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1
Petzinger, Jutta [Verfasser]. "Urokinase-Rezeptor (uPAR) und Zellkontakte : Mechanismen uPAR-abhängiger Zelladhäsion, Zellmigration und Signaltransduktion / Jutta Petzinger." Gießen : Universitätsbibliothek, 2011. http://d-nb.info/1063177480/34.
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Alsén, Maria, and Nils Järgenstedt. "Kommunikation med hjälp av mock-uper." Thesis, Blekinge Tekniska Högskola, Institutionen för programvaruteknik och datavetenskap, 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:bth-4919.
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In several cases, systems that have been developed have been very time consuming and cost a lot of money, but they still do not fulfil the users requirements and requests. To make new systems better, you have to find a way to communicate that allows the developers to understand the needs of the user. The aim for our thesis is to highlight the importance of communication in system development. To investigate this we have choosen to do a study of the real-estate system. The work methods that have been used include mock-ups and informal conversations with the user, who is employed by the Church of Sweden in Ronneby. The purpose of this thesis is, among other things, to provide the Church of Sweden in Ronneby with a report, which can be of help for further development of the system. The system was developed by a work group at Blekinge Institute of Technology. Our question of issue is: Would the Church of Sweden in Ronneby obtain a more useful system if the developers applied the guidelines and experience that exists within the area of HCI? Further more we have looked in to if the communication has improved with the use of mock-ups to increase the interaction? Human-computer interaction as a term was adopted in the mid-1980s as a means of describing this new field of study. The focus of interest described the new way of looking at the interaction between computers and people. In this field it is important to involve the user in the developing process from the beginning to the end. Together with the user, we have made some propositions based on previous documentation from the project. Mock-ups are a prototype of paper that shows the user what the system will look like. This method was applied together with the user, to find a more logical structure for the system. After gathering the result of the case study, we can honestly say that communication do increase because of mock-ups. Good communication is not something that you can learn from books; you have to adjust to the situation. It is important when you develop a system to work with a model that allows you to go back and change things in previous phases that are incorrect, and also to include the user in the whole process.
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SaÌnchez, Luis Gustavo Alvarez. "Suspended sediment dynamics in the uper gulf of California." Thesis, Bangor University, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.401909.
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Kean, Thomas. "Development of a synthetic uPAR targeted gene delivery system." Thesis, Cardiff University, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.635545.
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Barson, Helen. "Studies on the cellular function of the uPA/uPAR system." Thesis, University of Aberdeen, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.419648.
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The uPA receptor, uPAR, is GPI-linked and therefore contains no transmembrane domains. Yet, uPA:uPAR binding can initiate cell signalling and may involve adaptor proteins, such as integrins. Various responses to uPA binding have been described, but the exact mechanisms remain undefined. To identify potential downstream changes caused by uPA binding, MCF7 cells were treated ± uPA or ATF (the uPAR-binding part of uPA) for various times. Gene expression was studied using custom cDNA microarrays, containing genes relating to a range of cellular processes. Changes in expression were normalised to 0 min and buffer-only controls, and genes with a fold change less than 2.5-fold were discounted. Gene expression changes that were observed in two or more treatments were shortlisted, from which thirteen were selected fro verification by real-time RT-PCR. These experiments were done on cDNA from a further cell treatment with uPA. The results did not reflect those of the microarrays; no changes in expression were observed. The microarray data were then analysed in a different, more stringent, way, but not target genes were identified. This study identified no clear candidate genes but gene expression after uPA:uPAR binding remains an important question. uPAR is present in lipid rafts and these may allow its association with signalling molecules. This study investigated whether potential uPAR adaptor proteins, αv or β1 integrins, moved into rafts when cells bound uPA. Mouse cells transfected with human uPAR were treated ±uPA, and lipid rafts were extracted from the cells. uPAR was readily detectable in lipid rafts under al conditions, but the integrins were not found to associate with lipid rafts even after uPA treatment.
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Smith, Harvey W. "Signalling from uPAR to the Activation of the Small GTPase Rac." Thesis, Institute of Cancer Research (University Of London), 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.499157.
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Huber, Michaela Verfasser], Angelika [Akademischer Betreuer] [Gutachter] [Schnieke, Michaela M. [Gutachter] Aubele, and Jochen [Gutachter] Graw. "Das uPAR-System: Identifizierung neuer uPAR-Interaktionspartner und ihre Relevanz beim triple-negativen Brustkrebs / Michaela Huber ; Gutachter: Michaela M. Aubele, Jochen Graw, Angelika Schnieke ; Betreuer: Angelika Schnieke." München : Universitätsbibliothek der TU München, 2016. http://d-nb.info/1122482132/34.
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Papaioannou, Alexandra. "Fine-tuning UPR signals and subsequent cellular outputs." Thesis, Rennes 1, 2019. http://www.theses.fr/2019REN1B013.
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La présente thèse explore le monde de la biologie du stress du RE (réticulum endoplasmique). Une vue globale du RE et du stress du RE est d'abord fournie en commençant par les mécanismes de base impliqués pour aller vers de possibles applications cliniques. L'accent est ensuite mis sur le rôle crucial de l'UPR dans la cancérogénèse, qui est activée en réponse au stress du RE dans la micro-environnement de la tumeur. Après avoir passé en revue ces aspects, nous mettons en évidence des éléments manquants dans notre compréhension de la façon dont les signaux UPR sont affinés et conduisent soit à la restauration de l'homéostasie du RE et des cellules soit à la mort cellulaire. Parmi les branches de l'UPR, les signaux ATF6 et IRE1 deviennent notre sujet d'investigation en raison de leur convergence dans la régulation du facteur XBP1 favorisant la survie. D'une part, nous découvrons les mécanismes provenant du lumen du RE qui régulent l'activation de l'ATF6 en réponse au stress du RE et affectant la signalisation adaptative cellulaire de l'ATF6 en aval. D'autre part, nous observons l'existence d'un réseau autorégulateur de l'activité RNase de l’IRE1 consistant en un système tyrosine kinase-phosphatase ciblant la RtcB et impactant l'épissage de l'ARNm de XBP1. Ainsi, grâce à nos études, nous avons découvert un circuit de signalisation intégré capable d’ajuster avec précision les sorties cellulaires de l’activation conjointe ATF6 et IRE1 en réponse au stress du REThe present thesis explores the world of ER (endoplasmic reticulum) stress biology. A global view of ER and ER stress is first provided with a transition from the basic mechanisms involved to possible clinical applications. The focus is then placed to the crucial role of the UPR in carcinogenesis that is activated in response to ER stress in the micro-environment of the tumor. After reviewing these aspects, we point to missing parts in our comprehension of how UPR signals are fine-tuned and lead to either restoration of ER and cell homeostasis or cell death. Among the UPR branches, ATF6 and IRE1 signaling become our focus of investigation because of their convergence in the regulation of the pro-survival factor XBP1s. On the one hand, we unravel mechanisms originating from the ER lumen that regulate the ATF6 activation in response to ER stress and affect its downstream cell adaptive signaling. On the other hand, we witness the existence of an auto-regulatory network of IRE1 RNase activity consisted of a tyrosine kinase-phosphatase system that targets RtcB and impacts on XBP1 mRNA splicing. Hence, through our studies we uncover an integrated signaling circuit that can fine-tune the cellular outputs of the joint ATF6 and IRE1 activation in response to ER stress
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Huber, Timo Adrian. "Design and synthesis of BACE1 inhibitors and uPAR-Selective ligands for radiotherapy /." München : Verl. Dr. Hut, 2009. http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&doc_number=018861815&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA.
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Arendholz, Tanja [Verfasser]. "Bedeutung des uPA/uPAR-Systems für die Proliferation glatter Gefäßmuskelzellen / Tanja Arendholz." Gießen : Universitätsbibliothek, 2012. http://d-nb.info/1064024483/34.
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Patrizia, Marzorati. "Characterisation of Hematopoietic Stem/Progenitor cells and their mobilization in uPAR KO mice." Thesis, Open University, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.524734.
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Kuribayashi, Juliana Sayuri. "A desregulação da via UPR associada à imunodeficiência comum variável." Universidade de São Paulo, 2007. http://www.teses.usp.br/teses/disponiveis/42/42133/tde-05102007-153124/.
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A imunodeficiência comum variável (CVID) é caracterizada por hipogamaglobulinemia e infecções recidivantes. Neste estudo verificamos o papel da via Unfolded Protein Response (UPR) na patogênese da doença. Uma paciente com CVID apresentou expressão aumentada do RNAm XBP-1 unspliced e co-localização de IgM e BiP no retículo endoplasmático (RE). Verificamos a ausência de mutações nos produtos obtidos por RT-PCR de XBP-1 e nos domínios quinase/endonuclease da IRE-1a. Análises por Q-PCR dos RNAm XBP-1 spliced, IRE-1a e BiP após tratamento com LPS ou brefeldina A mostrou que, ao contrário dos controles saudáveis que respondem a estes estressores com ondas de transcrição destes três genes, esta paciente apresenta baixos níveis de transcrição, não atingindo o mesmo nível de resposta apresentado pelos indivíduos saudáveis. Nossos achados associam o splicing diminuído do RNAm XBP-1 ao acúmulo de IgM no RE e baixas taxas de transcrição de chaperonas, fornecendo um mecanismo para explicar a hipogamaglobulinemia observada em uma paciente com CVID.Common Variable Immunodeficiency (CVID) is characterized by hypogammaglobulinemia and recurrent infections. Herein we addressed the role of Unfolded Protein Response (UPR) in the pathogenesis of the disease. Augmented unspliced XBP-1 mRNA concurrent with co-localization of IgM and BiP was found in one CVID patient. Sequencing of RT-PCR amplicons did not reveal any mutation on XBP-1 neither on the kinase/endonuclease domains of IRE-1a. Q-PCR analysis of spliced XBP-1, IRE-1a and BiP after LPS or Brefeldin A treatment showed that, unlike healthy controls that respond to these ER stressors by presenting waves of transcription of these three genes, the cells presented lower rates of transcription, not reaching the same level of response of healthy subjects. Our findings associate diminished splicing of XBP-1 mRNA with accumulation of IgM within the ER and lower rates of chaperone transcription, therefore providing a mechanism to explain the observed hypogammaglobulinemia.
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Damasceno, Andreia Goreti Marques. "Mapping UPR elements in male reproductive system: a bioinformatics approach." Master's thesis, Universidade de Aveiro, 2017. http://hdl.handle.net/10773/22006.
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Mestrado em Biomedicina MolecularA Unfolded Protein Response (UPR) é um mecanismo de defesa crucial que protege as células contra o enrolamento incorreto de proteínas, através da ativação de três sensores principais: ATF6, PERK e IRE1. Cada sensor guia a célula em diferentes mecanismos de transdução de sinal culminando na produção de fatores de transcrição que, por sua vez, regulam genes que aumentam a capacidade da célula corrigir a conformação de proteínas mal enoveladas, impedindo, em último caso, a sua agregação. Nos últimos anos a UPR tem sido associada a várias patologias. Na infertilidade masculina, poucos estudos se têm focado na influência dos componentes da UPR, sendo importante numa primeira abordagem, a identificação destes componentes no sistema reprodutor masculino. Através de pesquisa de bases de dados e com abordagens bioinformáticas, com o objetivo de identificar potenciais candidatos associados a fenótipos de infertilidade, foi realizada uma recolha de proteínas UPR no testículo, espermatozoide e plasma seminal. De forma a determinar possíveis alvos envolvidos na infertilidade masculina, as interações proteínaproteína foram analisadas, destacando-se 6 proteínas com elevado grau de interação: HSP90AA1, HSPA5, SEC61A1, VCP, PERK e ATF4. Considerando ainda a sua importância funcional, as proteínas efetoras da via PERK, a GADD34 e a eIF2 foram destacadas para estudos de deteção experimentais. Neste sentido, foi confirmada pela primeira vez a presença das proteínas PERK e GADD34 em espermatozoides humanos. Estes resultados constituem o primeiro passo fundamental para avançar para estudos mais aprofundados relativamente à expressão e níveis de atividade destes candidatos, procurando perceber a contribuição dos mesmos na via de sinalização UPR e a sua eventual desregulação na infertilidade masculina.
The unfolded protein response (UPR) is an essential cell defense response against defects in protein folding and it is mainly triggered by the activation of ATF6, PERK and IRE1. Each sensor leads to different signal transduction mechanisms through the production of transcription factors that, in turn, regulate genes that increase the cell's ability to correct conformation of poorly folded proteins, ultimately hindering their aggregation. The past years shed light on the role of the UPR in several diseases. Regarding male infertility, few studies have focused on the implications of UPR components, hence the need to a prior approach concerning the presence of these components on the male reproductive system. Through a database search and using bioinformatics approaches, with the aim of identifying potential candidates associated with infertility phenotypes, a collection of UPR proteins in the testis, spermatozoa and seminal plasma was performed. To determine potential targets to scrutinize possible involvement in male infertility, a protein-protein interaction network analysis was performed, depicting 6 key proteins highly interconnected: HSP90AA1, HSPA5, SEC61A1, VCP, PERK and ATF4. Considering their functional value, the effector proteins of the PERK pathway, GADD34 and eIF2 were highlighted for experimental studies. Thus, the presence of the PERK and GADD34 were confirmed for the first time in human spermatozoa. These results constitute the first fundamental step towards further studies on the expression and activity levels of these candidates and understand their contribution to the UPR signaling pathway and their possible deregulation in male infertility
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Aßmann, Anke [Verfasser]. "Die Regulation von uPAR durch metabolische Faktoren in vivo und in vitro / Anke Aßmann." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2008. http://d-nb.info/1023098784/34.
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Bhaker, Sangita. "Novel insight into uPAR function in the bronchial epithelium in asthma using functional genomics." Thesis, University of Nottingham, 2017. http://eprints.nottingham.ac.uk/45133/.
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The urokinase plasminogen activator receptor (uPAR, PLAUR) is a cell surface receptor actively involved in the regulation of cell homeostasis. Expression is elevated in the bronchial epithelium in vivo and also in serum and sputum in asthma and elevated expression often indicates poor prognosis in a number of human diseases. The relative contribution of uPAR to asthma disease mechanisms is not fully understood and the functional roles of uPAR isoforms remains to be resolved. The key aims of this thesis were to i) investigate how the uPAR pathway may influence bronchial epithelial barrier properties; ii) investigate the gene expression patterns in the bronchial epithelium in asthma; iii) identify functions of different forms of uPAR in human bronchial epithelial cells (HBEC) and to iv) investigate the association between genetic polymorphisms spanning the PLAUR gene with clinical features and the presentation of asthma in moderate to severe asthma. Using two cell based approaches we identified an inverse relationship between soluble-cleaved uPAR expression and epithelial barrier properties. Importantly, we demonstrated that blocking uPAR-integrin interactions provides a potential therapeutic opportunity to improve epithelial barrier function. Using whole transcriptome analysis genes differentially expressed between cultured asthma and control subjects were identified which were related to cell growth, repair and immune regulation. Furthermore, uPAR expression was elevated in epithelial cells in asthma subjects compared to healthy controls, suggesting expression is inherently altered in the bronchial epithelium in asthma. Transcriptomics was used to provide novel insight into the specific and overlapping functions of uPAR isoforms and to determine the effects of elevated uPAR expression on HBEC function. Finally, the contribution of PLAUR genetic variants to clinical and immunological traits within asthma were investigated and found that PLAUR single nucleotide polymorphisms (SNPs) did not show an association with the traits measured in a severe asthma population. Overall this work has provided new insight into the function of uPAR as a regulator of the bronchial epithelium in asthma.
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Gonçalves, Amanda Hellen. "Estudo experimental do controle de movimento de uma plataforma Stewart do tipo 6-UPUR /." Bauru, 2019. http://hdl.handle.net/11449/183123.
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Orientador: Marcos SilveiraCoorientador: Mauricio Becerra Vargas
Banca: Douglas Domingues Bueno
Banca: Fabricio Cesar Lobato de Almeida
Resumo: Robôs paralelos ou robôs de cadeia cinemática fechada vêm ganhando destaque no cenário industrial e acadêmico, principalmente diante da necessidade de robôs com altas acelerações e velocidades, alta relação capacidade de carga/peso e alta rigidez e precisão, motivo pelo qual são usados em simuladores de voo e robôs pick-and-place. Muitos trabalhos foram publicados tratando sobre o controle de posição de robôs paralelos, porém muitos mantiveram-se restritos ao estudo teórico, sem considerar algumas limitações na aplicação prática. Neste contexto, esta dissertação apresenta o projeto e a implementação prática de um controlador PD (Proporcional-Derivativo) independente para cada junta de um robô paralelo de seis graus de liberdade do tipo 6-UPUR (universal-prismáticauniversal- rotational) acionado por atuadores lineares eletromecânicos. Inicialmente foi realizada a calibração e o acondicionamento do sinal dos sensores de realimentação, do driver e dos atuadores eletromecânicos. Posteriormente, modelos matemáticos do comportamento dinâmico dos atuadores lineares foram identificados e, finalmente, considerando critérios de desempenho específicos para simuladores de voo, foram projetados os controladores para cada atuador. O desempenho de cada controlador foi avaliado por meio de sinais de entrada em degrau, rampa e parábola em coordenadas cartesianas e, por meio da cinemática inversa, foram calculadas as entradas desejadas para cada atuador. O desempenho do robô na frequência foi ... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: Parallel robots or closed kinematic chain robots has gained more attention from both in industry and in academic research, especially in view of the need for robot whith high velocities and accelerations, high payload-weight ratio, high stiffness and accuracy. That is why they are used in flight simulators and robots pick-and-place. Many studies have been published addressing the problem of motion control of parallel robots, but many are limited to the theoretical study, without considering some limitations in practical application. In this context, this dissertation presents the design and practical imple- mentation of independent-joint PD (Proportional-Derivative) controller for a 6-UPRU (universal-prismatic-universal-rotational) degree-of-freedom parallel manipulator driven by electromechanical linear actuators. First, the feedback sensors, drive and electrome- chanical actuators are calibrated, and their signals are processed. Later, mathematical models of the dynamical behaviour of the linear actuators are identified. Then, conside- ring specific performance criteria for flight simulators, the controller for each actuator is designed. The performance of each controller was evaluated for step, ramp and parabolic inputs in cartesian coordinates, then the cartesian trajectory is converted to desired actu- ator trajectory by using inverse kinematics. The perfomance of the robot was evaluated in frequency domain using sinousoidal inputs in cartesian coordinates, describing fu... (Complete abstract click electronic access below)
Mestre
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Kacsinta, Apollo Daniel. "Determining Biological Effectors of alpha6 Integrin Cleavage." Diss., The University of Arizona, 2010. http://hdl.handle.net/10150/193604.
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Cancer metastasis is a multi–step process that initiates with a tumor cell obtaining the ability to migrate. A multitude of changes occur in such a cell including changes to cell adhesion molecules such as integrins. In cancer cells, integrins are known to be involved in migration, invasion and metastasis. Investigation by our group of the α6 integrin led to the discovery of a cleaved form of the integrin lacking the ligand binding domain, called α6p. While it is known that the integrin is cleaved by urokinase plasminogen activator (uPA) little is known about how this process is regulated. There is a need to better understand the players involved in regulation of α6 cleavage as inhibiting this event from occurring may contribute to prolonged or increased patient survival or ultimately a cure.The existence of the integrin–actin complex has been known for many years. In this study actin was identified as a potential regulator of α6 cleavage. Using a diverse set of tumor cell lines (DU145, PC3 and MDA–MB–231) and a number of actin modifing compounds (latrunculin A, jasplakinolide and siRNA) it is reported here that disassembling actin filaments leads to an increase in α6p production. Although the increase in cleavage product did not always correlate with an increase in uPA receptor, an increase in uPAR was observed when actin was complexed by small molecule inhibitors. Taken together the results demonstrate a potential role for actin filaments to protect α6 integrin from uPA–uPAR induced cleavage via a multi–protein complex.
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Randle, Diandra Dominique. "Snail mediates cell invasion through uPa-uPar and mark signaling in human prostate cancer cells." DigitalCommons@Robert W. Woodruff Library, Atlanta University Center, 2014. http://digitalcommons.auctr.edu/dissertations/1648.
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Epithelial-mesenchymal transition (EMT) is a process by which cancer cells acquire mesenchymal properties, such as induction of vimentin, while epithelial-associated genes like E-cadherin are lost. This enables the cells to be more metastatic. Factors that can induce EMT include growth factors like transforming growth factor -P (TGF-P) and epidermal growth factor (EGF), and transcription factors like Snail. Snail-induced EMT promotes migration and invasion and we hypothesized that this may be mediated by urokinase (uPA) and its receptor (uPAR) activities. LNCaP, 22Rvl and ARCaP human prostate cancer (CaP) cells stably transfected with constitutively active Snail displayed increased cell invasion as compared to the empty vector control (Neo). Superarray analysis revealed an up-regulation in uPA and uPAR RNA expression in Snailtransfected ARCaP cells as compared to Neo control. Next, the protein expression levels of Snail, uPA, and uPAR were measured by western blot analysis in various prostate cancer cell lines which showed that overexpression of Snail increased uPA and uPAR protein levels. The activity of uPA in conditioned media was measured using an ELISA assay which revealed that uPA activity was elevated in LNCaP, 22Rvl and ARCaP cells overexpressing Snail. Additionally, transient silencing of uPAR in ARCaP cells overexpressing Snail using siRNA resulted in abrogation of Snail-mediated invasion. Snail overexpression was associated with increased ERK activity and antagonism of this activity with MAPK inhibitor, UO126, inhibited cell invasion and decreased uPA activity. Therefore, Snail-mediated cell invasion in human prostate cancer cells may occur via the regulation of uPA/ uPAR and the MAPK signaling pathways.
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Guo, Jinbai. "Control of cell division by nutrients, and ER stress signaling in Saccharomyces cerevisiae." Texas A&M University, 2003. http://hdl.handle.net/1969.1/5912.
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Cell cycle progression of Saccharomyces cerevisiae cells was monitored in
continuous cultures limited for glucose or nitrogen. The G1 cell cycle phase, before
initiation of DNA replication, did not exclusively expand when growth rate decreased.
Especially during nitrogen limitation, non-G1 phases expanded almost as much as G1. In
addition, cell size remained constant as a function of growth rate. These results contrast
with current views that growth requirements are met before initiation of DNA replication,
and suggest that distinct nutrient limitations differentially impinge on cell cycle
progression. Therefore, multiple mechanisms are hypothesized to regulate the
coordination of cell growth and cell division.
Genetic interactions were identified between the dose-dependent cell-cycle
regulator 2 (DCR2) phosphatase and genes involving in secretion/unfolded protein
response pathway, including IRE1, through a genome-wide dominant negative genetic
approach. Accumulation of unfolded proteins in the endoplasmic reticulum triggers the
unfolded protein response (UPR). How the UPR is downregulated is not well
understood. Inositol requirement 1 (IRE1) is an endoplasmic reticulum transmembrane UPR sensor in Saccharomyces cerevisiae. When the UPR is triggered, Ire1p is
autophosphorylated, on Ser 840 and Ser 841, inducing the cytosolic endonuclease
activity of Ire1p, thereby initiating the splicing and translational de-repression of HAC1
mRNA. Homologous to Atf/Creb1 (Hac1p) activates UPR transcription. We found that
that Dcr2p phosphatase functionally and physically interacts with Ire1p. Overexpression
of DCR2, but not of a catalytically inactive DCR2 allele, significantly delays HAC1
splicing and sensitizes cells to the UPR. Furthermore, Dcr2p physically interacts in vivo
with Ire1p-S840E, S841E, which mimics phosphorylated Ire1p, and Dcr2p dephosphorylates
Ire1p in vitro. Our results are consistent with de-phosphorylation of
Ire1p being a mechanism for antagonizing UPR signaling.
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Sidenius, Nicolai. "Urokinase receptor cleavage and shedding : occurrence and consequences." Thesis, Open University, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.323274.
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Fattouh, Nour. "Caractérisation du mode de vie intracellulaire des endosymbiotes Wolbachia." Thesis, Montpellier, 2018. http://www.theses.fr/2018MONTT079.
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Les bactéries intracellulaires Wolbachia ont développé une vaste gamme d’interactions symbiotiques, du parasitisme reproductif au mutualisme chez les arthropodes terrestres et les nématodes filaires, devenant ainsi les endosymbiotes les plus répandus sur terre. Bien qu’elles se développent lentement dans les cultures cellulaires d’insectes pour lesquelles les marqueurs sont limités et qu’elles ne sont génétiquement pas manipulables, il existe un intéret croissant de déchiffrer leur mode de vie intracellulaire pour 2 raisons. Premièrement, Wolbachia intervient dans le développement et la transmission des arbovirus et deuxièmement, les filarioses lymphatiques sont traitables grâce à la susceptibilité des Wolbachia qui infectent les nématodes filaires aux antibiotiques. Au début de ce projet, j’ai infecté 2 lignées cellulaires de Drosophila melanogaster qui sont transcriptomiquement divergentes par une même souche de Wolbachia pouvant naturellement infecter Drosophila melanogaster. J’ai utilisé ces 2 lignées cellulaires qui sont différentiellement permissive à l’infection pour explorer l’interaction de Wolbachia avec le réticulum endoplasmique. Les observations par microscopie à fluorescence en temps réel et par microscopie électronique prouvent que cet organite est une source de membranes pour Wolbachia et possiblement, une source de nutriments. Pourtant, les analyses d’expression génique et les approches d’immunofluorescence démontrent que Wolbachia n’induit ni un stress au niveau du réticulum endoplasmique ni une protéolyse via la voie de signalisation ERAD suggérant dès lors, que Wolbachia subvertissent d’autres mécanismes pour assurer leur besoin en acides aminés. Au cours de ce projet, j’ai commencé à mettre en place une technique pour transformer Wolbachia par biolistique. La validation de cette technique de transformation a ouvert la voie vers l’optimisation de la procédure de sélection des transformants pour enfin pouvoir génétiquement manipuler WolbachiaThe intracellular bacteria Wolbachia have developed a wide range of symbiotic interactions, from being opportunistic reproductive parasites to mutualists with terrestrial arthropods and filarial nematode species, making them the most common endosymbionts on earth. The discovery that they interfere with arboviruses development and transmission by mosquito vectors and that filarial diseases can be cured by targeting Wolbachia, have created a strong interest in deciphering the mechanisms underlying their intracellular lifestyle. However, being obligate intracellular endosymbionts, Wolbachia remain genetically intractable. They grow slowly in insect cell cultures, for which markers are limited. Despite these obstacles, and to limit cell line-specific phenotypes, I chose to infect 2 Drosophila melanogaster cell lines presenting different sets of expressed genes, with a unique Wolbachia strain, naturally hosted by Drosophila melanogaster. Using these 2 cell lines that are differently permissive to the infection, I explored the interaction of Wolbachia with the endoplasmic reticulum (ER). Through fluorescence time-lapse confocal and electron microscopy observations, I provide strong evidence that this organelle is the source of membrane for Wolbachia, and possibly a source of nutrients. However, gene expression analyses and immunofluorescence approaches demonstrate that Wolbachia do not induce ER stress nor an increased ERAD- induced proteolysis, suggesting; unlike previously reported, that Wolbachia salvage amino acids by other subversion mechanisms. Additionally, I pioneered biolistic bombardement of Wolbachia-infected cells and the validation of this transformation technique has paved the way towards optimization of transformant selection steps and ultimately to the genetic engineering of Wolbachia
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FALEIRO, Mariana Batista Rodrigues. "Expressão de mmp-2, mmp-9 e upar em próstatas caninas normais e c lesões proliferativas." Universidade Federal de Goiás, 2010. http://repositorio.bc.ufg.br/tede/handle/tde/941.
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Previous issue date: 2010-03-02Humans and dogs show dysplastic lesions in the prostate, such as prostatic intraepithelial neoplasms (PIN) and proliferative inflammatory atrophy (PIA), which are studied due to their malignance potential. The matrix metalloproteinases (MMP) are a family of proteolytic enzymes thought to play an important role in tumor invasion and metastasis in face of their ability to degrade the extracellular matrix (ECM) and basement membrane. The plasminogen activator (PA) system has been suggested to play a central role in cell adhesion, migration, wound healing, angiogenesis, inflammation, regulation of growth factors and tumor invasion. The receptor of plasminogen activator type activator (uPAR) is a component of the PA, with a range of expression in tumor cell and stromal cells. So, this study was aimed to evaluated the expression and correlation between MMP-2 (gelatinase A) and MMP-9 (gelatinase B) as well as the expression of uPAR in normal canine prostate tissue and also in tissue with proliferative disorders, including benign prostatic hyperplasia (HPB), PIA, PIN and carcinoma. And therefore establish relation among the role of these enzymes in the remodeling of the extracellular matrix (ECM) and in the process of tumor invasion and metastasis. For this, it was performed immunohistochemical staining in tissue microarray of 149 paraffin-embedded fragments of prostate tissue selected from 57 prostates of non-castrated adult dogs with or without prostatic diseases. A total of 298 cores were analyzed and it was made 363 diagnoses: 36 (9.9%) normal, 49 (13.5%) BPH, 132 (36.3%) PIA, 75 (20.7%) PIN and 71 (19.6%) carcinomas. It was observed differences in cytoplasmatic immunohistochemical staining by MMP-2 and MMP-9 antibodies in relation to the cell number and intensity of labeling of the acinar epithelial and stromal perilobular cells between normal tissue and in those with proliferative disorders. A correlation between MMP-2 and MMP-9 antibodies occurred just in canine prostates with PIA in relation to the number of labeled cells in acinar epithelium and perilobular stroma, as well as, the staining intensity in the perilobular stromal cells. In relation to uPAR, it was observed differences of immunohistochemical staining of uPAR antibodies in canine prostate. Likewise, there was over expression in dysplastic and neoplasic specimens, but not in normal and benign prostate tissue. A number of epithelial cells labeled for uPAR showed variation among the diagnoses, except between PIN and carcinoma. Less intensity of labeling was observed in acinar epithelial cells of normal prostates compared with PIA, PIN and carcinoma. However, in the normal cells and in those with PIA, there was a difference in the number of cells, as well as in the intensity of stromal labeling. The intensity of labeling of stromal perilobular cells was higher in the PIA. PIA-A (accentuated) and PIA-M (moderated) cells showed greater intensity staining stroma and stromal cells labeled for uPAR, respectively. Thus, this study concludes that there was variation in gelatinases and uPAR expression in canine prostate according to the lesion. Also, there was Less labeling in normal and BPH and higher in PIA, PIN and carcinoma prostate tissues. The correlation between MMP-2 and MMP-9 in canine prostates with PIA indicates that the inflammation likely influenced the activity of these enzymes with simultaneous increase in their expression. The uPAR high expression in inflammatory and neoplasic tissues suggests high ECM proteolytic activity in these situations
Nas espécies humana e canina lesões displásicas da próstata, como a neoplasia intra-epitelial prostática (PIN) e a atrofia inflamatória proliferativa (PIA), são estudadas quanto ao potencial de malignidade. As metaloproteinases (MMP) são enzimas proteolíticas envolvidas no processo de invasão tumoral e metástase, causando destruição de barreiras biológicas como a matriz extracelular (MEC) e a membrana basal (MB). O sistema ativador de plasminogênio (PA) compreende proteínas com ação na adesão celular, regulação da migração, cicatrização, angiogênese, inflamação, regulação de fatores de crescimento e invasão tumoral. O receptor de ativador de plasminogênio tipo uroquinase (uPAR) é um dos componentes do PA, com variação de expressão em células neoplásicas e estromais. Este trabalho teve por objetivo verificar a expressão e a correlação entre MMP-2 e MMP-9, assim como a expressão do uPAR no tecido prostático canino normal e com alterações proliferativas, incluindo a hiperplasia prostática benigna (HPB), a PIA, a PIN e o carcinoma, buscando avaliar o papel dessas proteínas no remodelamento da MEC e no processo de invasão tumoral e metástase. Para isso, foi realizada a imunoistoquímica em lâminas de microarranjo tecidual (TMA), com 149 cores selecionadas de 57 próstatas de cães adultos, não castrados, com ou sem histórico de afecções prostáticas. Foram analisados, para cada anticorpo, 298 cores, perfazendo 363 diagnósticos, sendo 36 (9,9%) normais, 49 (13,5%) HPB, 132 (36,3%) PIA, 75 (20,7%) PIN e 71 (19,6%) carcinomas. Foi possível observar diferença de imunomarcação citoplasmática de MMP-2 e MMP-9 em relação ao número de células e intensidade de imunomarcação nas células epiteliais acinares e estromais periacinares em relação aos diagnósticos. A correlação entre os anticorpos MMP-2 e MMP-9 ocorreu em próstatas caninas com PIA quanto ao número de células imunomarcadas no epitélio acinar e no estroma periacinar, bem como quanto à intensidade de imunomarcação nas células estromais periacinares. Quanto ao uPAR, houve diferença na imunomarcação em relação ao diagnóstico, com maior expressão nas displásicas e neoplásicas em relação ás normais e com HPB. O número de células epiteliais imunomarcadas para uPAR variou entre os diagnósticos, exceto entre PIN e carcinoma. Menor intensidade de imunomarcação epitelial foi constatada nas próstatas normais em relação às com PIA, PIN e carcinoma. Entre as normais e com PIA houve diferença no número de células e intensidade de imunomarcação estromal. A intensidade de imunomarcação estromal foi maior nas com PIA. As PIA-M (inflamação moderada) e PIA-A (inflamação acentuada) apresentaram maior intensidade de imunomarcação estromal e células estromais imunomarcadas para uPAR, respectivamente. Concluiu-se que há variação na expressão das gelatinases e do uPAR na próstata canina, de acordo com a lesão, com menor expressão nas normais e com HPB e maior naquelas com PIA, PIN e carcinoma. A correlação entre MMP-2 e MMP-9 em próstatas caninas com PIA indica que a inflamação influencia a atividade dessas enzimas, com aumento simultâneo na expressão de ambas no microambiente inflamatório. Ainda, o aumento na expressão do uPAR nos microambientes inflamatório e neoplásico sugere maior atividade proteolítica na MEC nesses casos
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MABILAT, PRAGNON CHRISTELLE. "Systeme upa/upar dans la migration cellulaire : localisation subcellulaire dans les cellules endotheliales et les eosinophiles." Paris 7, 1998. http://www.theses.fr/1998PA077253.
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Que ce soit dans des circonstances physiologiques ou pathologiques, la migration cellulaire est un phenomene ubiquitaire. Nous pouvons citer comme exemples, la migration des cellules endotheliales pendant la formation des vaisseaux sanguins (l'angiogenese) et la migration des globules blancs lors des reactions inflammatoires de l'organisme. Le systeme urokinase/recepteur de l'urokinase (upa/upar) joue un role majeur dans la migration cellulaire. L'objectif de ce travail etait 1) de caracteriser le systeme upa/upar dans deux types cellulaires differents ; 2) d'etudier l'effet du blocage de l'upar sur la migration cellulaire. Les resultats de cette these montrent que 1) la distribution subcellulaire du systeme upa/upar est tres differente entre les cellules endotheliales et les eosinophiles et qu'elle est tres finement controlee. Dans les cellules endotheliales, l'upar est associe a des structures membranaires particulieres, les caveoles, qui sont des invaginations specifiques de la membrane plasmique. Dans les eosinophiles, le systeme upa/upar, stocke dans des vesicules intracytoplasmiques, est retrouve au niveau de la membrane plasmique apres l'activation des cellules. Ainsi, la localisation du systeme upa/upar depend de l'etat d'activation et du potentiel migratoire de la cellule ; 2) la rupture de l'axe upa/upar, en bloquant l'upar avec une proteine chimerique, inhibe de maniere spectaculaire la migration des cellules endotheliales in vitro. Ainsi, le blocage de l'upar pourrait conduire a l'inhibition de l'angiogenese en inhibant la migration des cellules endotheliales. L'ensemble de ces resultats ouvre de larges perspectives de recherche sur le developpement d'agents bloquant l'upar, qui, en inhibant la migration des cellules endotheliales, peuvent etre utilises comme therapeutique anti-angiogenique pour le traitement du cancer.
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Kruse, Kristina Beth. "ER quality control beyond ERAD and the UPR : uncovering the role of autophagy /." abstract and full text PDF (UNR users only), 2005. http://0-gateway.proquest.com.innopac.library.unr.edu/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3209117.
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de, Bock Charles Edo St George Clinical School UNSW. "Novel protein interactors of urokinase-type plasminogen activator receptor." Awarded by:University of New South Wales. St George Clinical School, 2005. http://handle.unsw.edu.au/1959.4/23009.
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The plasminogen activator (PA) system plays an important role in cell adhesion, migration and invasion, and may require the coordinated expression of various proteins. The human urokinase-type plasminogen activator (uPA) receptor (uPAR) is a central protein component of the PA system. By binding its ligand uPA, uPAR can direct proteolysis of the extracellular matrix. Also, it is now apparent that uPAR can initiate proteolytic independent signal transduction to influence angiogenesis, inflammation, wound repair and tumour progression. To determine whether any novel proteins interacted with uPAR, a yeast two-hybrid screening analysis was undertaken using alternate uPAR domain constructs as baits. These included full-length three domain uPAR (uPAR-DIDIIDIII), two domain uPAR (uPAR-DIIDIII), and each individual uPAR domain (uPAR-DI, uPAR-DII and uPAR-DIII). A number of proteins were identified as putative candidate interactors for the alternate constructs, with two of special interest for uPAR-DIDIIDIII. These were the heat shock protein Mrj, and the extracellular matrix protein fibulin-2. The protein Mrj was shown to bind uPAR both in vitro and in vivo using GST-pull down and co-immunoprecipitation assays respectively. The GST-pull down assay identified the interaction between Mrj and uPAR dependent on the C-terminal domain of Mrj and DI of uPAR. Using in vivo co-immunoprecipitation analysis, Mrj also bound to uPAR. Preliminary data suggest the association between uPAR and Mrj may play a role in the regulation of apoptosis. In regard to the uPAR interactor of fibulin-2, a calcium dependent binding interaction with uPAR was identified using the GST-pull down assay. However due to the large molecular weight and stringent conditions needed to solubilise fibulin-2, it was not possible to co-immunoprecipitate both uPAR and fibulin-2. Together, the identification of both Mrj and fibulin-2 amongst other candidate interactors of uPAR presented here provides further insight into the intricate relationship between uPAR and other proteins which may influence a range of biological functions.
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Malengo, Gabriele. "Dynamics and oligomerization of urokinase plasminogen activator receptor (uPAR): a GIP-anchored receptor studied by fluorescence micro-spectoscopy." Thesis, Open University, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.489898.
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This work is addressed to the search for functional links between GPI-protein monomeroligomer exchange and membrane dynamics and confinement. To this end, uPAR was chosen as a GPI-receptor involved in the regulation of cell adhesion, migration and proliferation. The work is focused on tracking the molecular dynamics and the homotypic interactions of uPAR, using fully fiinctional fluorescent protein-tagged chimeras expressed in HEK293 cells.
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Moreau, Marie. "La ß-caténine et le NF-Kß coopèrent pour réguler le système uPA/uPAR dans des cellules tumorale." Paris 7, 2010. http://www.theses.fr/2010PA077113.
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La voie Wnt/ß-caténine est impliquée dans de nombreux événements comprenant l'adhésion, la migration, et la différenciation cellulaires. L'activateur du plasminogène de type urokinase (uPA) et son récepteur uPAR ont été décrits comme des gènes cibles de la voie Wnt/ß-caténine dans des cellules de cancer du colon. En utilisant deux lignées tumorales mammaires, MCF-7 et MDA-MB-231 et une lignée tumorale de colon, SW480, nous avons observé que l'inhibition de l'expression de la ß-caténine augmente l'expression d'uPA, d'uPAR et de l'inhibiteur de l'activateur du plasminogène PAI-1 ainsi que l'invasivité des cellules tumorales. La stabilisation de la ß-caténine par un traitement au chlorure de lithium (LiCl), inhibiteur de la glycogène synthase kinase-3beta (GSK-3ß) ou la co-transfection de vecteurs d'expression ß-caténine/Tcf-4 conduit à la diminution de l'expression des transcrits uPA, uPAR et PAI-1 dans les trois lignées. Le traitement des cellules transfectées par des siRNA ß-caténine avec un inhibiteur de la translocation nucléaire du nuclear factor-kappaB (NF-KB), le SN50, réduit significativement l'augmentation de l'expression des transcrits uPA, uPAR et PAI-1 et de l'invasivité cellulaire. De plus, nous avons observé une translocation nucléaire du NF-KB dans les cellules transfectées par un siRNA ß-caténine. Dans cette étude nous montrons un nouveau mécanisme de régulation du système uPA/uPAR par la ß-caténine, en coopération avec NF-KB, dans des cellules de cancer du sein et du colon. La ß-caténine peut exercer des effets inattendus dans les cellules tumorales et des stratégies thérapeutiques d'inhibition de son expression doivent être envisagées avec précautionThe Wnt/ß-catenin signaling influences many cellular processes including cell adhesion, growth and differentiation. Urokinase plasminogen activator (uPA) and urokinase plasminogen activator receptor (uPAR) have been reported as target genes of Wnt/ß-catenin signaling in colon cancer cells, since their expression is directly regulated through ß-catenin, binding to the T-cell factor binding element (TBE) motifs present in their promoters. Using three cancer cell models (MCF-7, MDA-MB-231 and SW480, breast and colon cancer cell lines, respectively) we demonstrated that silencing of ß-catenin increased uPA, uPAR and plasminogen activator inhibitor-1 (PAI-1) expression and the invasive potential of cancer cells. In addition, p-catenin stabilization and accumulation by lithium chloride (LiCl) treatment, an inhibitor of glycogen synthase kinase-3ß (GSK-3ß) or by ß-catenin/Tcf-4 expression vectors transfection led to a decrease in uPA, uPAR and PAI-1 mRNA expression in the studied cancer models. Moreover, the treatment of P-catenin siRNA transfected cells with a specific inhibitor of nuclear factor-kappaB (NF-KB) translocation, SN50, significantly reduced enhancement of uPA, uPAR and PAI-1 expression and cancer cell invasion. Furthermore, ß-catenin siRNA treated cells exhibited NF-KB nuclear translocation. In this study we present evidence of a novel cross-talk between ß-catenin and uPA/uPAR System through NF-KB cooperation in breast and colon cancer cells. Our results strengthen the emerging view that ß-catenin exerts different effects on tumor cells and that the therapeutic strategy of its inhibition could involve more complex mechanisms than originally anticipated
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Oliveira, Susana João Cunha de. "Impact of the UPR on the expression of relevant genes for cellular iron metabolism." Tese, Instituto de Ciências Biomédicas Abel Salazar, 2009. http://hdl.handle.net/10216/24349.
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Mesquita, Caroline Costa 1986. "Estudo da variação circadiana da UPR no hipotálamo e suas implicações na ingestão alimentar." [s.n.], 2015. http://repositorio.unicamp.br/jspui/handle/REPOSIP/312647.
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Orientador: Gabriel Forato AnhêTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: Os ritmos circadianos de ingestão alimentar se estabelecem com objetivo de manter a homeostasia de nutrientes no meio celular, frente a variações intrínsecas ao ciclo claro/escuro. Neste sentido, a gliconeogênese de roedores é suprimida no período noturno, no qual há ocorrência de um surto alimentar bifásico que compreende aproximadamente 90% de todo o aporte calórico diário. Estes eventos apresentam, entre si, uma relação causal, onde o próprio aumento dos nutrientes circulantes, principalmente a glicose, controla a gliconeogênese. O padrão inverso é observado na fase clara do ciclo claro/escuro. Recentes estudos têm demonstrado que, a ativação farmacológica de vias da Unfolded Protein Response (UPR), no sistema nervoso central, resulta em resistência à ação anorexigênica da insulina e, consequentemente, aumento da ingestão alimentar através de um mecanismo não completamente esclarecido. A UPR é uma resposta celular adaptativa que atenua a taxa de tradução de mRNAs, aumenta a proteólise e, deste modo, recupera o fenótipo celular. Esta reposta, quando ativada cronicamente, pode resultar em morte celular programada e resistência à insulina. No entanto, ainda não estava claro se a via do ATF6 da UPR tem, de fato, uma relação com o ritmo alimentar. Para responder a esse questionamento, realizamos análises da variação circadiana das proteínas envolvidas na via da UPR, imunoprecipitações com animais adrenalectomizados, e aplicação de dexametasona subcutânea. Os resultados demonstram que o ATF6 teve um aumento noturno atingindo o máximo de transição da fase clara para fase escura. A partir desse fato, foram realizados ensaios de imunuprecipitações em ratos adrenalectomizados para evidenciar as associações dos complexos CRTC2/ATF6 e CRTC2/CREB1. Contudo, nossos dados suportam a hipótese que os níveis fisiológicos de glicocorticóides podem reprimir a expressão CRH e estimular a ingestão de alimentos, através de uma via dependente de ATF6. Estes eventos, por consequência, poderão reduzir a atividade transcricional do CREB1, sobre o CRH, corroborando com os dados da literatura que apontam que os glicocorticóides endógenos dos roedores (principalmente a corticosterona) exercem um conhecido papel no controle da ingestão alimentar, decorrente principalmente da modulação da expressão do neurotransmissor anorexigênico CRH
Abstract: The circadian cycles of food intake have an important role in the homeostasis of cellular environment, acting over intrinsic changes to the sleep/wake cycle. Therefore, mice gluconeogenesis is suppressed at night where a food outbreak, responsible by 90% of all daily caloric ingestion, occurs. These events are connected by a causal relation, where the current nutrient increasing, mostly glucose, controls gluconeogenesis. The oppose pattern is verified during the light stage of the sleep/wake cycle. Recent studies have indicated that pharmacological activation of Unfolded Protein Response (UPR) pathways, at central nervous system, implies in resistance to the anorectic insulin effect, and, consequently, increase of the food intake activity trough a not fully explained engine. UPR is an adaptive cellular response that reduces mRNA¿s transcriptional rate, increases proteolysis, and therefore, restores cellular phenotype. This response, when constantly enabled, may induce cellular death and insulin resistance. However, it was not clear yet if the UPR¿s ATF6 pathway has, indeed, a connection with the feed rhythm. To answer to this question, we did several analysis of the circadian variation of the proteins connected to the UPR¿s pathway, adrenalectomized animals immunopreciptations and subcutaneous dexamethasone applications. The results demonstrated that ATF6 has a nightly increase and has reached the maximum of transcription rate from the light to the dark cycle. From this point, it was made immunopreciptations tests in adrenalectomized mice to evidence the association between CRTC2/ATF6 and CRTC2/CREB1 complexes. However, our data support the hypothesis that the physiological levels of glucocorticoids may suppress CHR expression and stimulate food intake trough an ATF6 dependent pathway. Those events, therefore, may reduce CREB1¿s transcriptional activity, confirming other studies data that indicates that endogenous mice glucocorticoids (mainly corticosterone) play an well-known role in food intake control, mainly due from modulation of the expression of the anorectic neurotransmitter CRH
Doutorado
Farmacologia
Doutora em Farmacologia
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Oliveira, Susana João Cunha de. "Impact of the UPR on the expression of relevant genes for cellular iron metabolism." Doctoral thesis, Instituto de Ciências Biomédicas Abel Salazar, 2009. http://hdl.handle.net/10216/24349.
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Gerakis, Yannis. "Stress réticulaire et maladie d'Alzheimer : contribution du facteur de transcription XBP-1s." Thesis, Université Côte d'Azur (ComUE), 2016. http://www.theses.fr/2016AZUR4097/document.
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La maladie d'Alzheimer est une pathologie neurodégénérative progressive liée à l'âge qui détériore premièrement les fonctions liées aux mémoires de travail et épisodiques, avant de s'étendre à l'ensemble des procédures mémorielles dans les stades plus avancés. L'ensemble des traitements existant à ce jour sont palliatifs. Au niveau histologique, la maladie d'Alzheimer est caractérisée par l'accumulation extra- et intracellulaire de différentes protéines agrégées (appelées amyloïde) dans les tissus cérébraux, entrainant des dysfonctions importantes du circuit neuronal. De fait, la majorité des approches thérapeutiques en développement consistent à tenter de réduire ou supprimer ces agrégats protéiques. Cependant, la maladie d'Alzheimer étant étroitement corrélée au vieillissement, certaines de ses caractéristiques biologiques sont parfois confondues avec celles du vieillissement non pathologique. L'une de ces caractéristiques est la diminution des différents mécanismes liés à l'homéostasie protéique (protéostasie). L'hypothèse réalisée au cours de mes travaux est que le rétablissement de ces mécanismes diminués par l'âge constituerait une approche thérapeutique crédible, complémentaire aux approches actuelles, à la pathologie complexe qu'est la maladie d'Alzheimer. C'est en suivant cette optique que je me suis intéressé au rôle et à la régulation de l'un des systèmes majeusr du contrôle de la protéostasie : l'UPR (unfolded protein response), et en particulier au facteur de transcription XBP-1s, considéré comme l'une des pièces maîtresses de ce réseau de signalisation cellulaireAlzheimer's disease is a neurodegenerative pathology strongly correlated to aging. Its symptoms are characterized by an impaired short term memory process in the early stages of the disease and later on by a loss of all type of memory process. There is actually no cure for this pathology. At the histo-pathological levels, the disease show an accumulation of aggregated proteins in the brain (called amyloid protein) in the intra or extra cellular space, which act as a disruptor of the normal neuronal function and activity. Thus, most of the therapeutic approach to treat the disease aim at removing those proteins aggregates from the brain. However, some of the Alzheimer's disease characteristics could be melded with normal aging : One such case is the global decrease of the proteostasis mechanism in the cell which normally happen in normal brain. The assumption made during this work is that the recovery of these mechanisms impaired by age would constitute a credible therapeutic approach, complementary to the other existing approaches to the complex disease that is Alzheimer's disease. Following this hypothesis I was interested in the role and regulation of one of the major system controlling proteostasis: the UPR (unfolded protein response), and particulary to the XBP-1s transcription factor , considered one of the master regulator of this cellular network
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Mularczyk, Ewa. "Understanding molecular pathology of chondrodysplasias : the role of ER stress." Thesis, University of Manchester, 2012. https://www.research.manchester.ac.uk/portal/en/theses/understanding-molecular-pathology-of-chondrodysplasias-the-role-of-er-stress(86ad2dcd-fcb6-4860-90d8-74f17996ac0d).html.
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MCDS is an autosomal dominant disorder, with a mild dwarfed phenotype and is caused by mutations in collagen X. The majority of the mutations identified so far are localized almost exclusively within the NC1 domain, which is responsible for trimerization of the collagen X protein. Little is known about the onset of MCDS, but recently, up-regulation of ER stress has been suggested as an important mechanism promoting the MCDS phenotype. Several studies have shown that the mutated collagen X protein is retained within the ER triggering the UPR, which has proved to be the key pathway responsible for the pathogenesis of the MCDS phenotype. In order to study the consequences of the expressing the MCDS-causing COL10A1p.N617K mutation at the molecular level, we selected HeLa cells as an appropriate cell line for the characterisation of the UPR response, by showing that the three branches of the UPR can be activated by ER stress inducing conditions in a similar manner to that seen in vivo in the MCDS growth plate. Importantly we have also shown that HeLa cells can be transduced with the collagen X cDNA constructs and will express, fold and secrete collagen X into the supernatant.Having established the cellular model for MCDS studies we demonstrated for the first time direct evidence for the retention of mutant collagen X within the ER. Moreover, we demonstrated that the mutant collagen X was degraded via a proteasomal pathway. Nevertheless, the level of ER stress induced by expression of mutant collagen X, based on BiP induction at the protein level, was disappointingly low. We therefore directly compared the level of ER stress induced by the COL10A1p.N617K mutation with that of the chondrodysplasias-causing MATN3p.V194D mutation. The ER stress induced by the matrillin mutation was far greater than that caused by the mutant collagen X. We showed that general protein synthesis was reduced in cells expressing either of the mutant proteins, most likely by the mechanism associated with the phosphorylation of eIF2alpha. Moreover, we showed the mutant matrilin-3 protein was also retained specifically in the ER. However, we could find no evidence for either proteasomal or autophagic/lysosomal degradation of mutant matrilin 3.We tested a broad range of ER stress-relieving compounds on cells expressing mutant collagen X and matrilin 3. Carbamazepine, which was previously shown to reduce ER stress in alpha1-antitripsin deficiency, reduced ER stress in cells expressing the mutant collagen X (but not matrilin 3) by way of enhanced proteasomal degradation of the retained protein. This drug should now be tested in vivo against the MCDS mouse to determine its capacity to reduce disease severity.The results presented within this thesis have contributed to the understanding of how cells deal with mutant collagen X and matrilin-3 proteins. We have identified a potential therapeutic compound that may be of use in the treatment of MCDS. Furthermore, the data presented support the concept that generic approaches to relieving ER stress may not be suitable for treating a broad range of diseases. Treatments may need to be tailored not only in a gene-specific manner but also may need to be tailored to address the differing consequences of different mutations in the same gene.
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Sandoval, Rubenstein Cynthia Priscilla, and Rubenstein Cynthia Priscilla Sandoval. "Laminin Binding α6β1 Integrin Regulation in Aggressive Cancer Cells and Tissue." Diss., The University of Arizona, 2017. http://hdl.handle.net/10150/625446.
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Despite recent advances in early detection, in 2017 prostate cancer is estimated to claim over 26,000 lives in the United States alone. Prostate cancer related morbidity and mortality is a result of secondary skeletal metastasis. Therefore, better understanding of the underlying molecular mechanisms of prostate tumor cell migration and subsequent metastasis is vital for improved clinical outcomes. Interestingly, integrin α6, a laminin receptor, is highly expressed in a number of aggressive tumor types including prostate and is associated with increased metastasis and reduced patient survival. Preliminary studies by our group found that α6 integrin undergoes a post-translational modification mediated by the serine protease, uPA and its receptor, uPAR, leading to the cleavage of α6 integrin and production of the tumor specific structural variant integrin α6p. Cleavage of this laminin receptor and production of α6p variant gives rise to an aggressive phenotype, markedly increasing tumor cell migration and invasion. Thus, the work conducted here sought to identify the function and efficacy of these prominent proteins in various aspects of tumor cell migration as well as the factors regulating α6 integrin cleavage.
Interestingly, utilization of a co-culture system of prostate tumor cells and macrophages found that a direct and indirect interaction between the two cell populations influenced α6 integrin cleavage. Specifically, prostate tumor cell interactions with macrophages, a known immune cell population that is highly observed in a number of primary tumors, resulted in increased protein levels of uPAR on the surface of prostate tumor cells that led to a significant production of α6p and subsequently increased invasion. Additionally, key downstream effectors of integrin signaling, including FAK, ILK, and actin, were found to regulate production of the tumor specific variant integrin α6p. Depletion of FAK, ILK, or actin, resulted in a significant increase in uPAR protein expression and subsequent α6 integrin cleavage, a regulatory event previously not known of these integrin signaling effector molecules. In addition, silencing of another prominently expressed laminin receptor, integrin α3β1, led to a significant increase in the cohesive collective phenotype exhibited by aggressive prostate tumor cells that was found to be facilitated by α6 integrin cleavage. Depletion of integrin α3β1 resulted in increased surface uPAR expression and increased lateral association with α6 integrin, which resulted in a striking increase in α6p production, a novel finding showing the regulation of one laminin receptor is dependent on the expression of another. Furthermore, the expression of α6 integrin as well as uPAR, was found to be highly expressed in aggressive pancreatic tumor cells. This expression pattern was found to significantly increase in response to the development of drug resistance and increased invasive potential. This finding showed a never before seen efficacy of integrin and uPAR expression in dictating acquired drug resistance in pancreatic tumor cells and demonstrates their potential use as prognostic biomarkers for acquired chemotherapy resistance. Taken together, the work conducted here illustrates the utility in further understanding the role of integrins and their regulation in mediating tumor cell migration and subsequent metastasis in the progression of aggressive epithelial cancers.
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Sloan, Stakleff Kimberly Denise. "CHARACTERIZATION OF UROKINASE PLASMINOGEN ACTIVATOR RECEPTOR (UPAR) AND INTEGRIN SUBUNITS IN BREAST CARCINOMA CELL LINES WITH DIVERSE INVASIVE CAPACITIES." Kent State University / OhioLINK, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=kent1195663733.
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El-Hadi, Mariam. "Mdg1 und die UPR - Stellung und Funktion des Hsp40-Chaperones in der Unfolded Protein Response." [S.l. : s.n.], 2005.
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Fabrizio, Gaia. "Study of the cellular role of GRP78/BiP mono-ADP-ribosylation in UPR and cancer." Thesis, Open University, 2018. http://oro.open.ac.uk/55261/.
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Mono-ADP-ribosylation is a reversible post-translational protein modification that modulates the function of proteins involved in different cellular processes, including signal transduction, protein transport, transcription, cell cycle regulation, DNA (deoxyribonucleic acid) repair and apoptosis. In mammals, mono-ADPribosylation is catalyzed by three different classes of enzymes: ARTCs, ARTDs, and members of the sirtuin family. In the present study, hARTC1-mediated mono-ADP-ribosylation was investigated in terms of the cellular compartments involved, target(s) and roles. The collected results demonstrated that hARTC1 protein and enzymatic activity is mainly localized to the endoplasmic reticulum (ER), in contrast to other ARTCs, which are either typically GPI-anchored enzymes in the plasma membrane, or secreted enzymes. Previous studies in my laboratory demonstrated that a protein macro domain was useful for the study of APD-ribosylation. The data reported here indicate, for the first time, that the macro domain can be used for immunofluorescence, allowing visualization of ADP-ribosylated proteins in intact cells, and in far-Western Blotting, allowing the detection of specific ADPribosylated targets. These methodologies were employed to demonstrate that the ER-localized chaperone, GRP78/BiP, was a prime target of hARTC1. A doubly mutated hARTC1 mutant was designed, and used as a specific control for hARTC1 expression. The mutant enzyme localized to the ER, but did not catalyze GRP78/BiP ADP-ribosylation. The demonstration that GRP78/BiP was mono-ADP-ribosylated by hARTC1 suggested that hARTC1 could be a key regulator of GRP78/BiP-mediated functions. Consistent with the key role of GRP78/BiP in the ER stress response, it was found that hARTC1 was activated during short-term cell treatment with ER stressors, resulting in acute GRP78/BiP ADP-ribosylation. However, the monoADP-ribosylation of the chaperone did not trigger an unfolded protein response. Recently, hARTC1 has been associated with cancer, suggesting a possible role in cell proliferation. In line with these findings, the results presented here demonstrated that hARTC1 over-expression inhibited cell proliferation.
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Planus, Emmanuelle. "Adherence et mecanotransduction via le complexe : recepteur de l'urokinase/urokinase/inhibiteur (upar/upa/pai-1) du systeme activateur du plasminogene." Paris 12, 1996. http://www.theses.fr/1996PA120085.
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Le systeme activateur du plasminogene (pas) via l'urokinase est un des principaux systemes proteolytiques des composants de la matrice extracellulaire. La voie de l'urokinase permet la formation d'un complexe compose d'un recepteur membranaire (upar), de l'urokinase (upa) et de l'inhibiteur de type 1 (pai-1). L'expression des composants de ce systeme est frequemment associee a la migration et a l'invasion cellulaire. Dans le but d'etudier l'implication du systeme pas dans ces phenomenes, nous avons voulu comprendre le role joue par le complexe tripartite upar/upa/pai-1 dans les mecanismes de l'adherence et de la mecanotransduction de signaux qui en decoule. Dans une premiere partie, nous avons montre que les cellules adheraient et s'etalent normalement sur une matrice uniquement constituee de pai 1. Dans une deuxieme partie, nous avons montre que ce processus etait dependant de la presence de l'upa a la surface cellulaire dans une derniere partie, nous avons montre qu'a travers le complexe upar/upa/pai-1 a la surface cellulaire, il etait possible de transmettre des forces mecaniques a l'interieur de la cellule. Nous en avons deduit que la formation du complexe tripartite upar/upa/pai-1 pouvait representer un des ponts moleculaires entre la cellule et le substrat, necessaires a l'adherence et a l'etalement des cellules. Enfin, nous avons discute des implications possibles du systeme pas comme 1) mediateur direct de l'adherence 2) mediateur eventuel de la deadherence par son activite proteolytique des composants de la matrice et 3) ainsi par ces deux actions son role dans la migration cellulaire.
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Ourabah, Sarah. "Combinaison de l'inhibition du protéasome et d'un nouveau composé dans le traitement du myélome multiple." Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCB233.
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Pinto, Camila Bonin. "Efeito da desregulação da via UPR sobre a expressão da ciclina A1 em linfócitos B humanos." Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/42/42133/tde-30012013-103651/.
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A via Unfolded Protein Response (UPR) é uma via de sinalização ativada pelo estresse do Retículo endoplasmático (ER). Anteriormente descrevemos um Paciente com Imunodeficiência Comum Variável (CVID) que apresenta um atraso na ativação da via UPR associado com o acumulo de imunoglobulinas dentro do ER e uma taxa de proliferação diminuída. Nossos resultados demonstram que a ativação crônica da UPR interrompe o ciclo celular de EBV-B através da quebra da natureza cíclica da ciclina A1. Essa parada é depende da linhagem EBV-B estudada e da droga utilizada. Além disso, a ativação crônica da UPR aumenta a apoptose através da ativação do braço da PERK da via UPR. Células ex-vivo e EBV-B do Paciente P apresentaram uma taxa metabólica muito baixa e numero aumentado de células em apoptose. A deficiência da resposta do paciente P frente a ativação da via UPR parece ser somente no reconhecimento de proteínas não dobradas. Nossos resultados sugerem que a proliferação deficiente observada em diversos paciente com CVID pode ser resultado de uma ativação deficiente da via UPR.The unfolded protein response (UPR) is a signaling pathway activated by endoplasmic reticulum (ER) stress. Previously we described a patient (Patient P) with Common Variable Immunodeficiency (CVID) whose delayed activation of the UPR associates with accumulation of immunoglobulins and slower rate of proliferation. Our results showed that chronic UPR stress interrupted cell cycling of EBV-B cells through dysruption of the cyclic nature of cyclin A1. This interrption is depend of the cell type and drug. Furthermore, chronic ER stress triggered early apoptosis through activation of the PERK branch of the UPR. EBV-B and ex vivo cells from patient presented low metabolic rate and a high apoptosis rate even in the absence of ER stressors.. We noted that the deficiency of UPR pathway activation by Patient P apears to be on the recognition of unfolded proteins. Our results support the hypothesis that deficient proliferation observed in some CVID patients might be the result of deficient UPR activation.
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Pires, da silva Julie. "Rôle de la sirtuine 1 dans la modulation des réponses apoptotique et autophagique du coeur au stress du réticulum endoplasmique." Thesis, Université Paris-Saclay (ComUE), 2018. http://www.theses.fr/2018SACLS211/document.
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Le réticulum endoplasmique rugueux (RE), assure la synthèse, le repliement et la maturation des protéines de la voie de sécrétion. Les altérations des fonctions physiologiques du RE, entrainent l’accumulation de protéines mal repliées dans la lumière du RE, une condition appelée stress RE. En réponse au stress RE, un mécanisme compensatoire adaptatif appelé Unfolded Protein Response (UPR) est activé afin de restaurer l’homéostasie du RE et de permettre la survie de la cellule. Dans le cas d’un stress RE sévère ou prolongé, les altérations ne pouvant plus être compensées, la cellule est éliminée par apoptose contribuant ainsi au développement de pathologies cardiaques. Le but des recherches actuelles sur le stress RE en physiopathologie cardiaque n’est pas d’inhiber la réponse au stress RE, mais plutôt de la moduler afin de limiter l’apoptose des cardiomyocytes et de protéger le cœur. Dans ce contexte, nous avons mis en évidence que le stress RE induit une modification importante de l’architecture des cardiomyocytes associée à une altération de la fonction mitochondriale. De plus, nous avons montré que SIRT1, une désacétylase dépendante du NAD+, inhibe l’apoptose mitochondriale induite par un stress RE en limitant spécifiquement l’activation de la voie PERK de la réponse UPR via la désacétylation du facteur eIF2á sur la lysine K143. Enfin, nos résultats indiquent que SIRT1 protège les cardiomyocytes de l’apoptose induite par le stress RE en favorisant la mitophagie, via une activation de la voie de signalisation eEF2K/eEF2. Ces résultats montrent que SIRT1 est impliquée dans la régulation de la réponse autophagique et apoptotique des cardiomyocytes au stress RE et suggèrent que cette désacétylase serait une cible thérapeutique intéressante pour limiter le développement des pathologies cardiaques liées au stress REThe endoplasmic reticulum (ER) functions to properly synthesize, fold and process secreted and transmembrane proteins. Impairment of ER function induces an accumulation of misfolded proteins in the ER lumen, a condition termed ER stress. In response to ER stress, an adaptive compensatory mechanism called Unfolded Protein Response (UPR) is activated to restore ER homeostasis and promote cell survival. In the case of severe or prolonged ER stress, homeostasis cannot be restored and the cell is eliminated by apoptosis contributing to the development of cardiac pathologies. Currently, cardiac therapy based on ER stress modulation to conserve beneficial adaptations and to avoid cardiomyocyte apoptosis is viewed as a promising avenue towards effective therapies of ER stress-associated cardiac diseases.In this context, we demonstrated that ER stress induces architectural modifications and alterations of the mitochondrial function in cardiomyocytes. Furthermore, we showed that SIRT1, a NAD+-dependent deacetylase, inhibits mitochondrial apoptosis by modulating the activation of the PERK pathway of the UPR through deacetylation of the translation initiation factor eIF2á on lysine K143. Our results also indicate that SIRT1 protects cardiomyocyte from ER stress-induced apoptosis by activating mitophagy through eEF2K/eEF2 pathway. Collectively, these data demonstrate that SIRT1 regulates ER stress-induced autophagy and apoptosis in the heart and suggest that this deacetylase may be a therapeutic target to protect the heart against ER stress-induced injury
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Fuchs, Frieder [Verfasser], Julia [Akademischer Betreuer] Kitz, Philipp [Gutachter] Ströbel, Peter [Gutachter] Burfeind, and Margarete [Gutachter] Schön. "uPAR und c-MYC beim duktalen Adenokarzinom des Pankreas / Frieder Fuchs ; Gutachter: Philipp Ströbel, Peter Burfeind, Margarete Schön ; Betreuer: Julia Kitz." Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2018. http://d-nb.info/116586908X/34.
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Lebeau, Justine. "Stress du réticulum endoplasmique et tumorigenèse." Thesis, Lyon 1, 2014. http://www.theses.fr/2014LYO10175.
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Les signalisations oncogéniques induisent une consommation accrue de glucose qui n'est que partiellement satisfaite par le microenvironnement. Pour s'adapter et survivre à ce stress métabolique, les cellules malignes mettent en jeu des mécanismes qui restent mal compris. Nos travaux montrent que cette limitation en glucose a pour principale conséquence de déclencher une apoptose via la voie de signalisation PERK-CHOP de la réponse à un stress du réticulum endoplasmique (SRE), nommée Unfolded Protein Response (UPR). Nous avons découvert que le RE est capable de sentir la carence en glucose via la diminution de la disponibilité en UDP Nacétylglucosamine produit par la voie des hexosamines. La délétion du facteur pro-Apoptotique CHOP dans un modèle de cancer spontané du poumon induit par KrasG12V chez la souris augmente l'incidence tumorale, confirmant que le SRE constitue un mécanisme cellulaire de sauvegarde anti-Tumoral. Nous montrons également que le franchissement de cette barrière implique l'atténuation sélective de la voie PERK-CHOP par la protéine chaperon p58IPK, qui permet aux cellules de bénéficier en retour des effets protecteurs des autres voies d'un UPR devenu chronique. Ces résultats révèlent une dualité fonctionnelle pour le stress du RE dans la tumorigenèse contrôlée, au moins pour partie, par la protéine p58IPKDuring carcinogenesis, oncogene activation induces high glucose avidity that outstrips the microenvironment supply until angiogenesis occurs. How malignant cells cope with this potentially lethal metabolic stress remains poorly understood. We found that oncogene-Driven glucose shortage triggers apoptosis through the PERK-CHOP pathway of the endoplasmic reticulum (ER) unfolded protein response (UPR). Deletion of the pro-Apoptotic UPR effector CHOP in a mouse model of KrasG12V induced lung cancer increases tumour incidence, strongly supporting the notion that ER stress serves as a barrier to malignancy. Overcoming this barrier requires the selective attenuation of the PERK-CHOP arm of the UPR by the molecular chaperone p58IPK. Furthermore, p58IPK-Mediated adaptive response enables cells to benefit from the protective features of chronic UPR. Altogether, these results show that ER stress activation and p58IPK expression control the fate of malignant cells facing glucose shortage
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Bouvier, Nicolas. "Conséquences rénales de l'activation de la réponse UPR (Unfolded protein response) par des stress toxique et ischémique." Phd thesis, Université René Descartes - Paris V, 2012. http://tel.archives-ouvertes.fr/tel-00793364.
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Le rein natif et le greffon rénal peuvent être soumis à de multiples agressions conduisant à la détérioration progressive du parenchyme. Ces agressions peuvent être spécifiques (stress toxique, immunologique) et/ou non spécifiques (stress ischémique) et vont engendrer des réponses pouvant entraîner à la fois une diminution de la consommation d'énergie, une augmentation des apports afin de maintenir l'homéostasie tissulaire et la survie mais aussi une réaction inflammatoire et l'apoptose pouvant conduire à la fibrose. Parmi celles-ci, on peut nommer les voies HIF1α, mTOR, le stress du réticulum endoplasmique (RE), l'autophagie, l'activation de l'immunité innée et acquise. La réponse adaptative qui suit le stress du RE, la réponse UPR (Unfolded protein response), est une voie adaptative dont les implications sont actuellement encore peu connues dans le domaine de la pathologie rénale. Celle-ci se compose de trois effecteurs principaux : Perk, Ire1 et ATF6. A l'aide de deux modèles de stress toxique (ciclosporine) et ischémique (carence en glucose) sur deux modèles cellulaires distincts (cellulaires endothéliales artérielles et cellules tubulaires rénales), et dans des modèles in vivo, nous avons montré que le stress du RE était impliqué à la fois dans l'apparition de modifications phénotypiques endothéliales évocatrices de transition endothélio-mésenchymateuse induites par la ciclosporine et à la fois dans l'induction de réponses inflammatoire (régulation de NF-κB par Ire1) et angiogénique (régulation distincte de VEGF, bFGF et angiogénine par Perk et Ire1) induites par la carence en glucose. La réponse UPR semble modulée de façon subtile au cours de ces stress car les trois effecteurs n'engendrent pas des réponses identiques. Ces travaux apportent ainsi une meilleure compréhension des mécanismes d'adaptation au cours de stress variés, montrent que le stress du RE est impliqué dans ces réponses adaptatives et que la réponse peut être différente selon les effecteurs de la réponse UPR. Cette meilleure compréhension pourra permettre de valider des biomarqueurs précoces et des modulateurs de la réponse UPR afin de prévenir la dégradation du parenchyme rénal.
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Poncet, Anaïs. "Modulation de l’activité des cellules dendritiques par la réponse UPR induite lors de l’infection à Toxoplasma gondii." Thesis, Lille 2, 2019. http://www.theses.fr/2019LIL2S038.
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Toxoplasma gondii (T. gondii) est un parasite intracellulaire obligatoire responsable d’une zoonose cosmopolite, la toxoplasmose. Chez les sujets sains, les parasites de type II persistent sous forme de kystes cérébraux, responsables de maladies mentales sévères et augmentant le risque d’apparition de maladies neurodégénératives. Le contrôle de la toxoplasmose chronique dépend de la sécrétion de l’interleukine pro-inflammatoire IL-12 par les cellules dendritiques (DCs) permettant l’activation des lymphocytes T CD8+ (LTs CD8+) cytotoxiques et la sécrétion de l’IFN-g. Les LTs CD8+ jouent un rôle clé dans l’élimination des cellules parasitées durant la phase aigüe de l’infection, mais aussi dans l’établissement d’une immunité protectrice à long terme. Afin de survivre et persister, T. gondii sécrète de nombreux facteurs de virulence qui modulent les réponses immunitaires de son hôte.Des travaux récents ont mis en évidence le rôle clé de la réponse UPR (Unfolded Protein Response) dans la régulation des réponses immunitaires. La réponse UPR est une réponse cytoprotectrice induite durant un stress cellulaire déclenché lors de variations dans l’homéostasie protéique et lipidique au sein du réticulum endoplasmique mais aussi lors d’un stress infectieux. Jusqu’à présent, l’influence de l’infection par T. gondii sur la réponse UPR n’est pas connue. Nous avons émis l’hypothèse que l’induction de l’UPR par T. gondii dans les DCs pourrait moduler leur capacité de présentation antigénique et la sécrétion de cytokines inflammatoires, impactant ainsi la dissémination et la persistance du parasite.En utilisant, des DCs déficientes pour certains effecteurs de l’UPR (IRE1a et XBP1s), nous avons examiné l’impact de leur activité sur les DCs infectées. In vitro, nos résultats ont montré que T. gondii active la voie IRE1a de l’UPR d’une manière dépendante de la voieMyD88 et contrôle ainsi la production des cytokines pro-inflammatoires IL-6 et IL-12 et la présentation antigénique d’antigènes parasitaires par le CMH-I. Dans les souris infectées,la voie IRE1a est spécifiquement activée dans la sous-population de cDC1 et régule l’activation des LTs CD8+, essentiels à la production de l’IFN-g. De plus, les souris déficientes pour IRE1a et XBP1 spécifiquement dans les DCs ne contrôlent pas la prolifération des parasites et succombent à l’infection aigüe. Notre étude révèle donc un rôle protecteur essentiel de cette voie dans les DCs pour combattre l’infection à T. gondiiThe intracellular parasite Toxoplasma gondii (T. gondii) is one of the most common zoonotic pathogen invading all animals, including humans. In healthy individuals, type II parasite persists in cysts in the central nervous system leading to severe mental disorders and increasing the risk of developing neuro degenerative diseases. The control of chronic toxoplasmosis relies on dendritic cells (DCs) functions that activate the IL-12- induced Tcell IFN-g-derived response. In order to survive, T. gondii secretes an arsenal of virulencefactors that modulate host immune responses; however the interplay between DCs andT. gondii has been poorly explored. Recent studies highlighted the intricate molecularcross-talk between the Unfolded Protein Response (UPR) and the innate pathways. TheUPR response is a cytoprotective response induced during a cellular stress triggered byan imbalance in protein and lipid homeostasis, but also during intracellular pathogen infection.So far, nothing is known about the influence of T. gondii infection on the UPR.We hypothesized that T. gondii induction of the UPR could modulate the antigenic presentationability and cytokine secretion of DCs, thereby impacting parasite disseminationand persistence. Using, Bone-Marrow-derived DC (BMDCs) and mice deficient for the ERsensor IRE1a and the transcription factor XBP1, we examined the impact of the UPR onDC responses and T cell activation. Our results demonstrated that T. gondii infectionactivates the IRE1a arm of the UPR in BMDCs in a MyD88 dependent manner, therebyinducing a unique set of secreted pro-inflammatory cytokines. We also demonstrated thatthis pathway regulates MHC-I presentation of secreted parasite antigens. In infected mice,we found that the IRE1a/XBP1s pathway is specifically activated in splenic cDC1s, regulatesT CD8+ cell responses and thus, the IFN-g production. In addition, IRE1a/XBP1deficient mice do not control parasite proliferation and succomb during the acute phaseof the infection. Therefore, our work revealed an essential protective role of the IRE1abranch of the UPR in DCs to fight T. gondii infection
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Bouvier, Nicolas. "Conséquences rénales de l’activation de la réponse UPR (Unfolded protein response) par des stress toxique et ischémique." Thesis, Paris 5, 2012. http://www.theses.fr/2012PA05P626/document.
Full textAbstract:
Le rein natif et le greffon rénal peuvent être soumis à de multiples agressions conduisant à la détérioration progressive du parenchyme. Ces agressions peuvent être spécifiques (stress toxique, immunologique) et/ou non spécifiques (stress ischémique) et vont engendrer des réponses pouvant entraîner à la fois une diminution de la consommation d’énergie, une augmentation des apports afin de maintenir l’homéostasie tissulaire et la survie mais aussi une réaction inflammatoire et l’apoptose pouvant conduire à la fibrose. Parmi celles-ci, on peut nommer les voies HIF1α, mTOR, le stress du réticulum endoplasmique (RE), l’autophagie, l’activation de l’immunité innée et acquise. La réponse adaptative qui suit le stress du RE, la réponse UPR (Unfolded protein response), est une voie adaptative dont les implications sont actuellement encore peu connues dans le domaine de la pathologie rénale. Celle-ci se compose de trois effecteurs principaux : Perk, Ire1 et ATF6. A l’aide de deux modèles de stress toxique (ciclosporine) et ischémique (carence en glucose) sur deux modèles cellulaires distincts (cellulaires endothéliales artérielles et cellules tubulaires rénales), et dans des modèles in vivo, nous avons montré que le stress du RE était impliqué à la fois dans l’apparition de modifications phénotypiques endothéliales évocatrices de transition endothélio-mésenchymateuse induites par la ciclosporine et à la fois dans l’induction de réponses inflammatoire (régulation de NF-κB par Ire1) et angiogénique (régulation distincte de VEGF, bFGF et angiogénine par Perk et Ire1) induites par la carence en glucose. La réponse UPR semble modulée de façon subtile au cours de ces stress car les trois effecteurs n’engendrent pas des réponses identiques. Ces travaux apportent ainsi une meilleure compréhension des mécanismes d’adaptation au cours de stress variés, montrent que le stress du RE est impliqué dans ces réponses adaptatives et que la réponse peut être différente selon les effecteurs de la réponse UPR. Cette meilleure compréhension pourra permettre de valider des biomarqueurs précoces et des modulateurs de la réponse UPR afin de prévenir la dégradation du parenchyme rénalNative and grafted kidneys are stressed by multiple specific or non-specific insults leading to progressive structural deterioration. Responses to these insults are adaptive and preserve cell survival but may also promote inflammation, fibrosis and apoptosis. The most important of these adaptive pathways are HIF1α pathway, mTOR pathway, autophagy, unfolded protein response (UPR). The consequences of the UPR in kidney injuries are not well known. The objective of this study is to delineate the mechanisms and consequences of the activation of the UPR in response to toxic (cyclosporine) and ischemic (glucose starvation) stresses in two distinct cellular models (arterial endothelial cells and renal tubular cells). Here, we showed that UPR was engaged in cyclosporine-induced endothelial phenotypic changes, glucose starvation-induced inflammatory and angiogenic responses: NF-κB regulation by Ire1; distinct VEGF, bFGF and angiogenin regulation by Perk and Ire1. UPR is subtly modulated since its transducers do not induce identical processes. In conclusion these comprehensive works, we demonstrate the UPR is implicated in stress-induced adaptive pathways with different downstream responses according to the effector. Renal tissue degradation could be prevented by discovering and validating early biomarker and UPR modulators
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Forouhan, Mitra. "The role of ATF6α and ATF6β in the UPR associated with an ER stress-induced skeletal chondrodysplasia." Thesis, University of Manchester, 2016. https://www.research.manchester.ac.uk/portal/en/theses/the-role-of-atf6alpha-and-atf6-in-the-upr-associated-with-an-er-stressinduced-skeletal-chondrodysplasia(9e26ce51-f188-454c-8ee1-3832845ee014).html.
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Mutations in the COL10A1 gene cause metaphyseal chondrodysplasia type Schmid (MCDS) by triggering ER stress and unfolded protein response (UPR). MCDS is characterised by a mild short-limb dwarfism accompanied by expansion of the cartilage growth plate hypertrophic zone (HZ) and altered differentiation of hypertrophic chondrocytes (HCs). ATF6 is one of the UPR mediators, which exists in two isoforms, ATF6α and ATF6β. Activation and up-regulation of ATF6α was a prominent biochemical sign of ER stress in a mouse model of MCDS, COL10a1 p.N617K. Although ATF6β is induced and activated in response to ER stress in a similar fashion to ATF6α, the role and significance of ATF6β in the pathology of many ER stress-associated diseases including MCDS is unknown. Here we utilized a combination of in vitro and in vivo approaches to define the precise role of each isoform of ATF6 in MCDS.To investigate the functions of ATF6α and ATF6β in vitro, we developed a MCDS cell model system (expressing either the wild type collagen X or one of the following MCDS-causing mutant forms of the protein: p.N617K, G618V, Y598D, and NC1del10) in which the expression of either ATF6α or ATF6β was efficiently silenced using siRNAs. ATF6α knockdown in HeLa cells expressing different MCDS-causing mutations suppressed the increased expression of UPR-associated genes such as BiP leading to an elevated ER stress, based on increased XBP1 splicing and/or ATF4 protein. In contrast, ATF6β knockdown did not significantly affect the mutant collagen X-induced increased expression of UPR-associated genes. Furthermore, the ER stress levels were significantly reduced in the ATF6β knockdown MCDS mutant cells based on the lower levels of XBP1 splicing and/or ATF4 protein detected. We then crossed the ATF6α/β knockout mice models with COL10a1 p.N617K mouse model of MCDS to investigate the function of ATF6α and ATF6β in vivo. Ablation of ATF6α in MCDS mice further- reduced the endochondral bone growth rate, further expanded the growth plate hypertrophic zone, and disrupted differentiation of HCs. Therefore, ATF6α appeared to play a chondroprotective role in MCDS as its deficiency caused an increase in the severity of the disease. Of particular note, the level of ER stress was further increased in the absence of ATF6α in MCDS, based on enhanced activities of PERK and IRE1 signalling pathways in compensation for the ATF6α loss. Paradoxically, ablation of ATF6β in MCDS mice reduced the intracellular retention of collagen X protein, and alleviated the ER stress as judged by the attenuated activities of PERK and IRE1 signalling pathways. The reduced ER stress resulting from deficiency for ATF6β in MCDS mice restored the expression of collagen X mRNA towards normal and improved the differentiation of HCs, causing a mark decrease in the expansion of HZ. The results presented within this thesis greatly increased our understanding of the function of ATF6α and ATF6β and their interplay in the pathogenesis of MCDS. We demonstrated an indispensable beneficiary role for ATF6α but a detrimental role for its closely related isoform, ATF6β, in pathology of MCDS. We also showed that the role of ATF6β should not be ignored. These findings may be used to develop a potential therapeutic strategy for MCDS through targeting and enhancing ATF6α-dependent and/or attenuating/blocking of ATF6β-dependent signalling pathways.
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Sommerweiß, Dietlind. "Oleate rescues INS-1E β-cells from palmitate-induced apoptosis by preventing activation of the unfolded protein response." Doctoral thesis, Universitätsbibliothek Leipzig, 2015. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-172386.
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In this project I sought to analyse the effects of different free fatty acids (FFAs) on INS-1E β-cells. The saturated fatty acid palmitate is considered toxic whereas the monounsaturated fatty acid oleate is harmless. In my working hypothesis I assumed an additional protective effect of oleate when used in combination with palmitate. Furthermore I aimed to explore in detail the possible causes and signalling pathways responsible for apoptosis or sustained cell survival. I examined the Endoplasmic Reticulum (ER) stress response, called unfolded protein response (UPR), as one essential criterion deciding about cell death or life. Analysis of viability and apoptosis confirmed the deleterious effect of palmitate on INS-1E β-cells after 24h of incubation. Oleate proved not to be harmful and even reversed the toxicity of palmitate. When the main components of the UPR were assessed using Western blot analyses and quantitative PCR was performed I found positive proof that palmitate activated the UPR and ultimately led to apoptosis. By contrast, oleate completely prevented UPR signalling. I conclude that oleate rescues INS-1E β-cells by inhibiting ER stress and its signalling.
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Balthazor, James. "Studies of human Armet and of pea aphid transcripts of saliva proteins and the Unfolded Protein Response." Diss., Kansas State University, 2015. http://hdl.handle.net/2097/35218.
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Doctor of PhilosophyBiochemistry and Molecular Biophysics Interdepartmental Program
Gerald R. Reeck
Armet is a bifunctional protein that is apparently universally distributed among multicellular animal species, vertebrate and invertebrate alike. A member of the Unfolded Protein Response, (UPR) Armet promotes survival in cells that are under endoplasmic-reticulum (ER) stress. I have carried out biophysical studies on human Armet looking for compounds that bind to Armet and hence could reduce its anti-apoptotic function, thus potentially joining the growing class of pro-apoptotic drugs. Performed primarily with 1H-15N HSQC NMR, ligand studies showed that approximately 60 of the 158 residues are potentially involved with binding. The 60 residues are distributed throughout both domains and the linker suggesting multi-domain interaction with the ligand. Circular dichroism studies showed heat denaturation in a two-step unfolding process with independent unfolding of both domains of Armet with Tm values near 68°C and 83 C with the C-terminal domain unfolding first, as verified by 1H-15N HSQC NMR measurements. I also provide the first identification of UPR transcripts in pea aphids, Acyrthosiphon pisum, the genetic model among aphids. I measured transcript abundance with hope of finding future transcriptional targets for pest mitigation. I identified 74 putative pea aphid UPR components, and all but three of the components have higher transcript levels in aphids feeding on plants than those that fed on diets. This activated UPR state is attributed to the need for saliva proteins for plant feeding. Because aphids are agriculturally significant pests, and saliva is pivotal to their feeding on host plants, genes that encode saliva proteins may be targets for pest mitigation. Here I have sought the aphid’s saliva proteome by combining results obtained in several laboratories by proteomic and transcriptomic approaches on several aphid species. With these data I constructed a tentative saliva proteome for the pea aphid by compiling, collating, and annotating the data from several laboratories. I used RNA-seq to verify the transcripts in pea aphid salivary glands, thus expanding the proposed saliva proteome from approximately 50 components to around 130 components, I found that transcripts of saliva proteins are upregulated during plant feeding compared to diet feeding.
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Xing, Rosie Hongmei 1968. "Studies on the role of urokinase (uPA) and its cell surface receptor (uPAR) in the invasion and metastasis of hormone dependent malignancies." Thesis, McGill University, 1998. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=35651.
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Urokinase (uPA), a member of the serine protease family, and its cell surface receptor (uPAR) have been implicated in promoting the progression of various human malignancies including hormone dependent malignancies such as breast and prostate cancer. However, the underlying molecular mechanisms regulating uPA production in breast and prostate cancer progression are poorly understood.In the current studies, we have examined the role of uPAR in breast cancer progression by developing a homologous model of uPAR overexpression by a rat breast cancer cell line Mat B III. Overexpression of uPAR resulted in increased breast cancer growth, invasion and metastasis in vitro and in vivo. Development of this syngeneic breast cancer model allowed me to examine the ability of the anti-estrogen, tamoxifen (TAM) and a synthetic active site inhibitor of uPA, 4-iodo benzo[b]thiophene-2-carboxamidine (B-428), to prevent breast cancer progression. TAM and B-428 treatment alone or in combination effectively prevented breast tumor growth, invasion and metastasis in vitro and in vivo. Morever, TAM and B-428 treatments caused a decrease in uPAR gene expression and protein production. These results underscore the utility of anti-proteolytic agents (B-428) in addition to standard hormone therapy (TAM) in advanced breast cancer patients where the uPA/uPAR system plays a key role in tumor progression. Regulation of uPA production by androgens in prostate cancer was then examined in the androgen insensitive PC-3 cells transfected with the functional human androgen receptor cDNA (PC-3T). Androgens down regulate uPA gene expression and protein production in androgen sensitive PC-3T cells. Furthermore, restoration of androgen responsiveness in PC-3T cells caused a dramatic decrease in tumor growth, invasion and metastasis in vitro and in vivo. Due to the ability of sex steroids to inhibit uPA gene expression, I have also examined the correlation between hormone sensitivity and uPA expression in several hormone responsive (HR) and hormone insensitive (HI) breast and prostate cancer cell lines. uPA mRNA was expressed only in the highly invasive, HI breast (MDA-231) and prostate (PC-3) cell lines. Failure of uPA mRNA expression in the minimally invasive, HR breast (MCF-7) and prostate (LnCAP) cells was due to transcriptional suppression of uPA gene. Southern blot analysis usi
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Xing, Hongmei Rosie. "Studies on the role of urokinase (uPA) and its cell surface receptor (uPAR) in the invasion and metastasis of hormone-dependent malignancies." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape11/PQDD_0017/NQ44631.pdf.
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