brief pulses (10s or 30s) of extracellular medium containing Ca2+ (5mM), produced [Ca2+]i transients comparable to those observed in single hepatocytes treated with Areg8-vasopressin (duration = 1.0 -1.5min). Using a similar protocol to manipulate [Ca2+]i in hepatocytes prelabelled with [3H]-glucose, I demonstrated that single [Ca2+]i transients stimulate a 2-fold increase in [3H]-glucose release (n=4). Moreover, stimulated glucose release outlasted the transient elevation of [Ca2+]i having a duration of 7.4 ± 0.6min (n=4). In conclusion, stimulation of glucose release by imposed transients of [Ca2+]i in a population of hepatocytes indicates that the discontinuous signal of [Ca2+]i transients can be decoded to produce a continuous response. Further characterisation of this decoding process requires single cell measurements of glucose and [Ca2+]i. Such measurements are not yet possible with the presently available techniques for enzyme immobilisation on glucose microbiosensors. Overexpression of type I and type III InsP3 receptors results in cell death, the mechanism of which requires further study. It is possible, however, to induce the expression of the type I InsP3 receptor and the effects of increasing InsP3 receptor level on elementary Ca2+ release events should provide insight into the mechanism by which [Ca2+]i waves are generated.
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Righetti, Karima Maria. "Study of Rsm/Gac post-transcriptional regulation by quorum sensing, extracellular and intracellular signals in Pseugomonas aeruginosa." Thesis, University of Nottingham, 2011. http://eprints.nottingham.ac.uk/13853/.
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Bacteria have evolved ways to sense and respond to changes in their population density through quorum sensing (QS) systems, and to adapt to changes in the extracellular environment through two component systems (TCS). In Pseudomonas aeruginosa, QS and the GacS/GacA TCS are global regulatory systems that modulate the expression of virulence genes at the transcriptional and post-transcriptional level, respectively. Although in P. aeruginosa the QS network has been extensively characterized, the way the Gac/Rsm global regulatory system is regulated is still unclear. The study of QS and Gac/Rsm networks is crucial for the development of new drugs able to interfere with these regulatory systems. This thesis is dedicated to the study of the Gac/Rsm global regulatory system and its interaction with the QS network. An introduction to these systems is presented in Chapter 1. The materials and methods used in this study are described in Chapter 2. In Chapter 3 the methods to detect and identify the extracellular signals modulating Gac/Rsm system are investigated. This analysis led to the identification of the Pseudomonas Quinolone Signal (PQS) molecule, which is responsible for the activation of the gene coding for the small RNA RsmZ. RsmZ (in synergy with RsmY) antagonises by titration the effects of the global post-transcriptional regulator RsmA, a small RNA-binding protein which targets specific mRNAs. Since the discovery of QS, there have been many studies showing the importance of this type of regulatory mechanism in the global transcriptional control of gene expression. However, there has been no clear evidence to attribute to QS a key role in post-transcriptional regulation of terminal gene targets. In Chapter 4, the importance of PQS in the control of lecA is demonstrated. lecA encodes for the PA-I galactophilic lectin protein whose translation rates is modulated by the activity of the regulatory small RNA rsmZ in concert with RsmA. These results demonstrate that QS not only controls terminal target gene expression at the transcriptional level, but also at the translational level. Using a genetic bank, a transposon mutagenesis and a promoter pull-down approach, new regulators were identified together with regulatory networks involved in the modulation of the global Gac/Rsm system. These results are described in Chapter 5. Chapter 6 is focused on the effect of a library of compounds available in our laboratory, for their QS-inhibiting potential. The conclusions and future directions are presented in Chapter 7.
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Huang, Yun. "Integration of Extracellular and Intracellular Calcium Signals: Roles of Calcium-Sensing Receptor (CASR), Calmodulin and Stromal Interaction Molecule 1 (STIM1)." Atlanta, Ga. : Georgia State University, 2008. http://digitalarchive.gsu.edu/chemistry_diss/28/.
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Thesis (Ph. D.)--Georgia State University, 2008.Title from title page (Digital Archive@GSU, viewed July 1, 2010) Jenny J. Yang, committee chair; Edward Brown, Giovanni Gadda, Zhi-ren Liu, committee members. Includes bibliographical references (p. 230-258).
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Lemaire, Mathieu. "Intracellular signals underlying the inductive effects of agrin during neuromuscular junction formation : study on the roles of ras and Shc." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0030/MQ64388.pdf.
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Rinis, Natalie [Verfasser], Gerhard [Akademischer Betreuer] Müller-Newen, and Björn [Akademischer Betreuer] Usadel. "Characterization and localization of intracellular signals emanating from an oncogenic mutant of the cytokine receptor Gp130 / Natalie Rinis ; Gerhard Müller-Newen, Björn Usadel." Aachen : Universitätsbibliothek der RWTH Aachen, 2015. http://d-nb.info/1127531115/34.
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Liu, Ke. "Role of second messengers in controlling growth patterns of corneal epithelial cells." Thesis, View thesis, 2002. http://handle.uws.edu.au:8081/1959.7/387.
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The purpose of this thesis was to investigate mechanisms contolling the growth of corneal epithelial cells, particularly the intracellular signals involved with stratification compared with cellular migration and maturation. Buttons of epithelium were cultured in different culture media. The explants were monitored microscopically for their growth patterns and finally fixed and examined for cytokeratin, vimentin and actin. Different growth patterns were observed in the different media, indicating that different signalling patterns must be operating in these cells depending upon the media in which they were grown. To investigate the intracellular pathways controlling the different growth patterns, the protein phosphorylation of different cultures was investigated. The two proteins, p57 and p30, are strongly suggested to be associated with stratification of the epithelial cells. The possible involvement of the common serine kinase, PKC, in controlling the growth pattern of corneal epithelial cells were also investigated. The results suggested that an intracellular pathway involving PKC promotes the maturation and spread of the cells but is not involved in their stratification. These experiments taken together indicate that the different aspects of corneal epithelia cell growth are tightly controlled and may occur quite independently. Specific protein expression appears to be important for stratification, and phosphorylation of proteins by PKC appears to be involved with the maturation of epithelial cells from basal cells. It also indicates that the mature cells are capable of producing the extracellular matrix protein fibronectin which appears to have an important role in causing the spread as distinct from the stratification of the corneal epithelial cells.
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McKay, Jodi Ho-Jung. "HRas intracellular trafficking and signal transduction." [Ames, Iowa : Iowa State University], 2007.
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Legewie, Stefan. "Systems biological analyses of intracellular signal transduction." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2009. http://dx.doi.org/10.18452/16018.
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An der Interpretation extrazellulärer Signale beteiligte Regulationsnetzwerke sind von zentraler Bedeutung für alle Organismen. Extrazelluläre Signale werden gewöhnlich durch enzymatische Kaskaden innerhalb weniger Minuten in den Zellkern weitergeleitet, wo sie langsame Änderungen der Genexpression bewirken und so das Schicksal der Zelle beeinflussen. Im ersten Teil der Arbeit wird durch mathematische Modellierung untersucht, wie die MAPK Kaskade Signale von der Zellmembran in den Kern weiterleitet. Es wurden Netzwerkeigenschaften herausgearbeitet, die verhindern, dass die MAPK Kaskade fälschlicherweise durch genetische Mutationen aktiviert wird. Desweiteren wurde eine versteckte positive Rückkopplungsschleife identifiziert, welche die Aktivierung der MAPK Kaskade oberhalb eines gewissen Schwellwert-Stimulus verstärkt. Der zweite Teil der Arbeit konzentriert sich darauf, wie Änderungen der Genexpression auf langsamer Zeitskala in das Signalnetzwerk rückkoppeln. Eine systematische Genexpressionsdaten-Analyse ergab, dass transkriptionelle Rückkopplung in Eukaryoten generell über Induktion kurzlebiger Signalinhibitoren geschieht. Dynamische Modellierung und experimentelle Validierung von Modellvorhersagen ergab, dass das Inhibitorprotein SnoN als zentraler negativer Feedback Regulator im TGFbeta Signalweg fungiert. Der dritte Teil der Arbeit untersucht, wie die Genexpressionsmaschinerie intrazelluläre Signale interpretiert (“dekodiert“). Eine experimentelle und theoretische Analyse der cyanobakteriellen Eisenstress-Antwort ergab, dass IsrR, eine kleine regulatorische RNA, die Genexpression auf ausreichend starke und lange Stimulation beschränkt. Des Weiteren wurde ein “Reverse Engineering“-Algorithmus auf Hochdurchsatz-RNAi-Daten angewendet, um die Topologie eines krebsrelevanten Transkriptionsfaktornetzwerks abzuleiten. Zusammenfassend wurde in dieser Dissertation gezeigt, wie mathematische Modellierung die experimentelle Analyse biologischer Systeme unterstützen kann.Intracellular regulatory networks involved in sensing extracellular cues are crucial to all living organisms. Extracellular signals are rapidly transmitted from the cell membrane to the nucleus by activation of enzymatic cascades which ultimately elicit slow changes in gene expression, and thereby affect the cell fate. In the first part of this thesis, the Ras-MAPK cascade transducing signals from the cell membrane to the nucleus is analyzed using mathematical modeling. Model analysis reveals network properties which prevent the MAPK cascade from being inappropriately activated by mutations. Moreover, the simulations unveil a hidden positive feedback loop which ensures strong amplification of MAPK signalling once extracellular stimulation exceeds a certain threshold. The second part of the thesis focuses on how slow gene expression responses feed back into the upstream signalling network. A systematic analysis of gene expression data gathered in mammalian cells demonstrates that such transcriptional feedback generally involves induction of highly unstable signalling inhibitors, thereby establishing negative feedback regulation. Dynamic data-based modelling identifies the SnoN oncoprotein as the central negative feedback regulator in the TGFbeta signalling pathway, and corresponding model predictions are verified experimentally in SnoN-depleted cells. The third part of the thesis focuses on how intracellular signals are decoded by the downstream gene expression machinery. A combined experimental and theoretical analysis of the cyanobacterial iron stress response reveals that small non-coding RNAs allow cells to selectively respond to sufficiently strong and sustained stimuli. Finally, a reverse engineering approach is applied to derive the topology of a complex mammalian transcription factor network from high-throughput knock-down data. In conclusion, this thesis demonstrates how mathematical modelling can support experimental analysis of biological systems.
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Hao, Baixia, and 郝佰侠. "Regulatory and functional studies of store-operated calcium entry." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hdl.handle.net/10722/196486.
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Ca2+ signaling is essential for a wide variety of cellular activities, ranging from short term activities, such as synaptic and muscle contraction, to long term processes, such as proliferation and differentiation. Store-operated Ca2+ entry (SOCE), an important Ca2+ influx pathway in non-excitable cells, well coordinates Ca2+ release from ER and Ca2+ influx through plasma membrane. STIM1 and Orai1, serving as ER Ca2+ sensor and pore forming subunit, respectively, are the two essential components of SOCE machinery. In addition to activate Orai1 channel, studies have shown that STIM1 regulates other plasma membrane Ca2+ channels and senses a variety of cellular stresses to regulate SOCE. Therefore, it is of great interests to investigate the mechanisms and physiological functions of STIM1 and Orai1 mediated SOCE.
Here, we performed tandem affinity purification to identify STIM1 associated proteins in Hela cells stably expressing STIM1-His6-3×Flag. Four candidate proteins, including GRP78, HSP70, IQGAP1, and Actin, were identified by mass spectrometry analyses. Surprisingly, IQGAP1 failed to affect the activity of SOCE. Interestingly, GRP78 knockdown only affected the inactivation phase while exerted no effect on the activation phase of SOCE. In addition, GRP78 knockdown markedly induced cell apoptosis and dramatically increased the ER Ca2+ concentration. Moreover, GRP78 was involved in the regulation of SOCE by the ER stress. These data indicate that GRP78 is an important regulator of SOCE to prevent Ca2+ overload in cells. HSP70, however, significantly reduced the activity of SOCE by inhibiting STIM1 translocation to ER-PM junctions. Future studies will explore the mechanism of GRP78 and HSP70 in regulating SOCE by confocal and TIRF imaging. Embryonic stem (ES) cells proliferate unlimitedly and can differentiate into all fetal and adult cell types. This property endows ES cells to be the promising candidates in the therapy of neurodegenerative diseases. Thus, it is important to identify novel signaling molecules or events that could play a role in the neural commitment of ES cells. Accumulated evidences have documented the role of STIM1 and Orai1 mediated SOCE in neuronal activities. Yet, the role of SOCE in early neural development remains to be determined. Here we examined the role of STIM1 and Orai1 during neural differentiation of mouse ES cells. Both of STIM1 and Orai1 were expressed and functionally active in ES cells, and expressions of STIM1 and Orai1 were dynamically regulated during neural differentiation of mouse ES cells. STIM1 knockdown inhibited the differentiation of mouse ES cells into neural progenitors, neurons, and astrocytes. In addition, STIM1 knockdown caused severe cell death and markedly suppressed the proliferation of neural progenitors. Surprisingly, Orai1 knockdown had little effect on neural differentiation of mouse ES cells, but the neurons derived from Orai1 knockdown ES cells, like those from STIM1 knockdown cells, had defective SOCE. Taken together, our data indicate that STIM1 is required for neural differentiation of mouse ES cells independent of Orai1-mediated SOCE.published_or_final_version
Physiology
Doctoral
Doctor of Philosophy
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Kemp, Daniel M. "Reporter gene analysis of regulatory mechanisms in cAMP signalling." Thesis, University of Kent, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.310202.
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Juventin, Maxime. "Can the respiratory rhythm be a global signal promoting long-range communication in the brain?" Thesis, Lyon, 2021. https://tel.archives-ouvertes.fr/tel-03789626.
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Le cerveau est le siège d’une activité rythmique intense, chaque aire cérébrale exprimant un ou plusieurs rythmes. Une question centrale en neurosciences est de comprendre comment ces activités rythmiques peuvent se coordonner à travers des zones très distantes du cerveau pour résoudre des fonctions aussi complexes que la perception de l’environnement, des réponses motrices adaptées ou la formation de mémoires. Une possibilité est que le système utilise une référence temporelle commune, sorte d’horloge centrale, à partir de laquelle les différents réseaux neuronaux impliqués dans une fonction pourraient se coordonner. Nous faisons l’hypothèse que le rythme respiratoire pourrait être l’une de ces horloges centrales, constituant un signal de référence pour la coordination des différentes aires cérébrales. Comme horloge centrale, la respiration présente des avantages majeurs : fiabilité flexibilité, faible. Dans le système olfactif, le lien entre rythme respiratoire et l'activité neuronale est indéniable. La respiration entraîne des oscillations lentes à la fréquence respiratoire, des bursts de d'oscillations rapides et la décharge des neurones. La littérature récente, à laquelle mon équipe participe, a montré que cette influence respiratoire de l'activité neuronale n'est pas restreinte au système olfactif, mais bien au contraire s'étend au cerveau entier (néocortex, amygdale, hippocampe, thalamus). Dans la plupart des aires non-olfactives enregistrées le rythme respiratoire module également la décharge des neurones et les oscillations rapides. Les oscillations lentes liées à la respiration semblent donc bien affecter la dynamique globale du cerveau. Mon projet de thèse est composé de deux parties. Dans un premier temps, de manière à confirmer une influence du rythme respiratoire sur les neurones, j’ai réalisé des enregistrements intracellulaires dans quatre aires non-olfactives chez des rats anesthésiés. Les structures ciblées étaient le cortex préfrontal médian, le cortex somesthésique primaire, le cortex visuel primaire et enfin l’hippocampe. J’ai effectivement pu observer une modulation respiration dans la plupart de ces neurones. La quantification de ces données montre que les évènements de modulation respiratoire sont courts mais observés dans un nombre conséquent de neurones. Ces données apportent aussi la preuve que la modulation respiratoire des diverses aires cérébrales n’est pas uniquement due à de la conduction volumique. Dans un second temps, de manière à étudier la coordination d’aires cérébrales par le rythme respiratoire, j’ai analysé des enregistrements de potentiels de champ locaux (LFP) multisites chez le rat vigile. Les enregistrements contiennent sept aires cérébrales (bulbe olfactif, cortex piriforme antérieur, cortex visuel primaire, cortex préfrontal médian, cortex somesthésique primaire, CA1, gyrus denté) et la respiration. J’ai pu observer des oscillations lentes liées à respiration dans tous les états cérébraux. Mais c’est pendant l’éveil calme que la modulation respiratoire est la plus importante et apparaît dans toutes les aires enregistrées. En parallèle, ces oscillations lentes sont couplées avec plusieurs types d’oscillations rapides. Enfin, j’ai voulu savoir si, lors de l’état d’éveil calme, où les LFP d’un large réseau cérébral sont synchronisés à la respiration, les activités unitaires pouvaient aussi se synchroniser par rapport au signal respiratoire. Pour cela, j’ai mis en place un poste d’enregistrement électrophysiologique chez le rat vigile contraint permettant d’enregistrer de nombreux neurones dans des paires de structures cérébrales avec des « silicon probes ». Le poste est aujourd’hui fonctionnel et j’ai pu enregistrer 6 animaux. Ces dernières données ne seront pas entièrement traitées au moment où je soutiendrai ma thèse. Je présenterai des résultats préliminaires qui nous permettent d’ores et déjà de montrer que la respiration peut synchroniserThe brain is the site of intense rhythmic activity, each area of the brain expressing one or more rhythms. A central question in neuroscience is to understand how these rhythmic activities can coordinate across very distant areas of the brain to solve functions as complex as environmental perception, adapted motor responses or memory formation. One possibility is that the system uses a common time reference, a sort of central clock, from which the different neural networks involved in a function could coordinate. Today, the existence and nature of this clock are still debated. We hypothesize that the respiratory rate could be one of these central clocks, constituting a reference signal for the coordination of different areas of the brain. As a central clock, breathing has major advantages: reliability (because it is a vital function), flexibility (because it adapts to the needs of the organism), low cost (because it is a rhythm which is not not created specifically for this function). In the olfactory system, the link between respiratory rate and neuronal activity is undeniable. Respiration causes slow oscillations in the respiratory rate, bursts of rapid oscillations (gamma and beta) and the discharge of neurons. Recent literature, in which my team participates, has shown that this respiratory influence of neuronal activity is not restricted to the olfactory system, but on the contrary extends to the entire brain (neocortex, amygdala, hippocampus, thalamus). In most of the non-olfactory areas recorded the respiratory rate also modulates the discharge of neurons and rapid oscillations. The slow oscillations associated with breathing therefore seem to affect the overall dynamics of the brain. My thesis project is made up of two parts. First, in order to confirm an influence of the respiratory rate on neurons, I made intracellular recordings in four non-odor areas in anesthetized rats. The targeted structures were the median prefrontal cortex, the primary somatic cortex, the primary visual cortex and finally the hippocampus. I was able to observe respiration modulation in most of these neurons. The quantification of these data shows that the respiratory modulation events are short but observed in a significant number of neurons. These data also provide evidence that the respiratory modulation of various brain areas is not solely due to volume conduction. In a second step, in order to study the coordination of cerebral areas by the respiratory rhythm, I analyzed recordings of multisite local field potentials (LFP) in the vigilant rat. The recordings contain seven areas of the brain (olfactory bulb, anterior piriformis cortex, primary visual cortex, median prefrontal cortex, primary somatic cortex, CA1, dentate gyrus) and respiration. I was able to observe slow oscillations related to respiration in all brain states. But it is during calm awakening that respiratory modulation is greatest and appears in all recorded areas. In parallel, these slow oscillations are coupled with several types of fast oscillations. Finally, I wanted to know if, during the calm state of wakefulness, where LFPs of a large brain network are synchronized with respiration, unit activities can also synchronize with the respiratory signal. To do this, I set up an electrophysiological recording station in constrained vigilant rats allowing the recording of numerous neurons in pairs of cerebral structures with "silicon probes". The station is now functional and I was able to register 6 animals. These last data will not be fully processed when I am defending my thesis. I will present preliminary results which already allow us to show that respiration can synchronize the unit activities of many cells in even spatially distant regions of the brain
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Lidder, Sukhwinderjit. "Involvement of cortactin, Crk and Eps8 as intracellular signal transducers of the hepatocyte growth factor signal." Thesis, University College London (University of London), 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.411383.
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Bottomley, Matthew James. "Biophysical studies of intracellular signal transduction proteins : investigating the structure-function relationship." Thesis, University College London (University of London), 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.286570.
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Campion, Katherine. "Characterisation of calcium-sensing receptor extracellular pH sensitivity and intracellular signal integration." Thesis, University of Manchester, 2013. https://www.research.manchester.ac.uk/portal/en/theses/characterisation-of-calciumsensing-receptor-extracellular-ph-sensitivity-and-intracellular-signal-integration(e11adf01-4748-42ed-8679-f8b990d79dea).html.
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Parathyroid hormone (PTH) secretion maintains free-ionised extracellular calcium (Ca2+o) homeostasis under the control of the calcium-sensing receptor (CaR). In humans and dogs, blood acidosis and alkalosis is associated with increased or suppressed PTH secretion respectively. Furthermore, large (1.0 pH unit) changes in extracellular pH (pHo) alter Ca2+o sensitivity of the CaR in CaR-transfected HEK-293 cells (CaR-HEK). Indeed, it has been found in this laboratory that even pathophysiological acidosis (pH 7.2) renders CaR less sensitive to Ca2+o while pathophysiological alkalosis (pH 7.6) increases its Ca2+o sensitivity, both in CaR-HEK and parathyroid cells. If true in vivo, then CaR’s pHo sensitivity might represent a mechanistic link between metabolic acidosis and hyperparathyroidism in ageing and renal disease. However, in acidosis one might speculate that the additional H+ could displace Ca2+ bound to plasma albumin, thus increasing free-Ca2+ concentration and so compensating for the decreased CaR responsiveness. Therefore, I first demonstrated that a physiologically-relevant concentration of albumin (5% w/v) failed to overcome the inhibitory effect of pH 7.2 or stimulatory effect of pH 7.6 on CaR-induced intracellular Ca2+ (Ca2+i) mobilisation. Determining the molecular basis of CaR pHo sensitivity would help explain cationic activation of CaR and permit the generation of experimental CaR models that specifically lack pHo sensitivity. With extracellular histidine and free cysteine residues the most likely candidates for pHo sensing (given their sidechains’ pK values), all 17 such CaR residues were mutated to non-ionisable residues. However, none of the resulting CaR mutants exhibited significantly decreased CaR pHo sensitivity. Even co-mutation of the two residues whose individual mutation appeared to elicit modest reductions (CaRH429V and CaRH495V) failed to exhibit any change in CaR pHo sensitivity. I conclude therefore, that neither extracellular histidine nor free cysteine residues account for CaR pHo sensitivity. Next, it is known that cytosolic cAMP drives PTH secretion in vivo and that cAMP potentiates Ca2+o-induced Ca2+i mobilisation in CaR-HEK cells. Given the physiological importance of tightly controlled PTH secretion and Ca2+o homeostasis, here I investigated the influence of cAMP on CaR signalling in CaR-HEK cells. Agents that increase cytosolic cAMP levels such as forskolin and isoproterenol potentiated Ca2+o-induced Ca2+i mobilisation and lowered the Ca2+o threshold for Ca2+i mobilisation. Indeed, forskolin lowered the EC50 for Ca2+o on CaR (2.3 ± 0.1 vs. 3.0 ± 0.1 mM control, P<0.001). Forskolin also potentiated CaR-induced ERK phosphorylation; however protein kinase A activation appeared uninvolved in any of these effects. Pertussis toxin, used to block CaR-induced suppression of cAMP accumulation, also lowered the Ca2+o threshold for Ca2+i mobilisation though appeared to do so by increasing efficacy (Emax). Furthermore, mutation of the CaR’s two putative PKA consensus sequences (CaRS899 and CaRS900) to a non-phosphorylatable residue (alanine) failed to alter the potency of Ca2+o for CaR or attenuate the forskolin response. In contrast, phosphomimetic mutation of CaRS899 (to aspartate) did increase CaR sensitivity to Ca2+o. Together this suggests that PKA-mediated CaRS899 phosphorylation could potentiate CaR activity but that this does not occur following Ca2+o treatment in CaR-HEK cells. Together, these data show that cAMP regulates the Ca2+o threshold for Ca2+i mobilisation, thus helping to explain differential efficacy between CaR downstream signals. If true in vivo, this could help explain how multiple physiological signal inputs may be integrated in parathyroid cells.
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Kawano, Yuichi. "Effect of hyperglycemia on glucose transport and intracellular signal transduction in skeletal muscle /." Stockholm, 1999. http://diss.kib.ki.se/1999/91-628-3593-9/.
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Zhong, Zhihui. "Proinsulin c-peptide : membrane interactions and intracellular signaling /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7349-886-6.
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Sadreev, Ildar. "Mathematical modelling of inter- and intracellular signal transduction : the regulatory role of multisite interactions." Thesis, University of Exeter, 2015. http://hdl.handle.net/10871/21212.
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Signalling processes regulate various aspects of living cells via modulation of protein activity. The interactions between the signalling proteins can occur at single or multiple sites. Although single site protein interactions are relatively easy to understand, these rarely occur in living systems. It is therefore important to investigate multisite interactions. Despite the recent progress in experimental studies, the underlying molecular mechanisms and molecular functions of the multisite interactions are still not clear and therefore require systems approaches for deeper understanding, for example to understand how the system will react to perturbation of one of its components. The examples of the molecular functions that are studied in this thesis are: kinetics of multisite calcium binding to proteins such as calmodulin (CaM), multisite phosphorylation of interferon regulatory factor 5 (IRF-5) and signal transducers and activators of transcription (STATs). We also study the role of STATs in the overall immune response and in T cell phenotype switching as well as multisite phosphorylation of high osmolarity glycerol factor 1 (Hog1) in mitogen activated protein kinase (MAPK) cascade during the adaptation of Candida glabrata to osmotic stress. In this thesis, these examples are studied using the systems approach in the context of human diseases: cancer, candidiasis, immunity-related pathologies such as rheumatoid arthritis, inflammatory bowel disease and systemic lupus erythematosus. We discuss potential therapeutic implications of the proposed models in these diseases. The predictions of the models developed in this thesis are supported by the experimental data and propose possible mechanisms of the multisite interactions involved in the cellular regulation.
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Öberg, Camilla. "The life and death of the notch intracellular domain /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-464-X/.
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Li, Sen, and 李森. "Intracellular alkalinization induces cytosolic Ca2+ increases by inhibiting sarco/endoplasmic reticulum Ca2+-ATPase (SERCA)." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B46940546.
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Tong, Chun-kit Benjamin, and 唐俊傑. "Molecular mechanism of disrupted capacitative calcium entry in familial Alzheimer's disease." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hdl.handle.net/10722/205870.
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Presenilin (PS) is the catalytic subunit of the gamma-secretase which is responsible for the cleavage of amyloid precursor protein to form beta amyloid (Aβ). Mutations in PS cause familial Alzheimer’s disease (FAD) by increasing the Aβ plaques formation in the brain and thereby induce neurodegeneration. Apart from this, FAD-linked PS mutations have been demonstrated to disrupt cellular calcium (Ca2+) homeostasis. Ca2+is a vital secondary messenger that involved in various neurophysiological functions, including memory, learning, and neuroplasticity and mounting evidence suggesting that Ca2+dysregulation associated with PS mutations may play a proximal role in the AD pathogenesis. Yet, the molecular mechanism for Ca2+dysregulation in AD remains debatable. It has been reported that cellular Ca2+homeostatsis can be disrupted in various ways.
On the one hand, mutant PS has been demonstrated to exaggerate Ca2+release from the endoplasmic reticulum (ER) through different pathways. On the other hand, attenuatedCa2+influx from the extracellular medium through the capacitative Ca2+entry (CCE) pathway has also been reported to bring about cellular Ca2+disruption. However, the molecular mechanism for the PS mutation-mediated CCE deficits is largely unknown. For this reason, the objective of the current study is to elucidate the underlying molecular mechanism for attenuated CCE in AD.
In this study, human neuronal cell line SH-SY5Y is employed as a cellular model to investigate the effect of wild-type or FAD-linked PS1 mutation on CCE pathway. Using single cell Ca2+imaging technique, significant CCE deficits was observed in SH-SY5Y stably expressing FAD-linked PS1mutation, PS1M146L. Interestingly, this CCE attenuation in PS1 mutant expressing cells was not mediated by the down-regulation of STIM1 and Orai1 expression, the known essential molecular players in the CCE pathway. Instead, co-immunoprecipitation and proximity ligation assay have suggested a physical interaction between PS1 and STIM1 proteins. Moreover, a putative gamma-secretase mediated STIM1 cleavage was discovered by western blotting. In addition, confocal imaging showed that PS1M146L significantlyreduceSTIM1 puncta formation and ER translocation followed by the activation of CCE pathway by ER Ca2+store depletion with thapsigargin. This indicated that mutant PS1 attenuates CCE by affecting STIM1 oligomerization or its recruitment with Orai1. Taken together, our results suggested the negative regulatory role of PS on CCE pathway and hypothesized the molecular mechanism of CCE where FAD-linked PS mutation is perceived as a gain-of-function mutation and enhanced the negative impact on STIM1 to inhibit Ca2+entry.This hypothetic model provides new insights into the molecular regulation for CCE pathway and the identification of the interacting domains between PS1 and STIM1 may suggest novel targets for the development of therapeutic agents that help to treat the disease.published_or_final_version
Physiology
Master
Master of Philosophy
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Thompson, Lauren. "Intracellular Signaling Contributions to Behaviors Relevant to Nicotine Addiction." VCU Scholars Compass, 2011. http://scholarscompass.vcu.edu/etd/253.
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Nicotine is the primary addictive substance in tobacco, and most smokers who quit will relapse within a year. Evidence shows that cigarette craving increases over time, termed “incubation.” The purpose of these studies was to see if protracted abstinence from chronic nicotine increases rat self-administration, an animal model with good face validity for human tobacco use, and if nicotine self-administration during daily exposure/after 8+ days of abstinence is regulated by extracellular signal-regulated kinase (ERK) signaling in the nucleus accumbens (NAc) shell or anterior cingulate cortex (PFC). ERK kinase inhibitor U0126 was infused in the NAc shell or PFC of Long Evans rats immediately prior to daily self-administration sessions and following 8+ days of abstinence. U0126 in the PFC decreased responding for nicotine during daily sessions. Following 8+ days of abstinence, animals showed a robust increase in responding for nicotine, blocked by U0126 in the NAc shell, but not the PFC. Western blots revealed that nicotine treatment decreased levels of a substrate of ERK, ribosomal s6 kinase (RSK), in the NAc shell and increased it in the PFC, which occurred independent of abstinence period. In contrast, levels of RSK were increased in the NAc shell following a nicotine challenge during the abstinence period. In summary, our data show that the ERK signaling pathway plays a vital role in nicotine addiction during daily nicotine exposure and following periods of abstinence.
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Chan, Ming Hang (Stanley), and stanley chan@baker edu au. "Investigation of The Intracellular Signalling Pathway for Interleukin-6 Gene Expression in Skeletal Muscle." RMIT University. Medical Sciences, 2007. http://adt.lib.rmit.edu.au/adt/public/adt-VIT20080206.091026.
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Webb, Dominic-Luc. "Temporal monitoring of intracellular Ca²⁺ signaling and origins of Ca²⁺ oscillations /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-741-3/.
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Pasley, William. "Intracellular pH, the Proximate Signal for Cell Volume Changes that are Mediated by the Actin Cytoskeleton." VCU Scholars Compass, 2005. http://scholarscompass.vcu.edu/etd/1231.
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The relationship between initial intracellular pH (pHi) and associated cell volume change was investigated by simultaneous measurement of pHi and cell volume with fluorescence imaging in polarized fungiform taste receptor cells (TRCs) loaded with BCECF in vitro. Ammonium pulses caused a brief, reversible alkalinization in pHi and induced cell swelling. Sodium-acetate pulses reversible decreased TRC pHi and induced cell shrinkage. Removal weak acids and return to Control Ringer's solution (CR) causedTRC pHi and volume to overshoot baseline levels before fully recovering. Replacing CR with zero-sodium solution resulted in irreversible acidification of TRC pHi and induced cell swelling. Addition of sodium allowed reversal of TRC pHi and volume and return to baseline levels. Treating TRCs with cytoskeleton inhibitors, phalloidin and cytochalasin, before acidic stimulation did not affect TRC pHi, but did result in an altered TRC volume change. I conclude that a decrease in TRC pHi induces cell shrinkage via the actin cytoskeleton. Cell shrinkage as a result of a change in pHi activates NHE1 to restore TRC pHi and volume.
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Hassan, Mohamed. "Interference of Hepatitis C virus (HCV) core protein with intracellular signal transduction processes in liver cells /." Aachen : Shaker, 2001. http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&doc_number=012995533&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA.
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Bard, Frédéric. "Les transducteurs du signal src, cbl et cas et le trafic vesiculaire intracellulaire." Lyon, École normale supérieure (sciences), 1999. http://www.theses.fr/1999ENSL0131.
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Src, cbl et p 130cas sont lies a la transduction du signal issu des recepteurs aux facteurs de croissance et des integrines. Src est une tyrosine kinase regulant l'activite mitogenique, la motilite, le cytosquelette d'actine et peut-etre aussi le trafic vesiculaire des cellules. Cbl est un adaptateur multiple et un regulateur negatif des recepteurs a tyrosine kinase dont elle catalyse l'ubiquitination et l'orientation vers une degradation lysosomiale. L'observation par immunofluorescence en microscopie confocale (cif) de cellules cho, d'osteoclastes et de neurones revele cbl au niveau du golgi. Apres fractionnement subcellulaire, une portion de cbl est retrouvee dans les membranes et enrichie avec le golgi. Src est associee aux membranes et pourrait ancrer cbl au golgi ; en effet elle est partiellement colocalisee par cif et copurifiee biochimiquement avec des marqueurs du golgi. Dans la fraction membranaire, cbl est hyperphosphoryle et co-immunoprecipite avec src. La transfection d'un src active induit une augmentation, detectee par cif, de la quantite de cbl au niveau du golgi. Ces resultats indiquent que des complexes cbl-src se forment de facon regulee sur les membranes de golgi. Pp 130cas est une proteine associee a crk et un substrat de src et fak. Elle est phosphorylee apres stimulation des integrines et serait un adaptateur multiple. Sa perte de fonction induit des defauts d'organisation de l'actine et des contacts focaux et une perte de motilite cellulaire. L'observation par cif de cellules nih3t3 indique que cas est localise sur une nouvelle structure situee dans certains pseudopodes et constituee d'agregats de vesicules. Cette structure est revelee par deux anticorps anti-cas differents dont la neutralisation par des peptides specifiques abolit le marquage. Une structure similaire est detectee avec des anticorps anti-crk-l. La structure est associee avec des microtubules et un traitement au nocodazole induit sa disparition. Dans des osteoclastes, cas est localise a la fois sur des vesicules alignees sur des microtubules et dans les podosomes, suggerant un nouveau mecanisme de controle des contacts focaux par un trafic vesiculaire et les microtubules. Ces travaux suggerent des liens etroits entre transduction du signal par les tyrosines kinases et transport de membranes a l'interieur des cellules.
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Al-Khalili, Lubna. "Gene regulation, intracellular signaling and membrane traffic : studies in primary human skeletal muscle cultures /." Stockholm, 2004. http://diss.kib.ki.se/2004/91-7349-866-1/.
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Hui, Xin [Verfasser], and Peter [Akademischer Betreuer] Lipp. "Protein Kinase C, the Spatial and Temporal Modulator of Intracellular Signal Transduction / Xin Hui. Betreuer: Peter Lipp." Saarbrücken : Saarländische Universitäts- und Landesbibliothek, 2015. http://d-nb.info/1072409984/34.
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Teyssier, Catherine. "Mécanisme de l'interférence transcriptionnelle entre le récepteur des oestrogènes et les facteurs AP-1." Montpellier 1, 2000. http://www.theses.fr/2000MON1T007.
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Coudronnière, Nolwenn. "Régulation du cycle de réplication du virus de l'immunodéficience humaine de type (vih-1) par des signaux transmis par la molécule cd4." Montpellier 1, 1998. http://www.theses.fr/1998MON1T008.
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DA, SILVA CORREIA JEAN. "Les voies de signalisation intracellulaires mediees par les proteines kinases activees par les facteurs de stress, p38 et jnk : caracterisation, biologie et role dans la regulation de la transcription (doctorat : pharmacologie et pharmacochimie)." Strasbourg 1, 1998. http://www.theses.fr/1998STR15081.
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Hung, Chun-hin, and 孔進軒. "Effect of novel Chinese specific presenilin-1 V97L mutation on intracellular calcium homeostasis in human neuroblastoma." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hdl.handle.net/10722/193533.
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Presenilin-1 (PS1) mutations caused by the PSEN1 gene mutations are the major cause of early onset familial Alzheimer’s disease (EOFAD). Two Chinesespecific EOFAD related PS1 mutations, V97L and A136G, have been found. Studies suggested that V97L mutation lead to the overexpression of Aβ42 and tau hyperphosphorylation, which are the major hallmarks of Alzheimer’s disease (AD), while properties of A136G were unclear. Since calcium dysregulation was suggested to play an important role in AD, the research project investigated if V97L and A136G mutations also lead to altered endoplasmic reticulum (ER) 〖Ca〗^(2+) regulation. SH-SY5Y cells transduced with retrovirus carrying V97L mutant or A136 mutant PSEN1 were used as the experiment models.
In Western blotting, while the PS1 expression level was unaffected in V97L mutant, the expression level was significantly lower in A136G mutant. In carbachol (CCh) perfusion experiment, V97L mutant was found to exaggerate ER 〖Ca〗^(2+) release when stimulated by higher concentration (30, 100 and 300 μM) CCh, while A136G mutant exaggerated ER Ca2+ release when stimulated by 30 μM and 300 μM CCh, but not 100 μM CCh. In 5% fetal bovine serum (FBS) perfusion experiment, both V97L and A136G mutants were found to sensitize 〖Ca〗^(2+) oscillation, which the sensitization effect of V97L was 3 folds of A136G.
The results suggested that V97L mutation exaggerates ER 〖Ca〗^(2+) release, possibly via interaction with IP3R. However the results of A136G were inconclusive and contradicting, therefore further investigation is needed.published_or_final_version
Physiology
Master
Master of Medical Sciences
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Matos, Pinto Thiago. "Computational models of intracellular signalling and synaptic plasticity induction in the cerebellum." Thesis, University of Hertfordshire, 2013. http://hdl.handle.net/2299/11560.
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Many molecules and the complex interactions between them underlie plasticity in the cerebellum. However, the exact relationship between cerebellar plasticity and the different signalling cascades remains unclear. Calcium-calmodulin dependent protein kinase II (CaMKII) regulates many forms of synaptic plasticity, but very little is known about its function during plasticity induction in the cerebellum. The aim of this thesis is to contribute to a better understanding of the molecular mechanisms that regulate the induction of synaptic plasticity in cerebellar Purkinje cells (PCs). The focus of the thesis is to investigate the role of CaMKII isoforms in the bidirectional modulation of plasticity induction at parallel fibre (PF)-PC synapses. For this investigation, computational models that represent the CaMKII activation and the signalling network that mediates plasticity induction at these synapses were constructed. The model of CaMKII activation by calcium-calmodulin developed by Dupont et al (2003) replicates the experiments by De Koninck and Schulman (1998). Both theoretical and experimental studies have argued that the phosphorylation and activation of CaMKII depends on the frequency of calcium oscillations. Using a simplified version of the Dupont model, it was demonstrated that the CaMKII phosphorylation is mostly determined by the average calcium-calmodulin concentration, and therefore depends only indirectly on the actual frequency of calcium oscillations. I have shown that a pulsed application of calcium-calmodulin is, in fact, not required at all. These findings strongly indicate that the activation of CaMKII depends on the average calcium-calmodulin concentration and not on the oscillation frequency per se as asserted in those studies. This thesis also presents the first model of AMPA receptor phosphorylation that simulates the induction of long-term depression (LTD) and potentiation (LTP) at the PF-PC synapse. The results of computer simulations of a simple mathematical model suggest that the balance of CaMKII-mediated phosphorylation and protein phosphatase 2B (PP2B)-mediated dephosphorylation of AMPA receptors determines whether LTD or LTP occurs in cerebellar PCs. This model replicates the experimental observations by Van Woerden et al (2009) that indicate that CaMKII controls the direction of plasticity at PF-PC synapses. My computer simulations support Van Woerden et al’s original suggestion that filamentous actin binding can enable CaMKII to regulate bidirectional plasticity at these synapses. The computational models of intracellular signalling constructed in this thesis advance the understanding of the mechanisms of synaptic plasticity induction in the cerebellum. These simple models are significant tools for future research by the scientific community.
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Ontiveros, Steven J. "Intracellular trafficking of the hantaviral nucleocapsid protein and its function in modulation of immune signaling." Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2009. https://www.mhsl.uab.edu/dt/2010r/ontiveros.pdf.
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Dinerstein-Cali, Hélène. "Etude des molecules impliquees dans la transduction du signal du recepteur de l'hormone de croissance (doctorat : endocrinologie et interactions cellulaires)." Paris 11, 2000. http://www.theses.fr/2000PA11T005.
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Ng, Dominic Chi Hiung. "Characterizing intracellular signaling mechanisms involved in the progression of cardiac hypertrophy and failure : involvement of JAK/STAT and MAPK pathways." University of Western Australia. Biochemistry and Molecular Biology Discipline Group, 2003. http://theses.library.uwa.edu.au/adt-WU2003.0032.
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[Truncated abstract] The innate ability of the heart to compensate for an increase in workload as a result of disease or injury, through an increase in size and mass is known as cardiac hypertrophy. The hypertrophy of the heart compensates for an increase in workload with an increase in cardiac output. However, excessive hypertrophy can result in cardiac dysfunction and substantially increases the risk of cardiac failure and mortality. The molecular mechanisms that regulate the development of cardiac hypertrophy and cardiac failure are not entirely understood. Traditionally, the G-protein Coupled Receptor (GPCR) and the downstream Mitogen-Activated Protein Kinase (MAPK) family of proteins have been implicated. However, elevated circulating and ventricular levels of several classes of cytokines also suggested that signaling by the downstream effectors of cytokine receptors, such as the Signal Transducers and Activators of Transcription (STATs), may be important. The aim of this thesis was, therefore, to characterize the involvement of MAPK and STAT pathways in regulating cardiac hypertrophy and cardiac failure. A function for MAPK and STAT signaling in regulating cardiac hypertrophy stimulated by the inflammatory cytokine IL-1Β was initially defined in primary cultures of neonatal rat cardiac myocytes. In this study, it was demonstrated that the chemical inhibition of ERK or p38MAPK was sufficient to inhibit IL-1Β-stimulated ANF expression. In contrast, simultaneous inhibition of both ERK and p38MAPK was required to ablate the hypertrophic morphology of cardiac myocytes treated with IL-1Β. These results demonstrated differential signaling from the MAPK isoforms in regulating the gene expression and morphological components of cardiac hypertrophy. In addition, it was revealed that IL-1Β treatment resulted in a delayed response (>60 min) in STAT3α tyrosine phosphorylation, which was subsequently shown to require the initial rapid activation of either ERK or p38MAPK. IL-1Β-stimulated STAT3 phosphorylation was also dependent on the de novo synthesis of secondary signaling molecules. The ablation of the STAT3 tyrosine phosphorylation by the inhibition of ERK or p38MAPK activity, correlated with the attenuation of IL-1Β-stimulated ANF expression, suggesting that signaling through STAT3α may be involved in regulating gene expression associated with IL-1Β cardiac hypertrophy
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Ichas, François. "La mitochondrie, organelle excitable : participation active à la signalisation calcique intracellulaire." Bordeaux 2, 1997. http://www.theses.fr/1997BOR28475.
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Girard, Emmanuelle. "Caractérisation de nouveaux régulateurs du transport intracellulaire du cholestérol : mise en évidence du rôle de la dynamine et des GTPases Rab7 et Rab9." Phd thesis, Université Paris Sud - Paris XI, 2013. http://tel.archives-ouvertes.fr/tel-00923162.
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Le transport intracellulaire du cholestérol et sa distribution correcte au niveau des différentes membranes sont essentiels pour assurer de nombreuses fonctions cellulaires. Malgré l'importance de ce transport les mécanismes de sa régulation restent encore mal connus. L'objectif de cette thèse était de mieux caractériser les acteurs du transport intracellulaire du cholestérol. Dans ce contexte, nous nous sommes intéressés à deux acteurs de ce transport : la dynamine et les Rab GTPases. Dans la première partie de la thèse nous avons utilisé le dynasore, un inhibiteur pharmacologique de la dynamine pour étudier le rôle de la dynamine dans le contrôle du transport endolysosomal dans les cellules HeLa et les macrophages humains. Nous avons ainsi confirmé le rôle de la dynamine dans la sortie du compartiment endolysosomal et la régulation de l'homéostasie du cholestérol. Dans la deuxième partie de la thèse, nous avons étudié le rôle de Rab7 et de Rab9 dans le transport du cholestérol en utilisant la technique d'ARN interférence ainsi que l'expression de mutants dominant négatifs. Nous avons montré qu'en plus de son rôle classique dans les étapes tardives du transport du cholestérol, Rab7 contrôle les étapes précoces du transport endosomal. Enfin, nous avons évalué le rôle de Rab7 dans notre modèle de macrophages humains surchargés. Nous avons mis en évidence un effet limité de l'inactivation de Rab7 sur le contrôle de l'homéostasie du cholestérol mais à l'inverse un effet majeur pour l'efflux du cholestérol vers l'apo AI. En conclusion, notre étude a permis de mieux caractériser le transport vésiculaire du cholestérol et de démontrer son importance dans la régulation de l'homéostasie intracellulaire en cholestérol. Nos résultats permettent également d'établir le rôle critique de Rab7 dans le trafic des LDL au niveau des endosomes précoces.
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Pelletier, Nadine. "Régulation des gènes C/EBPS par des voies de signalisation intracellulaire dans les cellules épithéliales intestinales." Mémoire, Université de Sherbrooke, 1996. http://savoirs.usherbrooke.ca/handle/11143/3110.
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Nous avons utilisé la lignée épithéliale intestinale de crypte de rat IEC-6 afin de mieux comprendre le rôle des C/EBPs dans la différenciation et la prolifération de l'intestin. Nous avons vérifié l'expression des ARNm de C/EBP$\alpha$, C/EBP$\beta$ et C/EBP$\delta$ suite à la stimulation des cellules IEC-6 par la forskoline et l'IBMX qui stimulent la PKA, le TPA qui stimule la PKC et la thapsigargine qui augmente la concentration de Ca$\sp{2+}$ cytoplasmique. La forskoline et l'IBMX induisent les niveaux d'ARNm des trois C/EBPs avec différentes cinétiques tandis que le TPA induit seulement les niveaux d'ARNm de C/EBP$\alpha$ et de C/EBP$\beta.$ La thapsigargine induit les niveaux d'ARNm des trois isoformes par un mécanisme de régulation post-transcriptionnel sans affecter les niveaux de protéines. Les variations des niveaux d'ARNm, induits par les trois voies de signalisation, étaient indépendantes d'une synthèse nouvelle de protéines. Les analyses des niveaux de protéine par Western nous ont permis de constater une induction des trois isoformes en accord avec celle des ARNm suite à une stimulation par la forskoline et l'IBMX. Nous avons observé que le patron d'expression des protéines C/EBP$\alpha$ et C/EBP$\beta$ concorde avec celui des ARNm après une stimulation par le TPA. La capacité de liaison à l'ADN des C/EBPs n'est pas affectée significativement par les voies de la PKA, de la PKC et du Ca$\sp{2+}.$ Les voies de la PKA et de la PKC peuvent moduler l'expression de certains gènes de la réponse inflammatoire comme l'haptoglobine et le thiostatin. La stimulation de ces différentes voies inhibe la prolifération cellulaire des cellules IEC-6 en absence et en présence de sérum. Finalement, nous avons observé que ces différentes voies pouvaient induire à des niveaux variables l'ARNm de p21, un gène très important dans l'arrêt de la prolifération cellulaire. [Résumé abrégé par UMI] [Symboles non conformes]
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Arastoo, Mohammed. "Characterisation of phospholipase C-η enzymes and their relevance to disease." Thesis, University of St Andrews, 2016. http://hdl.handle.net/10023/15698.
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Phospholipase C enzymes are a class of enzymes that catalyse the cleavage of the membrane phospholipid, phosphatidylinositol bisphosphate (PtdIns(4,5)P₂) into the second messengers, inositol trisphosphate (Ins(4,5)P₃) and diacylglycerol (DAG). Six classes of PLC enzymes have been identified based on their structure and mechanism of activation. PLCηs are the most recently identified family and consist of two isozymes, PLCη1 and PLCη2. The aim of this thesis is to further understand the mechanisms of PLCη activation, the role of PLCη2 in relation to neuritogenesis and their roles in certain disease states. Both isoforms were found to be activated by physiological concentrations of intracellular Ca²⁺. Activation of PLCη2 by Gß₁γ₂ was confirmed using a bacterial 2A co-expression system to allow expression of PLCη2, Gß₁ and Gγ₂ with a single plasmid. Localisation studies show a nuclear distribution for PLCη2, but a cytoplasmic distribution for PLCη1 in a neuroblastoma cells line (Neuro2A). PLCη2 has been implicated in brain development and neurite formation. Building on this, a neuronal differentiation model using RA-treated Neuro2A cells stably expressing mutant forms of PLCη2 was utilised, revealing that PLCη2 activity is essential for neuritogenesis but that this process is independent of the enzymes high sensitivity towards Ca²⁺. Furthermore, the direct interaction of PLCη2 and LIMK-1, a previously identified PLCη2 associated protein, is confirmed in the aforementioned neuronal model. Due to the high sensitivity of PLCη enzymes to Ca²⁺ and because of their presence within neurons, they may be involved in Ca²⁺ dysregulation that occurs in certain diseases such as Alzheimer's disease (AD). The role of PLCη2 was assessed in amyloid-ß (Aß) treated differentiated Neuro2A cells, a cellular model for AD pathogenesis. Also a developmental role for PLCη1 was investigated due to a recently identified PLCη1 polymorphism in patients with holoprosencephaly, an embryonic midline defect.
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Waxman, Joshua S. "Functions of the Dapper family of Dishevelled-interacting proteins in Xenopus and zebrafish /." Thesis, Connect to this title online; UW restricted, 2004. http://hdl.handle.net/1773/5062.
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Kinkl, Norbert. "Mechanisms of action of fibroblast growth factor 2 (FGF2) in rat retinal cells : photoreceptor survival and intracellular signaling." Université Louis Pasteur (Strasbourg) (1971-2008), 2001. http://www.theses.fr/2001STR13166.
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La dégénérescence des photorécepteurs est à l'origine de nombreuses pathologies rétiniennes aboutissant à une malvoyance voire à la cécité. Les facteurs neurotrophiques représentent une approche thérapeutique potentielle. Au cours de cette thèse nous nous sommes intéressés aux mécanismes d'actions in vitro d'un facteur neurotrophique exprimé dans la rétine, le FGF2. Afin d'étudier les effets directs du FGF2 sur la survie des photorécepteurs, nous avons mis au point un nouveau modèle de culture pure en photorécepteurs à partir de rétine jeune de rat. La pureté en photorécepteurs des cultures est > 99,5%, les cellules gliales de Müller (CGM) représentant < 0,5% de la population cellulaire. Grâce à ce modèle, nous avons montré que le FGF2 stimule la survie des photorécepteurs in vitro et qu'un autre facteur neurotrophique, l'EGF, accélère leur dégénérescence, en activant leurs récepteurs respectifs à activité tyrosine kinase. Les FGFR1-4 ainsi que différentes protéines impliquées dans la transduction du signal du FGF2 (ERK1/2, MEK1, MEK2, PLCg1, SHPTP-2, SOS1, SOS2, Grb2, Shc, Akt), sont exprimés de façon ubiquitaire, mais possèdent des niveau d'expression distinct, selon les différentes populations de cellules rétiniennes (photorécepteurs, rétine interne et CGM) in vivo et in vitro. Néanmoins, le FGF2 y induit des cascades de signalisation distinctes. Ceci indique l'existence de différentes voies de transduction du signal au FGF2 dans la rétine aboutissant toutes à l'activation de ERK1/2. L'inhibition pharmacologique de MEK bloque l'activation de ERK1/2 dans les photorécepteurs et inhibe leur survie induit par le FGF2, alors qu'au niveau des cellules de la rétine interne et des CGM, le FGF2 stimule également des voies d'activation de ERK1/2 indépendantes de MEK. L'ensemble de ces résultats apporte des données originales concernant les effets du FGF2 sur la survie des photorécepteurs ainsi que sur sa signalisation dans la rétine de rat in vitro, et pourrait contribuer à une application potentielle du FGF2 dans une approche clinique.
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LAGAUD, GUY. "Mecanisme de couplage entre les recepteurs a l'atp et a la noradrenaline, signal calcique et contraction dans les arteres de resistance : effets du gmp c." Strasbourg 1, 1996. http://www.theses.fr/1996STR15071.
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Davezac, Noélie. "La phosphatase CDC25B: bases moléculaires de sa localisation intracellulaire et recherche de nouveaux partenaires." Phd thesis, Université Paul Sabatier - Toulouse III, 2001. http://tel.archives-ouvertes.fr/tel-00010040.
Full textAbstract:
La progression des cellules dans le cycle cellulaire est gouvernée par une famille de complexes à activité protéine kinase : les complexes CDK/cycline. L'activité de ces complexes est régulée notamment par la déphosphorylation activatrice de résidus tyrosine et thréonine par les phosphatases à double spécificité CDC25. Trois phosphatases CDC25 ont été identifiées dans les cellules de mammifères, et lors de notre travail, nous avons étudié la phosphatase CDC25B. Dans les cellules d'adénocarcinome humain (HeLa), nous avons montré que CDC25B présente une localisation nucléaire ou cytoplasmique stricte ou pan cellulaire, suggérant un trafic nucléo-cytoplasmique actif. Par des approches de mutagenèse dirigée et d'expression transitoire de la protéine sauvage ou mutante, nous avons identifié un signal de localisation nucléaire (NLS) et d'export nucléaire (NES) fonctionnels, et montré que la rétention cytoplasmique de CDC25B nécessite son interaction avec les protéines 14-3-3. Afin de caractériser les mécanismes régulant la fonction de CDC25B in vivo, nous avons entrepris la recherche de nouveaux partenaires de cette phosphatase. Partant d'observations biochimiques : la phosphorylation in vitro de CDC25B par la protéine kinase Eg3, nous avons établi que ces deux protéines interagissent in vivo, dans une lignée surexprimant de manière conditionnelle CDC25B. Une collection de protéines mutantes de CDC25B, nous a permis d'identifier (i) le site d'interaction avec la protéine kinase Eg3, (ii) un site de phosphorylation. Aucune modification de l'activité phosphatase de CDC25B, phosphorylée par Eg3 n'est observée in vitro. Cependant, nous avons montré in vivo, par une analyse en cytométrie de flux, que l'expression de CDC25B est capable d'annuler l'accumulation des cellules en phase G2 induite par la surexpression de Eg3. Ces derniers résultats suggèrent fortement une interaction fonctionnelle entre CDC25B et Eg3, dont les mécanismes in vivo restent à préciser. L'isolement de nouveaux partenaires protéiques de CDC25B a été entrepris par leur co-purification grâce à l'utilisation de lignées U2OS exprimant HA-CDC25B de manière conditionnelle, ou de protéines recombinantes MBP-CDC25B. Certains problèmes techniques ne nous ont pas encore permis d'isoler des partenaires, mais les derniers résultats sont prometteurs.