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1
Fish, Richard James. "RANTES derivatives and CCR5". Thesis, University of York, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.369362.
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PORTAS, DANUSA DEPES. "IMÁGENES MI(G)RANTES". PONTIFÍCIA UNIVERSIDADE CATÓLICA DO RIO DE JANEIRO, 2014. http://www.maxwell.vrac.puc-rio.br/Busca_etds.php?strSecao=resultado&nrSeq=29990@1.
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PONTIFÍCIA UNIVERSIDADE CATÓLICA DO RIO DE JANEIROCOORDENAÇÃO DE APERFEIÇOAMENTO DO PESSOAL DE ENSINO SUPERIOR
CONSELHO NACIONAL DE DESENVOLVIMENTO CIENTÍFICO E TECNOLÓGICO
PROGRAMA DE SUPORTE À PÓS-GRADUAÇÃO DE INSTS. DE ENSINO
Esta tese se propõe à construção de uma perspectiva teórica que observe as aporias e antinomias reveladas pelo regime contemporâneo das imagens. As imagens constituem um ponto de peculiar fricção e desconforto junto às ciências humanas, não só como um tópico de estudo, mas como característica cultural divisada. Esse campo vem se definindo de modo interdisciplinar e alargando sua perspectiva na linha de pesquisa denominada Cultura Visual (Visual Culture). T.W. Mitchell fala de um pictorial turn ou inclusive um visual turn que estariam relacionados com um enfoque apoiado por infiltrações mútuas entre duas epistemologias, a visual e a linguística, o que problematiza a premissa naturalizada de se entender o ato interpretativo como o núcleo da competência profissional dos especialistas de nossa área. As imagens ou as visualidades demandam seus próprios modos de análise e exigem do investigador um tratamento operacional e uma consequente definição de termos que suportem suas particularidades. Ao tópico, acrescenta-se a reinstalação warburguiana que coincide, não por acaso, com este giro e induz à pesquisa fundamental atenção em algumas vertentes heurísticas do trabalho de Aby Warburg, pensador alemão que ao princípio do século XX explorou um campo de inter-relações entre a antropologia, imagens e arte. No exemplo do projeto Der Bilderatlas Mnemosyne, antecipa-se a reflexão atual. As proposições de Warburg, bem como as pesquisas teóricas de importante exegeta de sua obra George Didi-Huberman, buscam entender qualquer imagem como um cruzamento de múltiplas migrações – tanto em seu modelo de tempo, Nachleben, como em seu modelo de sentido, Pathosformel – e oferecem ferramenta metodológica central a essa investigação. A partir de uma moldura teórica sistêmica, a tese enfoca o projeto de artistas visuais, como Harun Farocki, cujo trabalho realiza uma arqueologia do saber visual através da prospecção e montagem de tempos heterogêneos, mediante imagens animadas por uma energia expressiva e por uma enorme espessura histórico-cultural. A análise desses agenciamentos procura delinear sua inserção ambivalente na cena contemporânea em que o sistema de comunicação impõe-se como força estruturante de novas formas de socialização através de práticas culturais e tecnologia, com amplas consequências para o campo humanístico, oferecendo enfoques inovadores à dinâmica de articulação de formas de vida e de cultura com as tecnologias de imediação. A dimensão transnacional do tráfico e da produção de imagens situa a imagem no centro dos debates sobre o papel da representação nas culturas globais. Estas questões poderiam cumprir-se em dois problemas fundamentais, a hibridação dos campos disciplinares e a relação entre a imagem e o arquivo com relação à memória, à história, à justiça. No horizonte destes problemas, o objetivo da tese é distinguir o papel constitutivo das sobrevivências (Nachleben) na dinâmica da imaginação ocidental e as funções politicas dos agenciamentos memorialísticos de que se revelam portadores.
Esta tesis se propone a la construcción de una perspectiva teórica que amaitine las aporías y antinomias reveladas por el régimen contemporáneo de imágenes. Las imágenes son un punto de fricción y desasosiego junto de las ciencias humanas, no sólo como un tema de estudio, sino como característica cultural percebida. Este campo se ha definido de manera interdisciplinaria y amplía su perspectiva a una línea de investigación denominada Cultura Visual (Visual Culture). T. W. Mitchell habla de un pictorial turn o incluso un visual turn que estarían relacionados con un enfoque respaldado por infiltraciónes recíprocas entre dos epistemologías, visual y lingüística, lo que cuestiona la premisa naturalizada de comprender el acto interpretativo como el núcleo de la competencia profesional de los especialistas en nuestra área. Las imágenes o visualidades exigen sus propios modos de análisis y requieren del investigador un tratamiento operativo y una consecuente definición de términos que sostenga sus particularidades. Al tema, se suma la reinstalación warburguiana que coincide, no por causalidad, con este giro e induce a investigación fundamental atención sobre la figura y algunas vertientes heurística del trabajo de Aby Warburg, pensador alemán que exploró a principios del siglo XX, un campo de interrelaciones entre antropología, imágenes y arte. En el exemplo Der Bilderatlas Mnemosyne, se anticipa todo una reflexión actual. Las proposiciones de Warburg, así como la investigación teórica de importante exégeta de su obra George Didi-Huberman buscan entender cualquier imagen como un cruce de múltiples migraciones – tanto en su modelo de tiempo, Nachleben, como en su modelo de sentido, Pathosformel – y ofrecen herramienta metodológica central a esta investigación. Desde un marco teórico sistémico, la tesis enfoca el proyecto de artistas visuales, como Harun Farocki, cuyo trabajo realiza una arqueología del saber visual a través de la prospección y montaje de tiempos heterogéneos, mediante imágenes animadas por una potencia expresiva y por un enorme espesor histórico-cultural. La análisis de estos agenciamientos busca delinear su inserción ambivalente en la escena contemporánea, donde se impone el sistema de comunicación como una fuerza estructurante de nuevas formas de socialización a través de prácticas culturales y tecnología, con amplias consecuencias para el campo humanístico, ofrecendo enfoques innovadores a dinámica de articulación de formas de vida y de cultura con las tecnologías de inmediación. La dimensión transnacional del tráfico y la producción de imágenes situa la imagen en el centro de los debates sobre el papel de la representación en las culturas globales. Estas cuestiones podrían cumplirse en dos problemas fundamentales, la hibridación de los campos disciplinarios, la relación entre la imagen y el archivo con respecto a la memoria, la historia, la justicia. En el horizonte de estos problemas, el objetivo de este trabajo consiste en distinguir el papel constitutivo de supervivencias (Nachleben) en la dinámica de la imaginación occidental y las funciones políticas de los agenciamientos de que se revelan portadores.
3
Turner, Lynn. "RANTES and T lymphocytes". Thesis, University of Bath, 1996. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.307048.
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Machado, Renes de Resende. "Mediadores envolvidos na resposta febril induzida pela RANTES". Universidade de São Paulo, 2009. http://www.teses.usp.br/teses/disponiveis/60/60138/tde-13022009-160445/.
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Em estudo anterior, observamos que o Met-RANTES, antagonista de receptores CCR1 e CCR5 para quimiocinas, injetado pela via endovenosa (i.v.) reduziu a resposta febril induzida pelo lipopolissacarídeo (LPS) de E. coli, demonstrando o envolvimento da quimiocina RANTES (Regulada sob ativação, expressa e secretada por células T normais) nesta resposta. Além disso, a injeção intrahipotalâmica (i.h.) da RANTES dose-dependentemente aumentou a temperatura corporal de ratos, o qual foi caracterizado como febre, pois foi acompanhada de redução da temperatura da cauda, uma resposta termorregulatória para retenção de calor. Observamos também, que a RANTES aumenta a concentração de prostaglandinas no fluido cerebroespinhal (CSF) e que a febre por ela induzida é sensível aos inibidores não-seletivos para as ciclooxigenases e seletivo para COX-2 (Machado et al., 2007). No presente estudo, aprofundamos a investigação sobre os mediadores, incluindo as prostaglandinas, envolvidos na resposta febril induzida pela RANTES. Verificamos que o paracetamol reduziu, enquanto o diclofenaco de sódio aboliu a resposta febril induzida pela RANTES. Ainda, a injeção i.h. da RANTES promoveu significativa expressão do RNAm para COX-2 no hipotálamo, confirmando ser a COX-2 a enzima responsável pela síntese de prostaglandinas envolvidas no efeito pirogênico desta quimiocina. Através da administração de corante in situ e de cortes histológicos, pode-se averiguar o trajeto da cânula bem como a profundidade alcançada pela agulha durante a injeção na área pré-óptica hipotalâmica anterior (AH/POA). Padronizamos a dose do Met-RANTES (i.h.) que não seria capaz de alterar a temperatura retal dos animais. Posteriormente, avaliou-se o efeito de diferentes doses do Met-RANTES, administrado via intrahipotalâmica, na resposta febril induzida pelo LPS ou pela RANTES. Entretanto, nas doses administradas o pré-tratamento com o antagonista não foi capaz de reduzir a febre induzida por ambos os estímulos. Contudo, o Met-RANTES (i.v.) reduziu a febre induzida pelo TNF-alfa (i.h.), reproduzindo resultados anteriores. O pré-tratamento com Met-RANTES (i.v.) não modificou a febre induzida pela injeção central de interleucina (IL)-6, fator liberador de corticotropina (CRF) e bradicinina (BK). Adicionalmente, a injeção de LPS (i.v.) ou TNF-alfa (i.h.) elevou a concentração da RANTES no tecido hipotalâmico. Antalarmina (antagonista de receptores CRF1) e alfa-helical CRF9-41 (antagonista de receptores CRF1 e CRF2) que reduziram a febre induzida pelo CRF, não alteraram a febre induzida pela administração i.h. da RANTES. O antagonista de receptores B1 (DALBK) que reduziu a segunda fase da resposta febril induzida pela BK, não foi capaz de modificar a febre induzida pela RANTES. Da mesma forma, o antagonista de receptores B2 (Hoe-140) que reduziu a resposta febril induzida pela BK durante todo o período de experimentação, não modificou a febre promovida pela RANTES. Por outro lado, verificamos que o anticorpo anti-IL-6 administrado i.h. reduziu a febre induzida pela IL-6 e pela RANTES. Ainda, a injeção de LPS (i.v.) ou RANTES (i.h.) elevou a concentração de IL-6 no CSF, mas não de IL-1 e TNF-. A RANTES promoveu ativação do fator nuclear-kB (NF-kB) e aumentou a expressão do RNAm para as citocinas IL-1beta, TNF-alfa e IL-6 no hipotálamo dos animais. O pré-tratamento com Met-RANTES reduziu, na 2,5 e 6 h, a neutrofilia induzida pelo LPS. Em síntese, nossos resultados demonstram que durante a resposta febril induzida pelo LPS, este induz a síntese de TNF-alfa o qual promove a síntese da quimiocina RANTES que, ativando os receptores CCR1 e CCR5 promove a transmigração do NF-kB do citoplasma para o núcleo e a subseqüente síntese de IL-6 e de COX-2, esta última, a responsável pela síntese de prostaglandina E2 (PGE2), um dos mediadores finais da resposta febril induzida pelo LPS. Além disso, a RANTES parece ser um mediador da resposta de fase aguda, uma vez que, promove dois sinais importantes desta resposta, febre e neutrofilia.We showed before that Met-RANTES, CCR1 and CCR5 receptor antagonist, intravenously injected (i.v.) reduced fever induced by lipopolysaccharide (LPS, E. coli), demonstrating the involvement of RANTES (Regulated on activation, normal T cells expressed and secreted) in this response. Also, intrahypothalamic (i.h.) injection of RANTES dose-dependently increased body temperature of rats, this increase was characterized as fever, because it was accompanied of a reduction in the tail skin temperature, a thermoregulatory response for heat retention. We also verified that RANTES increased the concentration of prostaglandin (PG)E2 in the cerebrospinal fluid (CSF), which was sensible to non-selective and selective blockers to cyclooxygenase (COX)-2 (Machado et al., 2007). In the present study, it was investigated which others mediators, including prostaglandins, are involved in the RANTES-induced fever. The effect of paracetamol and sodium diclofenac on fever induced by RANTES was also investigated. Paracetamol reduced, while sodium diclofenac abolished the RANTES-induced fever. The intrahypothalamic (i.h.) RANTES injection promoted a significant COX-2 mRNA expression in the hypothalamus, confirming the role of the COX-2 enzyme in the synthesis of prostaglandin involved in the pyrogenic effect of this chemokine. Through administration of dye in situ and histological analyses, we confirmed that the injection in the preoptic area of the anterior hypothalamus (AH/POA) was correct. Subsequently, we evaluated the effect of different doses of Met-RANTES (i.h.) in the fever induced by both LPS and RANTES. Centrally injected, Met-RANTES did not modify the fever induced by LPS or RANTES. On the other hand, Met-RANTES (i.v.) reduced TNF-alpha-induced fever, but did not modify the fever induced by interleukin (IL)-6, corticotrophin releasing factor (CRF) and bradykinin (BK). Additionally, the injection of LPS (i.v.) or TNF-alpha (i.h.) increased RANTES concentration in the hypothalamus. Antalarmin (a CRF receptor 1 antagonist) and alpha-helical CRF9-41 (CRF 1 and 2 receptor antagonist) that reduced CRF-induced fever did not modify the fever induced by RANTES (i.h.). DALBK (bradykinin B1 receptor antagonist) that reduced the second phase of BK-induced fever did not modify RANTES-induced fever. In the same way, Hoe-140 (bradykinin B2 receptor antagonist) that reduced the fever induced by BK during the whole period of observation, did not modify RANTES-induced fever. On the other hand, we verified that anti-rat IL-6 antibody (i.h.) reduced the fever induced by both IL-6 and RANTES. In addition, the administration of LPS (i.v.) or RANTES (i.h.) increased the CSF IL-6 concentration, but not of IL-1 and TNF-. RANTES promoted nuclear factor-kB (NF-kB) activation and increased IL-1beta, TNF-alpha and IL-6 mRNA expression in the hypothalamus. Pretreatment of the animals with Met-RANTES reduced the LPS-induced neutrophilia. In synthesis, our results suggest that in the fever induced by LPS, RANTES induces TNF- synthesis, which promotes the synthesis of RANTES that, activating CCR1/CCR5 receptors, promotes NF-kB transmigration of cytoplasm to the nucleus and subsequent synthesis of IL-6 and COX-2. The latter, in turn, is responsible by (PGE2) synthesis, one of the final mediators of the febrile response induced by LPS. Moreover, RANTES seem to be a mediator of the acute phase response since it promoted two important signs of this response, fever and neutrophilia.
5
Campbell, Emma Michelle. "The role of RANTES in guinea pig inflammatory responses". Thesis, University of Bath, 1996. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.362252.
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Charni, Faten. "Rôles de la chimiokine RANTES/CCL5 dans la carcinogenèse hépatique". Paris 13, 2011. http://www.theses.fr/2011PA132043.
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La liaison de la chimiokine RANTES/CCL5 à son récepteur couplé aux protéines G, CCR1, entraîne des effets pro-tumoraux sur les cellules d’hépatome humain Huh7. Notre étude indique également l’implication de deux protéoglycannes à héparane sulfate, le syndécanne-1 et le syndécanne-4 dans les effets chimiotactiques et l’étalement des cellules d’hépatome humain Huh7, HepG2 et Hep3B induits par RANTES/CCL5. Le ciblage de l’interaction entre chimiokine et syndécanne, aboutissant à la modulation des effets cellulaires médiés par RANTES/CCL5, pourrait représenter une nouvelle approche thérapeutique du carcinome hépatocellulaire (CHC). Nous avons également développé parallèlement un axe de recherche bioclinique consistant en l’étude de l’influence de deux polymorphismes affectant le gène codant pour la chimiokine RANTES/CCL5 (RANTES/CCL5 C-28G et RANTES/CCL5 G-403A) dans l’évolution de maladies hépatiques chroniques d’étiologie alcoolique ou virale C vers le CHC. Nous avons démontré que l’allèle A-403 du dimorphisme RANTES/CCL5 G-403A semble protéger les patients atteints de cirrhose alcoolique du risque de développer un CHC. Au contraire, le dimorphisme RANTES/CCL5 C-28G ne semble pas avoir d’effets chez nos deux cohortes de patientsIn addition to their physiologic effects in inflammation and angiogenesis, chemokines are involved in cancer pathology. This study demonstrates that chemokine RANTES/CCL5 induce the migration, invasion and spreading of human hepatoma Huh7, HepG2 and Hep3 cells. This study also indicates that the receptor CCR1 and the two membrane heparan sulfate proteoglycans, syndecan-1 and syndecan -4, may be required for HepG2, Hep3B and Huh7 cells migration, invasion and spreading induced by the chemokine. Targeting the RANTES/CCL5-glycosaminoglycan interaction could be a new therapeutic approach for HCC. We have also developed a parallel line of bio-clinical research consisting of study of the influence of two functional genetic polymorphisms in the RANTES/CCL5 promoter RANTES/CCL5 C-28G and RANTES/CCL5 G-403A on the risk of HCC occurrence in patients with alcoholic or HCV-related cirrhosis. RANTES/CCL5 C-28G and G-403A promoter dimorphisms and RANTES/CCL5 serum levels were assessed in 243 HCV-infected patients and 253 alcoholic patients, included at the time of diagnosis of cirrhosis and prospectively followed-up. This study suggests an influence of the chemokine RANTES/CCL5 G-403A dimorphism on the occurrence of HCC in patients with alcoholic cirrhosis
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Marfaing, Koka Anne. "Role de la chemokine rantes dans la reaction d'hypersensibilite retardee". Paris 11, 1997. http://www.theses.fr/1997PA11T023.
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Frink, Michael. "Zur Funktion des CC-Chemokins CCL5/RANTES bei der Immunkomplex-Glomerulonephritis". Diss., lmu, 2003. http://nbn-resolving.de/urn:nbn:de:bvb:19-17119.
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Pattison, James Michael. "Aspects of the function and regulation of the human chemokine RANTES". Thesis, University of Oxford, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.308849.
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Chaffey, Benjamin T. "Investigations into the biological functions of the CC chemokine CCL5/RANTES". Thesis, University of Newcastle Upon Tyne, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.413418.
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Dorfmüller, Peter. "RANTES and fractalkine the role of the chemokines in pulmonary arterial hypertension /". [S.l.] : [s.n.], 2001. http://deposit.ddb.de/cgi-bin/dokserv?idn=965026248.
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Schultes, Claudia Gertrud [Verfasser]. "Untersuchungen zur Rolle des Zytokins RANTES bei interstitiellen Lungenerkrankungen / Claudia Gertrud Schultes". Gießen : Universitätsbibliothek, 2013. http://d-nb.info/1064991181/34.
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Mamoune, Hadjer. "Recrutement monocytaire : effet de la chimiokine RANTES/CCL5 sur les cellules endothéliales". Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCD084.
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L’inflammation vasculaire est caractérisée par le recrutement monocytaire qui englobe l’arrêt, l’adhérence puis la migration trans-endothéliale des monocytes à travers l’endothélium vasculaire. Ce processus nécessite une interaction entre les médiateurs inflammatoires tels que les chimiokines, les leucocytes et les cellules endothéliales. Dans ce projet, nous avons évalué les mécanismes moléculaires induits par la chimiokine RANTES/CCL5 sur les cellules endothéliales permettant le recrutement des monocytes. Sur les cellules endothéliales, RANTES/CCL5 exerce ses effets biologiques grâce à ses interactions avec ses récepteurs protéiques (CCR1 et CCR5) et protéoglycanniques tels que le syndécane-4. L’implication du domaine intracellulaire (C1, V, C2) du syndecane-4 dans le recrutement monocytaire induit par RANTES/CCL5 démontre son rôle de co-récepteur fonctionnel. La stimulation des cellules endothéliales par RANTES/CCL5 augmente fortement, par rapport aux cellules non stimulées, le recrutement monocytaire via les voies de signalisation Rho GTPases, PKCα et PKCδ qui régulent la phosphorylation de protéines de jonctions inter-endothéliales notamment la VE-cadhérine et la β-caténine. Ainsi, le développement d'une nouvelle stratégie thérapeutique ciblant le système endothélial pourrait permettre de réguler l’initiation du processus inflammatoire induit par la chimiokine RANTES/CCL5Vascular inflammation is characterized by monocytes recruitment which includes arrest, adhesion and trans-endothelial migration of leukocytes through the vascular endothelium. This process requires an interaction between inflammatory mediators such as chemokines, leukocytes and endothelial cells. In this study, we evaluated the molecular mechanisms induced by the chemokine RANTES/CCL5 on endothelial cells allowing monocytes recruitment.RANTES/CCL5 exerts its biological effects through its interaction with its protein receptors (CCR1 and CCR5) and its interaction with proteoglycans such as syndecan-4. The involvement of the intracellular domain of syndecan-4 (C1, V, C2) in RANTES/CCL5-induced monocytes recruitment demonstrates its role as functional co-receptor. The stimulation of endothelial cells by RANTES/CCL5 strongly increases monocytes recruitment through Rho GTPase, PKCα and PKCδ signaling pathways. PKCα and PKCδ regulate the phosphorylation of inter-endothelial junction proteins, mainly VE-cadherin and β-catenin. Thus, the development of a new therapeutic strategy targeting the endothelial system might be allowing to regulate the initiation of the inflammatory process induced by the chemokine RANTES
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Eckart, Christoph Reiner [Verfasser]. "Posttranskriptionelle Regulation des Chemokins CCL5 (RANTES) durch den TAB1-p38 Signalweg / Christoph Reiner Eckart". Gießen : Universitätsbibliothek, 2014. http://d-nb.info/1068376163/34.
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Fessele, Sabine. "Funktionelle Charakterisierung und in silico-Modellierung LPS-induzierbarer Elemente des RANTES-Promotors in humanen Monocyten". [S.l. : s.n.], 2001. http://www.bsz-bw.de/cgi-bin/xvms.cgi?SWB9157751.
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Skwor, Troy Arthur. "The role of CCL5 (RANTES) in the immune response against Mycobacterium tuberculosis in the guinea pig". Texas A&M University, 2004. http://hdl.handle.net/1969.1/1506.
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Tuberculosis is the second leading cause of morbidity and mortality worldwide due to an infectious disease. Development of a new tuberculosis (TB) vaccine would be facilitated by a better understanding of the mechanisms of protection induced by the current TB vaccine, Mycobacterium bovis BCG. Recombinant guinea pig (rgp)CCL5 and anti-rgpCCL5 were developed and characterized. The biological activity of rgpCCL5 was determined in a chemotaxis assay using T lymphocytes and pleural exudate cells. The specificity of rabbit anti-rgpCCL5 polyclonal antibody was confirmed by Western blot. RgpCCL5 was used to stimulate alveolar and peritoneal macrophages in vitro. and cytokine/chemokine gene expression was evaluated using real-time PCR. RgpCCL5 stimulated TNFα, IL-1β, CCL2, and CXCL8 mRNA
expression and TNFα protein production (as assessed in the L929 cell bioassay) in macrophages. The effect of BCG-vaccination on CCL5 expression and production in leukocytes infected with M. tuberculosis was examined in vitro and in vivo. Polyclonal anti-rgpCCL5 was used to develop an ELISA assay to quantify gpCCL5 protein levels, and real-time PCR was used to detect CCL5 mRNA. Leukocytes isolated from BCG-vaccinated guinea pigs and infected in vitro with virulent M. tuberculosis demonstrated significantly elevated gpCCL5 mRNA and protein compared to cells from naive animals. The response of gpCCL5 to M. tuberculosis in vivo was studied in tuberculous pleural effusions, where peak levels of CCL5 mRNA and protein were reached at day 4 post-induction. Disease severity, cellular differentiation, histology, and cytokine/chemokine mRNA levels in pleural cells and granulomas were analyzed on day 4 in guinea pigs induced with tuberculous pleurisy and treated with either rgpCCL5 or anti-rgpCCL5 by direct intra-pleural injection. In these studies, neutralizing CCL5 resulted in reduced macrophage accumulation, diminished levels of IFNγ, TNFα, and CCL5 mRNA in pleural effusion cells, and reduced spontaneous lymphocyte proliferation. Together these studies suggest an important role for gpCCL5 in activating leukocytes during M. tuberculosis infection.
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Pfirstinger, Jochen. "Bindung von rekombinantem humanem RANTES und NH2-terminaler Modifikationen an den Chemokinrezeptor CCR5 und an Zelloberflächen". Diss., lmu, 2003. http://nbn-resolving.de/urn:nbn:de:bvb:19-10601.
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Di, Palma Stefanie. "An investigation of the prognostic utility of RANTES levels in predicting mortality in an angiography population". Thesis, University of British Columbia, 2014. http://hdl.handle.net/2429/50175.
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RANTES (Regulated upon activation, normal T cell expressed and secreted) is a chemokine involved in the recruitment and transmigration of leukocytes across the vascular endothelium. A large body of experimental evidence suggests the role of RANTES and its receptor, CCR5, in atherosclerosis and has prompted the study of RANTES as a biomarker of coronary artery disease (CAD).
We sought to investigate baseline plasma RANTES as a marker of mortality in a cohort of patients referred for angiography. RANTES levels were measured in 831 patients who were classified by angiogram as positive or negative for CAD. At the time of recruitment, blood samples were collected and later assayed using a commercial ELISA kit for RANTES. Mortality data was collected in 2009 to identify deceased patients and the cause of death.
RANTES levels were significantly different between men and women (27.7 ng/mL and 34.2 ng/mL, p=0.001) and between subjects with and without family history of CAD (30.3 ng/mL and 28.1 ng/mL, p=0.006). The predictive value of RANTES levels for CAD was assessed using a multivariate logistic regression model adjusting for traditional markers of CAD. Triglycerides and apolipoprotein B levels were independent predictors, with odds ratios of OR 2.65 [95% CI: 1.05-6.69] and OR 2.65 [95% CI: 1.01-6.93], p<0.001 respectively. RANTES levels were associated with CAD, OR 1.67 [95% CI: 1.00-2.76], p=0.047, although this association was moderate. When divided into quartiles, subjects with a RANTES level above the fourth quartile were associated with a greater risk of CAD, OR 1.73 [95% CI: 1.05-2.86], p=0.031. After a mean follow-up of 11.1 years, 256 of the 831 subjects were deceased. Using a Cox regression model, we assessed the ability of RANTES to predict cardiovascular and all-cause mortality. Only age and smoking status independently predicted death due to any cause (p<0.001 and p=0.015, respectively).
Our results suggest that RANTES levels do not enhance cardiovascular risk prediction in a population of patients with stable CAD. Further studies to explain the association between RANTES, family history of CAD and female gender could determine whether risk prediction would be improved for these groups.Medicine, Faculty of
Pathology and Laboratory Medicine, Department of
Graduate
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Mawela, Kedibone Gloria. "Evaluation of RANTES analogue expression in Nicotiana benthamiana and Lycopersicon esculentum and their topical microbicidal activity". Thesis, University of Pretoria, 2013. http://hdl.handle.net/2263/32946.
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The HIV/AIDS pandemic has dramatically altered patterns of morbidity and mortality in
sub-Saharan Africa during the last two decades. In the absence of HIV vaccine,
microbicides may offer viable option for protection against HIV infection. Microbicides
are products that are applied topically inside the vagina or rectum that act to impede
transmission of HIV and other sexually transmitted diseases. Small human chemokines
such as RANTES (regulated upon activation, normal T cell expressed and secreted) are
currently been investigated as microbicides candidates.
A number of N-terminally modified RANTES analogues such as 5P12 and 6P4 with a
much higher antiviral potency have been developed and they have strong potential for
use as microbicides. Since plants offer an alternative option for cost effective production
of protein therapeutics, we evaluated the feasibility of expressing 5P12 and 6P4 in
Nicotiana benthamiana species. 5P12 is considered the most promising candidate for
use in the microbicide pipeline because it inhibits HIV infection through cellular receptor
antagonism. Hence its feasibility of expression was also evaluated in Lycopersicon
esculentum (tomato). The two analogues were transiently expressed in the selected
plant species via agrobacterium-mediated transfection.
For expression in N. benthamiana, two different vectors (pTRA and MagnICON) were
used to deliver the two analogues for transient expression. About 6-8 weeks-old N.
benthamiana plants were agroinfiltrated via needle injection and vacuum infiltration
methods and targeted to four subcellular compartments viz: apoplast, chloroplast,
cytosol and endoplasmic reticulum (ER). The agroinfiltrated leaves were replanted,
grown in a tissue culture laboratory and harvested after different periods. For
expression in L. esculentum, the MagnICON constructs were used to deliver the 5P12
gene into four different developmental stages of tomato fruits viz: mature green (MG),
breaker (B), pink (P) and ripe (R) via needle injection. The agroinjected tomato fruits
were incubated in a dark cupboard and harvested after different periods.
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Proteins were extracted from the harvested material and evaluated for 5P12 and 6P4
expression. ELISA results showed expression of 5P12 and 6P4 in N. benthamiana
leaves which was detectable at 3-9 days post infiltration (dpi). Similar results were
obtained for 5P12 and 6P4, consequently only results for 5P12 are reported. The
vacuum infiltrated leaves of both pTRA and MagnICON constructs led to higher yields
than the needle injected leaves. The highest yields were obtained with the MagnICON
constructs. The highest 5P12 expression level of 603 μg/kg fresh weight leaf tissues
(~0.024% TSP) was obtained in the apoplast at 9 dpi. The pTRA constructs had the
highest expression levels of 0.63μg/kg FW in the cytosol at 3 dpi.
5P12 was also detectable at 3-9 dpi in L. esculentum, based on ELISA results. The
highest 5P12 expression of 23.56 μg/kg FW and pH 4.75 tissues was obtained at the
MG stage in the apoplast at 9 dpi. Western blot analysis confirmed the size of plantmade
5P12. Moreover, the plant extracts had anti-viral activity and were not toxic to
TZM-bl cells.
Our results show that the RANTES can be made in both N. benthamiana and L.
esculentum and that the levels are not different from other systems reported previously.
Furthermore, this is the first report that a chemokine has been expressed in plants. The
quantities expressed were low making the commercial development of a microbicide
from these species impractical. However, production of bulky leaf material may enhance
the quantities.Thesis (PhD)--University of Pretoria, 2013.
gm2013
Paraclinical Sciences
unrestricted
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Suffee, Nadine. "Rôle de la chimiokine RANTES/CCL5 et de ses ligands membranaires dans l’angiogenèse : Application en biothérapie". Paris 13, 2012. http://www.theses.fr/2012PA132026.
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L’angiogenese est un processus physiopathologique consistant en la formation de nouveaux vaisseaux. Parmi ies facteurs responsables de cette angiogenese les chimiokines sont des médiateurs de la formation des néo-vaisseaux. Le role angiogénique de la chimiokine RANTES/CCL5 est encore source de controverses. Nos travaux démontrent que RANTES/CCLS délivrée localement a l’aide de biomatériau de nitrocellulose induit la formation de capillaires sanguins dans un modele de délivrance sous-cutané chez le rat. L’effet angiogénique de RANTES/CCL5 a été caractérisé in vitro dans les cellules endothéliales HUV-EC-Cs. Nous demontrons que RANTES/CCL5 induit l’étalement et la migration de cellules HUV-EC~Cs et participe a la formation de réseaux vasculaires par le biais d’une sécrétion de VEGF. La liaison de RANTES/CCL5 a ses récepteurs protéiques, CCR1 et CCR5 ainsi qu’aux protéoglycannes membranaires, CD44, syndécanne-1 et syndécanne-4 est indispensable a l’induction de son effet pro-angiogénique. De plus, la liaison de RANTES/CCL5 aux chahes glycosaminoglycannes de type héparane sulfate est essentielle a ses effets biologiques in vitro. Ayant pour objectif de développer une stratégie thérapeutique permettant de lutter contre Vangiogenése, nous avons utilisé deux mutants de RANTESXCCLS caractérisés par une incapacité de lier les chaines lycosaminoglvcanniques. Ces mutants [44ANAA4I]-RANTES/CCL5 et [E66A]-RANTES/CCL5 sont moins efficaces que RANTES/CCL5 pour induire des effets cellulaires impliques dans l'angiogenese in vivo et in vitro. A Finverse, nous avons envisagé l’utiIisation d’un biomatériau permettant la déiivrance locale de RANTES/CCL5 dans un modele d’ischémie de patte de souris, pathologie pour laquelle un traitement induisant Fangiogenese aurait un effet bénéfique pour la survie tissulaireAngiogenesis is a physiopathological process defined by new blood vessel formation. Chemokines are described as possible mediators of angiogenesis. The angiogenic role of the chemokine RANTES/CCL5 is controversial. Our study demonstrated that the local delivery of RANTES/CCL5 by a nitrocellulose biomaterial in a rat subcutaneous model leads to the formation of vessels around the biomaterial. We described that the treatment with RANTES/CCL5 of the endothelial cells line (HUV-EC-Cs) induced the cell spreading, migration and the vascular network formation through VEGF secretion, in vitro. We performed the analysis of the role of the RANTES/CCL5 receptors, CCR1 or CCR5 and membrane proteogiycans, CD44, syndecan-1 or syndecan-4 in angiogenesis process induced by RANTES/CCL5. Moreover the binding of RANTES/CCL5 on glycosaminoglycan heparan sulfate chains was essential for these effects. The aim of this study was to develop therapeutics strategies in pathologies characterized by a deleterious angiogenesis such as cancers. The glycosaminoglycan-binding deficient mutants [MANAAQ]-RANTES/CCL5 and [E66A]- RANTES/CCL5 were less effective than RANTES/CCL5 to induce angiogenesis. In contrary, the association of RANTES/CCL5 with a polysaccharide biomaterial could constitute a strategy to local diffusion of this chemokine in order to induce a neovascularization in hypoxic tissue such as in the ischemic mice leg model
21
Leung, Chung Yee Joey. "Effects of indirubin on the expression of RANTES in influenza virus infected human bronchial epithelial cells". HKBU Institutional Repository, 2004. http://repository.hkbu.edu.hk/etd_ra/505.
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Sotsios, Yannis. "Chemokines and T cells : activation requirements for RANTES secretion and CXCR4 signalling in mature T cells". Thesis, University of Bath, 2000. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.323606.
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Wang, Siyao. "Total Synthesis of Homogeneous Glycopeptides and Glycoproteins". Thesis, The University of Sydney, 2018. http://hdl.handle.net/2123/18329.
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Glycosylation is a ubiquitous post-translational modification of proteins. Access to pure glycoproteins is extremely challenging owing to the enzymatic glycosylation process which is not templated and, as such, affords heterogeneous mixtures of glycoforms. Chemical synthesis provides an attractive avenue to access homogeneously glycosylated peptides and proteins, thus providing a means to elucidate the role of specific glycan modifications on structure and function. This thesis outlined the development of a number of novel synthetic methods to access biologically important glycopeptides and glycoproteins in pure form. Examples would include the synthesis of an unusual glycan modification of arginine which is present on key proteins from pathogenic bacteria and the synthesis of a library of homogenously glycosylated chemokines and cytokines. The results from these studies would inform new anti-infective and anti-inflammatory strategies in the future.
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Jones, Katie Louise. "The chemokine receptor CCR5 and its ligands MIP-1α, MIP-1β and RANTES in human cardiovascular disease". Thesis, University of Cambridge, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.609094.
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Paquette, Linda Lee Jared Heather Lee. "The effect of using a powered toothbrush on MCP-1 and RANTES levels in patients with gingivitis". Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2008. http://dc.lib.unc.edu/u?/etd,1632.
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Thesis (M.S.)--University of North Carolina at Chapel Hill, 2008.Title from electronic title page (viewed Sep. 16, 2008). "... in partial fulfillment of the requirements for the degree of Master of Science in Dental Hygiene Education in the Department of Dental Ecology." Discipline: Dental Ecology; Dental Hygiene Education; Department/School: Dentistry.
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Lintomen, Leticia. "Estudo da inibição do oxido nitrico sobre funções de eosinofilos humanos estimulados com eotaxina e RANTES in vitro". [s.n.], 2008. http://repositorio.unicamp.br/jspui/handle/REPOSIP/308929.
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Orientador: Edson ArantesTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
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Resumo: Os eosinófilos participam da patogênese de várias doenças inflamatórias, incluindo infecções parasíticas e doenças alérgicas. Dentre as doenças alérgicas, a eosinofilia tem presença marcante na asma. Atualmente, a asma afeta 300 milhões de indivíduos no mundo, sendo considerada um problema de saúde pública mundial. A asma é uma doença inflamatória crônica que envolve interações entre fatores externos e genéticos, e tem como características principais a inflamação pulmonar e a hiperresponsividade brônquica. O recrutamento de eosinófilos para as vias aeríferas contribui para o caráter crônico da asma. A migração de eosinófilos para o tecido inflamado é um processo complexo, que é regulado por numerosos fatores, incluindo citocinas, quimiocinas, óxido nítrico (NO) e interações de moléculas de adesão. Estudos prévios investigaram as interações funcionais entre NO e CC-quimiocinas. Young e colaboradores (1999) mostraram que o número de eosinófilos no lavado broncoalveolar (LBA) de macacos desafiados está marcadamente aumentado 24 horas após o desafio, e que este aumento é acompanhado de altos níveis de NO no ar exalado e de eotaxina no LBA. Em pacientes com rinite, a eotaxina aumentou o número de eosinófilos no fluido do lavado nasal e também os níveis de NO nasal (Hanazawa et al., 1999). Em contraste, em modelos murinos de asma a inibição seletiva da NOS induzível resultou na redução da migração eosinofílica para os pulmões (Feder et al., 1997; Iijima et al., 2001), que estava associada com o aumento da expressão da CC-quimiocina proteína quimiotática para monócito-1 (MCP-1) no tecido pulmonar (Trifilieff et al., 2000). Além disso, NO (ou doadores de NO) também são capazes de inibir a produção de RANTES (Frank et al., 2000). O NO via formação de peroxinitrito (ONOO-) também pode reduzir a migração de eosinófilos induzida por eotaxina (Sato et al., 2000). Entretanto, o papel modulatório do NO nas funções do eosinófilo mediadas por CC-quimiocinas ainda permanece contraditório. Portanto, o presente trabalho investigou o efeito modulatório do NO na adesão aumentada, quimiotaxia e desgranulação do eosinófilo induzidas pelas Ccquimiocinas eotaxina e RANTES in vitro, e a expressão de VLA-4 e Mac-1 na superfície do eosinófilo. Nós realizamos ensaios funcionais (adesão e desgranulação), análise da expressão de moléculas de adesão por citometria de fluxo (VLA-4 e Mac-1) e a investigação de resíduos de tirosina nitrada para avaliar interações do NO com CC-quimiocinas em eosinófilos humanos. Os ensaios de MTT mostraram que as incubações de eosinófilos por 2, 3, ou 4 horas com eotaxina (10, 100 e 1000 ng/ml) ou RANTES (10, 100 e 1000 ng/ml) não afetam a viabilidade celular e, em determinadas condições, até promovem a ativação das células. Os resultados de adesão à fibronectina mostraram que a eotaxina (10, 100 e 1000 ng/ml) ou RANTES (10, 100 e 1000 ng/ml) não aumentam a adesão de eosinófilos em períodos de incubação de 2 e 3 horas. Entretanto, a incubação de eosinófilos por 4 horas com eotaxina ou RANTES aumentou significativamente a adesão à fibronectina. O L-NAME (0.1 mM), individualmente, aumentou significativamente a adesão de eosinófilos à fibronectina; porém a co-incubação de L-NAME com eotaxina (ou RANTES) não afetou a adesão observada com cada agente isoladamente. Além disso, a expressão de VLA-4 e de Mac-1 não foi modificada em nenhuma das condições experimentais testadas. Eotaxina e RANTES também não foram capazes de aumentar os níveis de GMPc nos eosinófilos, em condições onde o SNP (0.1 mM), usado como controle positivo, aumentou significativamente os níveis desse segundo mensageiro. Além disso, eosinófilos tratados com L-NAME, eotaxina e RANTES, individualmente, foram capazes de desgranular estas células, mas a co-incubação de LNAME com eotaxina (ou RANTES), não alterou esta resposta. Os resultados de quimiotaxia mostraram migração significativa de eosinófilos (tratados ou não com LNAME) em resposta à eotaxina ou RANTES. Os resultados obtidos de Western blotting para 3-nitrotirosina mostraram ausência de proteínas nitradas nos eosinófilos de indivíduos sadios ou asmáticos. No conjunto, nossos resultados mostram que, nas condições experimentais estabelecidas, o NO não modula adesão, migração e desgranulação em eosinófilos estimulados com eotaxina ou RANTES
Abstract: Eosinophils participate in the pathogenesis of many inflammatory diseases, including parasitic infections and allergic diseases. Of the allergic diseases, asthma is characterized by eosinophilia. Currently, asthma affects 300 million people in world, and is an important public health problem. Asthma is an inflammatory chronic disease that involves interactions between external and genetic factors, and has lung inflammation and bronchial hyperresponsiveness as major features. The recruitment of eosinophils into airways contributes to the asthma chronic character. The eosinophil migration to inflamed tissue is a complex process regulated by several factors, including cytokines, chemokines, nitric oxide (NO) and adhesion molecule interactions. Previous studies have investigated the functional interactions between NO and CC-chemokines. Young et al. (1999) showed that the number of eosinophils in the bronchoalveolar lavage (BAL) fluid of challenged monkeys is markedly increased at 24 h post-challenge, accompanied by higher levels of both exhaled NO and eotaxin in BAL fluid. In rhinitis patients, eotaxin increased the number of eosinophils in the nasal lavage fluid, and that was also accompanied by elevated nasal NO levels (Hanazawa et al., 1999). In contrast, in murine models of asthma, selective inhibition of inducible NOS resulted in a reduction in pulmonary eosinophil migration (Feder et al., 1997; Iijima et al., 2001), with an increased expression of the CC-chemokine monocyte chemoattractant protein-1 (MCP-1) in the lung tissue (Trifilieff et al., 2000). Moreover, NO (or NO donors) have also been shown to inhibit the production of RANTES (Frank et al., 2000). Nitric oxide via peroxynitrite (ONOO-) formation is reported to reduce eotaxin-induced eosinophil migration (Sato et al., 2000). However, the modulatory role of NO in the CC-chemokines-mediated eosinophil functions is still not well understood. Therefore, the present study was designed to investigate the modulatory effect of NO in the enhanced eosinophil adhesion, chemotaxis and degranulation induced by the Ccchemokines eotaxin and RANTES in vitro, and the expression of VLA-4 and Mac-1 on the eosinophil surface. We therefore carried out functional assays (adhesion and degranulation), flow cytometry analysis of adhesion molecules (VLA-4 and Mac-1 expression) and investigation of tyrosine nitration to evaluate the interactions between NO and CC-chemokines in human eosinophils. MTT assays showed that incubation of eosinophils for 2, 3 or 4 hours with eotaxin (10, 100 and 1000 ng/ml) or RANTES (10, 100 and 1000 ng/ml) did not affect cellular viability and, in some conditions, even caused cellular activation. The results of adhesion to fibronectin showed that eotaxin (10, 100 and 1000 ng/ml) or RANTES (10, 100 and 1000 ng/ml) did not increase eosinophil adhesion at 2 or 3 hours of incubation. Nevertheless, the incubation of eosinophils for 4 hours with eotaxin or RANTES significantly increased adhesion to fibronectin. L-NAME (0.1 mM), alone, significantly increased eosinophil adhesion to fibronectin; however the co-incubation of L-NAME with eotaxin (or RANTES) did not affect the adhesion of each agent. Moreover, expression of VLA-4 and Mac-1 were not modified by any of the experimental conditions. Eotaxin and RANTES did not increase eosinophil cGMP levels under the same conditions in which SNP (0.1mM), used as a positive control, significantly increased the levels of this second messenger. Furthermore, eosinophils treated with L-NAME, eotaxin and RANTES, alone, demonstrated degranulation, however the co-incubation of eosinophils with L-NAME and eotaxin (or RANTES) did not alter this response. Chemotaxis assays showed a significant eosinophil (treated or not with L-NAME) migration in response to eotaxin or RANTES. Western blotting for 3-nitrotyrosine-3 showed a lack of nitrated proteins in eosinophils from healthy or asthmatic donors. Taken together, results show that, under the experimental conditions established, NO does not modulate adhesion, migration and degranulation in eotaxin or RANTES-stimulated eosinophils
Doutorado
Doutor em Farmacologia
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Maillard, Loïc. "Implication du domaine intracellulaire du syndécane-4 dans l’angiogenèse et le recrutement monocytaire induits par la chimiokine RANTES/CCL5". Thesis, Paris 13, 2014. http://www.theses.fr/2014PA132051/document.
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L’athérosclérose est caractérisée par la formation d’une plaque d’athérome au niveau de la paroi d’un vaisseau sanguin. L’infiltration monocytaire participe à la phase précoce du développement de la plaque d’athérome. Le risque de rupture de la plaque est accru suite à sa néo-vascularisation. La chimiokine Regulated upon Activation, Normal T-cell, Expressed and Secreted (RANTES/CCL5) est impliquée dans le recrutement monocytaire. De plus, elle exerce un effet pro-angiogénique de manière dépendante de sa fixation aux glycosaminoglycanes (GAG) endothéliaux. Les syndécanes (SDC) sont des protéoglycanes transmembranaires à chaînes GAG exprimés par les cellules endothéliales. Le but de cette étude est de déterminer l’implication du domaine intracellulaire du SDC-4 dans l’angiogenèse et le recrutement monocytaire induits par la chimiokine RANTES/CCL5. Des mutants intracellulaires du SDC-4 ont été développés pour étudier le rôle de la PKC-α, de la liaison du PIP2 ou de protéines à domaine PDZ dans l’angiogenèse et le recrutement monocytaire induits par RANTES/CCL5. Nos résultats montrent que la chimiokine RANTES/CCL5 stimule l’angiogenèse et le recrutement monocytaire par le biais d’une signalisation intracellulaire induite par le domaine intracellulaire du SDC-4, activant notamment la PKC-α. Le développement de thérapies ciblant l’activation du SDC-4 pourrait permettre de réguler les effets physiopathologiques exercés par RANTES/CCL5Atherosclerosis is a pathology characterized by the formation of an atheroma plaque in the blood vessel wall. Monocyte infiltration participates to the early phase of atheroma plaque development. Plaque rupture is induced by its neovascularization. The chemokine Regulate upon Activation, Normal T-cell, Expressed and Secreted (RANTES/CCL5) is involved in monocyte recruitment. Moreover, RANTES/CCL5 induces angiogenesis through its binding to endothelial glycosaminoglycans (GAG) chains. Syndecans (SDC) are transmembrane proteoglycans with GAG chains expressed at the membrane of endothelial cells. The aim of this study is to analyze the involvement of SDC-4 intracellular domain in RANTES/CCL5-induced angiogenesis and monocyte recruitment. SDC-4 intracellular mutants were developed to analyze the role of PKC-α, PIP2 binding or PDZ domain proteins in RANTES/CCL5-induced angiogenesis and monocyte recruitment. Our data show that RANTES/CCL5 induces angiogenesis and monocyte recruitment through intracellular signaling, including the activation of PKC-α, mediated by SDC-4 intracellular domain. The development of new therapeutic strategy targeting SDC-4 activation may counteract RANTES/CCL5 physiopathological effects
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Nellen, Andreas Verfasser], Hermann Elard [Akademischer Betreuer] Wasmuth i Ralph [Akademischer Betreuer] [Panstruga. "Die Rolle des Chemokins CCL5/RANTES im Rahmen der akuten und chronischen Leberschädigung / Andreas Nellen ; Hermann Elard Wasmuth, Ralph Panstruga". Aachen : Universitätsbibliothek der RWTH Aachen, 2018. http://d-nb.info/1181193052/34.
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Brulé-Donneger, Séverine. "Accélération par les chimiokines RANTES /CCL5 ou SDF-1/CXCL12 du relargage d'éctodomaines de protéoglycannes de la famille des syndécannes". Paris 13, 2007. http://www.theses.fr/2007PA132001.
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Les chimiokines sont des cytokines chimioattractantes, impliquées dans la pathogenèse de maladies inflammatoires, dans l’angiogénèse et la croissance tumorale et dans l’infection par le virus de l’immunodéficience humaine (VIH). Nous avons mis en évidence que RANTES se lie à des protéoglycannes : les syndécannes-1 et -4, de manière directe et glycosaminoglycannes dépendante, et accélère significativement le relargage des ectodomaines de ces protéoglycannes, à partir de cellules HeLa exprimant CCR5, mais pas à partir des cellules HeLa n’exprimant pas CCR5. Parallèlement, nous avons observé, par cytométrie de flux, que RANTES induit une diminution de l’expression des syndécannes-1 et -4 à la membrane plasmique des cellules HeLa CCR5+, mais pas à celle de cellules HeLa CCR5-. Nos résultats montrent aussi que ce relargage des ectodomaines des syndécannes-1 et -4, accéléré par RANTES, est dépendant des voies de transduction impliquant les MAPK et la PKC. Les études similaires réalisées avec la chimiokine SDF-1 montrent que le traitement des cellules HeLa par SDF-1 accélère significativement le relargage des ectodomaines des syndécannes-1 et -4. Ce relargage, accéléré par SDF-1 est dépendant des voies de transduction impliquant la PKC mais pas les MAPK. De plus, nous avons montré que la MMP9 est impliquée dans ce relargage. Parallèlement, nous avons mis en évidence que non seulement RANTES ou SDF-1, mais aussi des glycoprotéines d’enveloppe virales de deux isolats de VIHX4 ou R5, les gp120 augmentent de manière significative le relargage des ectodomaines des syndécannes-1 et -4 par des cellules en culture primaire, les macrophages humains dérivés des monocytes en culture. Mots clés : Chimiokines ; RANTES ; SDF-1 ; CXCR4 ; CCR5 ; Protéoglycannes ; Syndécannes ; relargageChemokines and their G protein coupled receptors (GPCRs), play roles in inflammatory responses, cancer cell proliferation and HIV infection. In our recent works, we demonstrate that RANTES binds to the heparan sulfate proteoglycans: syndecan-1 and -4 (SDC-1 and -4), and accelerates the shedding of SDC-1 and -4 ectodomains from HeLa cells. This shedding requires the GPCR CCR5 and involves MAPK and PKC activation. SDF-1 binds to SDC-4, and accelerates the shedding of SDC-1 and -4 from HeLa cells. This shedding requires PKC activation and is mediated by MMP9, but does not depend on the GPCR CXCR4 expression. We show that RANTES, SDF-1 and HIV envelop glycoproteins gp120 X4 and R5, accelerate the shedding of SDC-1 and -4 ectodomains, from human monocyte-derived macrophages. Keywords : chemokines ; RANTES ; SDF-1 ; CXCR4 ; CCR5 ; proteoglycans ; syndecans ; shedding
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Nellen, Andreas [Verfasser], Hermann Elard Akademischer Betreuer] Wasmuth i Ralph [Akademischer Betreuer] [Panstruga. "Die Rolle des Chemokins CCL5/RANTES im Rahmen der akuten und chronischen Leberschädigung / Andreas Nellen ; Hermann Elard Wasmuth, Ralph Panstruga". Aachen : Universitätsbibliothek der RWTH Aachen, 2018. http://d-nb.info/1181193052/34.
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Fredrich, Andréa Longoni. "Imunoexpressão de rankl, CCL5/RANTES e CCR5 em inflamação pulpar aguda em ratos, induzida por exposição tecidual, ácido lipoteicóico ou lipopolissacarídeo". Pontifícia Universidade Católica do Rio Grande do Sul, 2014. http://hdl.handle.net/10923/6650.
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Previous issue date: 2014Studies on dental caries demonstrate inflammation on dental pulp tissues following infection. Cytokines are able to activate those cells linked to inflammatory and immune response thus neutralizing potentially aggressive agents and allowing tissue repair. Some of those cytokines, denominated chemokines, could contribute to the establishment of an immunotherapy able to control those cytokines involved with the triggering of dental pulp inflammation. Research on chronic inflammation has provided some relevant insights. However, the role of certain chemokines on acute inflammation is yet not conclusive. This study attempts to unveil the role of the chemokines CCL5/RANTES, CCR5 and RANKL on initial and acute pulpal inflammation. Methods: 18 Wistar rats were subjected to anesthesia. Access was performed on their first lower molars until pulp exposure. They were divided into three experimental groups considering the solution administered: Saline, lipopolysaccharide (LPS) and lipoteichoic acid (LTA) (n=6 each group). Higid second lower molars were used as controls. The cavities were sealed with amalgam and euthanasia occurred after 48 h and the jaws were dissected for histologic evaluation. CCL5/RANTES is expressed in all groups, unlike CCR5, that was not expressed. RANKL appears only in inflammatory cells, including control group. Only RANKL could be expressed during initial pulpal inflammation, being able to detect inflammatory cell activity.
Estudos de cárie demonstraram aspectos inflamatórios nos tecidos pulpares decorrentes de infecção estabelecida. Citocinas seriam capazes de ativar células ligadas à resposta inflamatória e imune no sentido de neutralizar potenciais agentes invasores e permitir o reparo dos tecidos pulpares. Algumas destas, denominadas quimiocinas, poderiam contribuir no estabelecimento de uma imunoterapia capaz de bloquear aquelas citocinas responsáveis pelo processo inflamatório. Na inflamação crônica estas pesquisas já possuem resultados satisfatórios. Na inflamação aguda, os estudos ainda estão inconclusivos. Este estudo teve como objetivo testar as quimiocinas CCL5/RANTES, CCR5 e RANKL na inflamação pulpar aguda. Métodos: 18 Ratos Wistar foram anestesiados. Foram feitas cavidades até a exposição pulpar nos primeiros molares inferiores. Eles foram divididos em três grupos onde se administrou solução salina estéril, lipopolissacarídeo (LPS) e ácido lipoteicóico (LTA) (n= 6 por grupo). Os segundos molares inferiores hígidos foram utilizados como controle. As cavidades foram seladas com amálgama e a eutanásia foi realizada após 48h. As mandíbulas foram dissecadas para exame histológico e da imunoexpressão das quimiocinas em estudo. Obteve-se como resultados: CCL5/RANTES é expressa em todos os grupos, ao contrário do CCR5, que não foi expressa. RANKL aparece apenas em células inflamatórias. Somente a expressão de RANKL foi capaz de demonstrar atividade celular na inflamação pulpar inicial.
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Martin, Elizabeth Ashley Wilder Rebecca S. "Are the GCF levels of MCP-1 and RANTES elevated in peri-partum women with periodontitis as compared to healthy controls?" Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2009. http://dc.lib.unc.edu/u?/etd,2476.
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Thesis (M.S.)--University of North Carolina at Chapel Hill, 2009.Title from electronic title page (viewed Sep. 3, 2009). "... in partial fulfillment of the requirements for the degree of Master of Science in the Department of Dental Hygiene Education, School of Dentistry." Discipline: Dental Hygiene Education; Department/School: Dentistry.
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McManus, Andrew. "The identification of equine genes represented by expressed sequence tags and the subsequent characterisation of two immunologically relevant genes, RANTES and CD19". Thesis, University of Cambridge, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.627443.
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Silveira, Ilson Dias da. "Níveis da quimiocina RANTES na placenta, plasma materno e plasma do cordão umbilical em gestantes normais e com síndrome de pré-eclâmpsia". Pontifícia Universidade Católica do Rio Grande do Sul, 2012. http://hdl.handle.net/10923/4346.
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Previous issue date: 2012Objective: To estimate RANTES levels at maternal plasma, umbilical cord blood plasma and placenta in preeclampsia syndrome and normal pregnancy.Methods: A cross-sectional study was conducted to estimate RANTES levels in maternal plasma, placenta and cord blood plasma in preeclampsia syndrome (n=33) compared to a control group of women with normal pregnancy (n=36) attended at São Lucas Hospital/PUCRS, Porto Alegre, RS Brazil. Concentrations of RANTES were measured using a human RANTES ELISA assay.Results: Women with preeclampsia syndrome showed significantly higher RANTES levels in plasma and placenta in comparison to women with normal pregnancy (P<0. 01). The cord blood plasma of infants born from women with preeclampsia syndrome had a significantly decreased RANTES levels compared to infants born from a normal pregnancy (P<0. 01). The concentration of placental RANTES was positively correlated with RANTES in the maternal plasma (Pearson´s correlation r= 0. 697; p<0. 001), and negatively with the cord blood plasma (r= -0. 818; p<0. 001). A strong negative correlation was also demonstrated between maternal plasma and cord blood plasma RANTES (r= -0. 751, p<0. 001).Conclusion: This study shows a distinct inflammatory response between mother and new born in preeclampsia syndrome and normal pregnancy. In preeclampsia syndrome maternal plasma and placenta displayed increased pro-inflammatory RANTES cytokine concentration, however a reduced levels were detected in the umbilical cord plasma from women with preeclampsia syndrome, suggesting a fetal antiflammatory response.
Objetivo: O objetivo deste trabalho foi estimar os níveis de RANTES na placenta e nos plasmas materno e do cordão umbilical na síndrome de pré-eclâmpsia e gestação normal.Métodos: Estudo transversal e observacional estimou os níveis de RANTES na placenta e nos plasmas materno e do cordão umbilical na síndrome de pré-eclâmpsia (n=33) comparando com um grupo controle de gestantes normais (n=36) atendidas no Hospital São Lucas/PUCRS, Porto Alegre, RS, Brasil. As concentrações de RANTES foram verificadas através do método de enzima imuno ensaio (ELISA) específico para humanos.Resultados: Mulheres com síndrome de pré-eclâmpsia apresentaram níveis significativamente maiores de RANTES no plasma e placenta quando comparadas a gestantes normais (P<0,01). O plasma do cordão umbilical de recém-nascidos de gestantes com pré-eclâmpsia mostraram níveis de RANTES significativamente menores que o plasma do cordão umbilical de recém-nascidos de gestantes normais (P<0,01). A concentração de RANTES placentário correlacionou-se positivamente com a concentração de RANTES no plasma materno (r= 0,697; P<0,001) e negativamente com o plasma do cordão umbilical (r= - 0,818; P< 0,001). Forte correlação negativa na concentração de RANTES foi demonstrada entre plasma materno e plasma do cordão umbilical (r= - 0,751; P<0,001).Conclusão: Este estudo mostra uma resposta inflamatória distinta entre a mãe e o recém-nascido em ambas as condições, gestação normal e síndrome de pré-eclâmpsia. A placenta e o plasma materno demonstraram uma concentração da citocina inflamatória RANTES aumentada na síndrome de pré-eclâmpsia, entretanto, no plasma do cordão umbilical dos recém-nascidos dessas gestantes estava reduzida, sugerindo uma resposta fetal anti-inflamatória.
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Nießen, Christoph [Verfasser], Claus [Akademischer Betreuer] Hellerbrand i Andreas [Akademischer Betreuer] Schreyer. "Hepatic steatosis causes induction of the chemokine RANTES in the absence of significant hepatic inflammation / Christoph Nießen. Betreuer: Claus Hellerbrand ; Andreas Schreyer". Regensburg : Universitätsbibliothek Regensburg, 2012. http://d-nb.info/1027410189/34.
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Dudley, Dawn M. "HIV-1 Env impacting HIV-1 fitness, entry inhibitor drug sensitivity, and in vivo selection of a resistant virus to the microbicide PSC-Rantes /". Connect to text online, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=case1186757280.
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Thesis (Ph. D.)--Case Western Reserve University, 2007.[School of Medicine] Department of Molecular Biology and Microbiology. Includes bibliographical references. Available online via OhioLINK's ETD Center.
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Friand, Véronique. "Rôles des chimiokines SDF-1/CXCL12 et RANTES/CCL5 dans la carcinogenèse hépatique : Modulation de leurs effets pro-tumoraux par des mimétiques de glycosaminoglycannes". Paris 13, 2010. http://www.theses.fr/2010PA132009.
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L’axe SDF-1/CXCR4 d’une part et RANTES/CCR1 d’autre part jouerait un rôle majeur dans la tumorigenèse hépatique. Ces chimiokines induisent la migration et l’invasion de cellules d’hépatome humain Huh7, in vitro, via leurs récepteurs de type récepteurs couplés aux protéines G (RCPGs) mais également via leur liaison à des chaînes glycosaminoglycanniques, notamment celles portées par des protéoglycannes (PGs) membranaires nommés syndécannes (SDCs). Outre l’utilisation classique d’antagoniste spécifique des RCPGs (comme l’AMD3100 pour le CXCR4) ou d’anticorps bloquant dirigés contre ces mêmes RCPGs, l’inhibition des effets pro-tumoraux des chimiokines dans notre modèle cellulaire Huh7 a été réalisée selon une démarche originale consistant en la modulation de l’interaction des chimiokines avec les chaînes de glycosaminoglycannes (GAGs) par l’utilisation de b-D-xylosides, par ARNi, et par des composés synthétiques mimant la structure des chaînes de GAGs nommés RGTA®. Ces mimétiques de GAG agissent comme inhibiteurs des effets pro-tumoraux des chimiokines SDF-1/CXCL12 ou RANTES/CCL5 in vitro. Cette inhibition se produit de par l’action de compétition des mimétiques de GAGs avec les chaînes HS (séquestration de la chimiokine et diminution de la liaison avec son RCPG) mais aussi en induisant des modifications cellulaires (diminution de l’induction, par SDF-1/CXCL12 ou RANTES/CCL5, de voies de signalisation intracellulaire, inhibition de la production d’enzyme telle que l’héparanase). Cibler cette interaction chimiokine/GAG et comprendre les mécanismes associés pourraient permettre d’établir de nouveaux outils thérapeutiques visant le carcinome hépatocellulaireIn addition to their physiologic effects in inflammation and angiogenesis, chemokines are involved in cancer pathology. This study demonstrates that the CXC-chemokine Stromal cell-Derived Factor 1 (SDF-1)/CXCL12 and the CC-chemokine Regulated on Activation, Normal T-cell expressed, and presumably Secreted (RANTES)/CCL5 induce the growth, migration, and invasion of human hepatoma Huh7 cells. This biological effects induction depends on chemokine binding to the cell. SDF-1/CXCL12 and RANTES/CCL5 bind to their respective GPCR: CXCR4 and CCR1 at the plasma membrane of Huh7 cells. In addition to GPCR, chemokine binding depends on glycosaminoglycans (GAGs). Indeed, SDF-1/CXCL12 and RANTES/CCL5 associate with syndecan-4 (SDC-4), a heparan sulfate proteoglycan at the plasma membrane of Huh7 cells. In this study, we demonstrate that GAG mimetics inhibit SDF-1/CXCL12 and RANTES/CCL5-mediated chemotaxis effects. Indeed, GAG mimetics may compete with cellular heparan sulfate chains for the binding to SDF-1/CXCL12 and RANTES/CCL5 and, in case of SDF-1/CXCL12, may affect heparanase expression, leading to reduced chemokines-mediated chemotaxis and growth of hepatoma cells in vitro. Targeting the chemokine-glycosaminoglycan interaction could be a new therapeutic approach for human hepatocellular carcinoma
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Boulègue, Cyril. "Synthèse d'analogues peptidiques de la chimiokine RANTES : une nouvelle approche dans le traitement des infections par VIH. Etude méthodologique des synthèses stéréosélectives de thiazolines". Montpellier 2, 2000. http://www.theses.fr/2000MON20161.
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Ce travail est scinde en deux parties distinctes l'une portant sur la synthese d'analogues de la chimiokine rantes et l'autre sur une etude methodologique de syntheses stereoselectives de thiazolines. Pour infecter les cellules cibles, le vih a besoin de se lier conjointement en plus du marqueur de surface cd4 a un corecepteur appele recepteur aux chimiokines (ccr et cxcr). Le recepteur ccr5, recepteur des chimiokines mip-1, mip-1 et rantes est connu comme etant le corecepteur principal du vih presentant un tropisme pour les macrophages. Ainsi, la conception de nouveaux antagonistes du recepteur aux chimiokines ccr5 pourrait aboutir a une nouvelle approche therapeutique anti-sida. Sur la base de donnees structurales issues de la modelisation des sites probables d'interaction entre rantes et ccr5 et des etudes deja realisees sur d'autres chimiokines, nous avons realise la synthese de plusieurs analogues peptidiques cycliques, lineaires et ramifies. Ces analogues miment les regions de rantes pouvant etre impliquees dans son interaction avec ccr5. Les thiazolines sont des motifs structuraux presents dans de nombreux composes naturels biologiquement actifs. Ces composes permettent egalement l'elaboration de precurseurs de peptides aldehydiques qui sont connus comme etant de puissants inhibiteurs naturels de cysteyl et seryl proteases ou encore des intermediaires utilises en synthese peptidique comme agents de ligation. Apres avoir recense les differentes methodes de synthese existantes pour l'elaboration de thiazolines chirales, nous avons consacre une partie de ce travail a l'etude de methodes pouvant permettre une obtention rapide et stereoselective de thiazolines. Pour cela, nous avons reevalue des methodes enoncees dans la litterature qui font appel a la cyclisation de -mercaptoamides. Ces methodes chimiquement productives ne permettent cependant pas d'assurer un controle de la chiralite de maniere reproductible.
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Dudley, Dawn M. "HIV-1 ENV: IMPACTING HIV-1 FITNESS, ENTRY INHIBITOR DRUG SENSITIVITY, AND IN VIVO SELECTION OF A RESISTANT VIRUS TO THE MICROBICIDE PSC-RANTES". Case Western Reserve University School of Graduate Studies / OhioLINK, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=case1186757280.
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Domínguez, Hernández Francisco. "Implicación de las quimoquinas IL-8, MCP-1, rantes, los receptores CXCR1, CXCR4, CCr2, CCr5 y el factor IGFBP-rP1 en la interfase materno-embrionaria". Doctoral thesis, Universitat de València, 2003. http://hdl.handle.net/10803/10135.
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La implantación embrionaria es la fijación del blastocisto al endometrio materno. El conocimiento de los factores moleculares implicados en su regulación es crucial para comprender los mecanismos que controlan la reproducción humana Las quimoquinas y sus receptores participan activamente en este proceso así como otros factores como IGFBP-rP1.Los objetivos principales de la tesis doctoral fueron los siguientes - Investigar la expresión y localización de la quimoquinas IL-8, MCP-1, RANTES y SDF-1 en el endometrio humano.- Estudiar la expresión y localización de los receptores de las quimoquinas antes citadas CXCR1, CCR2b, CCR5 y CXCR4 en el endometrio humano.- Determinar la presencia de dichos receptores en el blastocisto humano.- Analizar la expresión de qué genes están regulados en el endometrio durante la ventana de implantación y establecer su implicación en la receptividad endometrial humana.- Evaluar la expresión y localización de IGFBP-rP1 en el endometrio humano.Las conclusiones de la tesis doctoral fueron las siguientes- IL-8 y MCP-1 a nivel de proteína se localizan en el epitelio luminal y glandular así como en células endoteliales. RANTES fue localizada principalmente en células del estroma y endoteliales.- Los niveles de IL-8 y MCP-1 aumentaron debido a la administración de progesterona durante la fase receptiva del ciclo menstrual.- El blastocisto humano no produce cantidades medibles de IL-8, MCP-1 y RANTES, pero induce un aumento en el ARN mensajero de IL-8 en células epiteliales endometriales en cultivo.- Los receptores de quimoquinas CXCR1 (IL-8), CCR5 (RANTES) y CCR2b (MCP-1) a nivel de ARNm esta aumentado en el endometrio premenstrual, mientras que CXCR4 (SDF-1) se encontró aumentado ligeramente durante la ventana de implantación (fase secretora media). El blastocisto humano posee los receptores CCR5 (RANTES) y CCR2b (MCP-1) a nivel de proteína. - Las células endometriales epiteliales en cultivo poseen los receptores CXCR1 (IL-8), CCR5 (RANTES) y CCRb (MCP-1). El embrión humano induce una polarización de dichos receptores endometriales.- IGFBP-rP1 fue la segunda molécula más expresada tanto por el endometrio receptivo (LH+7) como en la línea celular RL95-A (receptiva) entre más de 375 genes analizados de citoquinas, quimoquinas, factores de crecimiento y sus receptores.- El ARN mensajero de IGFBP-rP1 aumentó unas 35 veces durante la fase receptiva comparado con el endometrio pre-receptivo, mostrando además un pico de expresión en la fase lútea tardía. La separación de estroma, y epitelio demostró que la expresión de IGFBP-rP1 aumentaba principalmente en células del estroma.- La localización del ARNm de IGFBP-rP1 por hibridación in situ confirmó la localización de dicha molécula en células del estroma aunque también se observó en epitelio y células endoteliales. La localización de la proteína se concentró en la superficie apical del endometrio, sugiriendo su posible función en la fisiología de la receptividad endometrial. Concluimos por todo ello que algunas quimoquinas secretadas por el endometrio de forma local como IL-8, RANTES, MCP-1 u otras pueden activar sus receptores en la superficie del blastocisto, lo que supondría su heterodimerización y con ello, se provocaría un fenotipo adhesivo en el blastocisto y su posterior implantación.Human implantation is the process of the adhesion of the blastocyst to the human endometrium. The knowledge of the biochemical factors involved in this process is crucial for the understanding of the mechanisms of the human reproduction.Chemokines, a subfamily of cytokines, and their receptors are actively implicated in this process. Another factor, IGFBP-rP1, is also related to the molecular basis of implantation. Our objectives in this doctoral thesis are: - To investigate the localization and expression of IL-8, MCP-1, RANTES and SDF-1 in the human endometrium. - To study the localization and expression of the chemokine receptors CXCR1, CCR2b, CCR5 and CXCR4 in the human endometrium. - To determine the presence of these receptors in the human blastocyst - To analyze the expression of genes expressed differentially in human receptive endometrium versus pre-receptive endometrium. - To evaluate the expression and localization of IGFBP-rP1 in the human endometrium. The major conclusions of this doctoral thesis are: - IL-8 and MCP-1 are localized in the luminal and glandular epithelium. RANTES was localized in stroma and endothelial cells. The levels of IL-8 and MCP-1 were up-regulated with the administration of progesterone. - The human blastocyst doesn't produce IL-8, MCP-1 nor RANTES, but induces an up-regulation of IL-8 mRNA in endometrial epithelial cells in culture. - The chemokine receptors CXCR1, CCR5, CCR2 are up-regulated in the premenstrual endometrium, whereas CXCR4 is up-regulated in the implantation window. The human blastocyst expresses the CCR5 and CCR2 receptors. - The epithelial endometrial cells in culture express the CXCR1, CCR5 and CCR2 receptors. The human blastocyst produces an up-regulation and polarization of these receptors in this culture. - IGFBP-rP1 was the second most up-regulated molecule in receptive endometrium and in RL95A (receptive) cell line, among more than 375 genes analyzed. - IGFBP-rP1 mRNA was up-regulated more than 35 times during receptive phase compared to pre-receptive one. Stromal cells were responsible for the expression of this molecule. mRNA of IGFBP-rP1 was localized by in situ hybridization in luminal and glandular epithelium and stromal cells. The protein was localized in the apical zone of the luminal epithelium, suggesting a possible role in endometrial receptivity.
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Durpès, Marie-Claude. "Les mécanismes d'activation du globule rouge : implication dans la physiopathologie de la drépanocytose : effet des chimiokines IL-8 et RANTES et rôle du récepteur DARC". Antilles-Guyane, 2010. http://www.theses.fr/2010AGUY0360.
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La drépanocytose se caractérise par la survenue de crises vaso-occlusives très douloureuses de fréquence et gravité variables d'un patient à l'autre. Les mécanismes physiopathologiques impliqués sont complexes, mettant en jeu de nombreux acteurs cellulaires, surtout le globule rouge (GR), et des processus d'activation cellulaire faisant intervenir un contexte pro-inflammatoire. Nous avons voulu déterminer l'impact du contexte inflammatoire sur les propriétés d'adhérence anormale et déshydratation du GR drépanocytaire (GRSS), anomalies fonctionnelles favorisant la survenue des crises. Pour cela, nous avons évalué l'effet des chimiokines inflammatoires RANTE et IL-8, aptes à se lier au GR grâce à leurs récepteurs DARC (Duffy Antigen Receptor for Chemokines). L'étude a été menée chez les patients présentant les phénotypes Duffy-positifs: [Fy(a+b+), Fy(a+b-), Fy(a-b+») ou Duffy-négatifs: [Fy(a-b-»). Nos résultats ont montré qu'IL-8 et RANTES favorisent, seulement chez les patients Duffy-positifs: la déshydratation des GR via l'activation des canaux Gardos (CG) et l'adhérence des GR aux ligands VCAM-1 et Fibronectine, via l'activation de l'intégrine VLA-4 exprimée par des réticulocytes. De plus, nous avons observé sans ces chimiokines: un taux de GR irréversiblement falciformés 17 fois plus important chez les sujets Duffypositifs, et un état d'activation supérieur des intégrines VLA-4 des GRSS Duffy-positifs comparé aux GRSS Duffy-négatifs. Ces résultats suggèrent l'existence de couplages DARC avec CG et VLA-4. D'autres travaux sont nécessaires pour déterminer si ces associations sont directes et explorer les voies de signalisation induisant les processus d'activationSickle cell disease is characterized by the occurrence of painful vaso-occlusive crises (VOC) whose frequency and severity are highly variable from one patient to another. The pathophysiology of VOC is complex, involving cellular interactions between endothelial cells anc the circulating cells, especially the red blood cells (RBC). Cellular activation induced by pro-inflammatory events is the most likely initiating step. We investigated the impact of an inflammatory environ ment on functional abnormalities of the sickle RBC (SSRBC) that promote the development of VOCs: the abnormal adhesion properties and the dehydration process of sickle red cells. Therefore, we evaluated the effect of the inflammatory chimiokines RANTES and IL-8 that bind to the SSRBC through their receptors DARC (Duffy Antigen Receptor for Chemokines). The study was conducted with Duffy-positive and Duffy-negative patients. Our results showed that the chemokines IL-8 and RANTES promote, only in Duffy-positive patients: • SSRBC dehydration via Gardos channel activation, • SSRBC adhesion to immobilized VCAM-1 and Fibronectin via the activation of the integrin VLA-4 expressed on reticulocytes. Furthermore, we observed in absence of stimulation by the chemokines: • A percentage of irreversibly sickled RBC (density> 1,120) 17 times more important in the Duffy-positif group. • A higher activation state of VLA-4 in Duffy-positive reticulocytes. These results suggest the coupling of DARC to the Gardos channel and to VLA-4. Additional work is necessary to determine if these interactions are direct and to explore the signaling pathways related to the activation processes
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Maxwell, Stropes Melissa Page. "Signaling and Regulation of the Human Cytomegalovirus G-Protein Coupled Receptor US28 in HCMV Infected Cells". University of Cincinnati / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1236016578.
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Fredrich, Andr?a Longoni. "Imunoexpress?o de Rankl, CCL5/RANTES e CCR5 em inflama??o pulpar aguda em ratos, induzida por exposi??o tecidual, ?cido lipoteic?ico ou lipopolissacar?deo". Pontif?cia Universidade Cat?lica do Rio Grande do Sul, 2013. http://tede2.pucrs.br/tede2/handle/tede/1253.
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Previous issue date: 2013-11-29Studies on dental caries demonstrate inflammation on dental pulp tissues following infection. Cytokines are able to activate those cells linked to inflammatory and immune response thus neutralizing potentially aggressive agents and allowing tissue repair. Some of those cytokines, denominated chemokines, could contribute to the establishment of an immunotherapy able to control those cytokines involved with the triggering of dental pulp inflammation. Research on chronic inflammation has provided some relevant insights. However, the role of certain chemokines on acute inflammation is yet not conclusive. This study attempts to unveil the role of the chemokines CCL5/RANTES, CCR5 and RANKL on initial and acute pulpal inflammation. Methods: 18 Wistar rats were subjected to anesthesia. Access was performed on their first lower molars until pulp exposure. They were divided into three experimental groups considering the solution administered: Saline, lipopolysaccharide (LPS) and lipoteichoic acid (LTA) (n=6 each group). Higid second lower molars were used as controls. The cavities were sealed with amalgam and euthanasia occurred after 48 h and the jaws were dissected for histologic evaluation. CCL5/RANTES is expressed in all groups, unlike CCR5, that was not expressed. RANKL appears only in inflammatory cells, including control group. Only RANKL could be expressed during initial pulpal inflammation, being able to detect inflammatory cell activity.
Estudos de c?rie demonstraram aspectos inflamat?rios nos tecidos pulpares decorrentes de infec??o estabelecida. Citocinas seriam capazes de ativar c?lulas ligadas ? resposta inflamat?ria e imune no sentido de neutralizar potenciais agentes invasores e permitir o reparo dos tecidos pulpares. Algumas destas, denominadas quimiocinas, poderiam contribuir no estabelecimento de uma imunoterapia capaz de bloquear aquelas citocinas respons?veis pelo processo inflamat?rio. Na inflama??o cr?nica estas pesquisas j? possuem resultados satisfat?rios. Na inflama??o aguda, os estudos ainda est?o inconclusivos. Este estudo teve como objetivo testar as quimiocinas CCL5/RANTES, CCR5 e RANKL na inflama??o pulpar aguda. M?todos: 18 Ratos Wistar foram anestesiados. Foram feitas cavidades at? a exposi??o pulpar nos primeiros molares inferiores. Eles foram divididos em tr?s grupos onde se administrou solu??o salina est?ril, lipopolissacar?deo (LPS) e ?cido lipoteic?ico (LTA) (n= 6 por grupo). Os segundos molares inferiores h?gidos foram utilizados como controle. As cavidades foram seladas com am?lgama e a eutan?sia foi realizada ap?s 48h. As mand?bulas foram dissecadas para exame histol?gico e da imunoexpress?o das quimiocinas em estudo. Obteve-se como resultados: CCL5/RANTES ? expressa em todos os grupos, ao contr?rio do CCR5, que n?o foi expressa. RANKL aparece apenas em c?lulas inflamat?rias. Somente a express?o de RANKL foi capaz de demonstrar atividade celular na inflama??o pulpar inicial.
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Silveira, Ilson Dias da. "N?veis da quimiocina RANTES na placenta, plasma materno e plasma do cord?o umbilical em gestantes normais e com s?ndrome de pr?-ecl?mpsia". Pontif?cia Universidade Cat?lica do Rio Grande do Sul, 2012. http://tede2.pucrs.br/tede2/handle/tede/1706.
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Previous issue date: 2012-08-28Objective: To estimate RANTES levels at maternal plasma, umbilical cord blood plasma and placenta in preeclampsia syndrome and normal pregnancy. Methods: A cross-sectional study was conducted to estimate RANTES levels in maternal plasma, placenta and cord blood plasma in preeclampsia syndrome (n=33) compared to a control group of women with normal pregnancy (n=36) attended at S?o Lucas Hospital/PUCRS, Porto Alegre, RS Brazil. Concentrations of RANTES were measured using a human RANTES ELISA assay. Results: Women with preeclampsia syndrome showed significantly higher RANTES levels in plasma and placenta in comparison to women with normal pregnancy (P<0.01). The cord blood plasma of infants born from women with preeclampsia syndrome had a significantly decreased RANTES levels compared to infants born from a normal pregnancy (P<0.01). The concentration of placental RANTES was positively correlated with RANTES in the maternal plasma (Pearson?s correlation r= 0.697; p<0.001), and negatively with the cord blood plasma (r= -0.818; p<0.001). A strong negative correlation was also demonstrated between maternal plasma and cord blood plasma RANTES (r= -0.751, p<0.001). Conclusion: This study shows a distinct inflammatory response between mother and new born in preeclampsia syndrome and normal pregnancy. In preeclampsia syndrome maternal plasma and placenta displayed increased pro-inflammatory RANTES cytokine concentration, however a reduced levels were detected in the umbilical cord plasma from women with preeclampsia syndrome, suggesting a fetal antiflammatory response.
Objetivo: O objetivo deste trabalho foi estimar os n?veis de RANTES na placenta e nos plasmas materno e do cord?o umbilical na s?ndrome de pr?-ecl?mpsia e gesta??o normal. M?todos: Estudo transversal e observacional estimou os n?veis de RANTES na placenta e nos plasmas materno e do cord?o umbilical na s?ndrome de pr?-ecl?mpsia (n=33) comparando com um grupo controle de gestantes normais (n=36) atendidas no Hospital S?o Lucas/PUCRS, Porto Alegre, RS, Brasil. As concentra??es de RANTES foram verificadas atrav?s do m?todo de enzima imuno ensaio (ELISA) espec?fico para humanos. Resultados: Mulheres com s?ndrome de pr?-ecl?mpsia apresentaram n?veis significativamente maiores de RANTES no plasma e placenta quando comparadas a gestantes normais (P<0,01). O plasma do cord?o umbilical de rec?m-nascidos de gestantes com pr?-ecl?mpsia mostraram n?veis de RANTES significativamente menores que o plasma do cord?o umbilical de rec?m-nascidos de gestantes normais (P<0,01). A concentra??o de RANTES placent?rio correlacionou-se positivamente com a concentra??o de RANTES no plasma materno (r= 0,697; P<0,001) e negativamente com o plasma do cord?o umbilical (r= - 0,818; P< 0,001). Forte correla??o negativa na concentra??o de RANTES foi demonstrada entre plasma materno e plasma do cord?o umbilical (r= - 0,751; P<0,001). Conclus?o: Este estudo mostra uma resposta inflamat?ria distinta entre a m?e e o rec?m-nascido em ambas as condi??es, gesta??o normal e s?ndrome de pr?-ecl?mpsia. A placenta e o plasma materno demonstraram uma concentra??o da citocina inflamat?ria RANTES aumentada na s?ndrome de pr?-ecl?mpsia, entretanto, no plasma do cord?o umbilical dos rec?m-nascidos dessas gestantes estava reduzida, sugerindo uma resposta fetal anti-inflamat?ria.
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Zdanavičiūtė, Greta. "Per rankas veikiančios vibracijos perdavimo priklausomybė nuo rankos ir darbo priemonės sąlyčio jėgų". Master's thesis, Lithuanian Academic Libraries Network (LABT), 2014. http://vddb.library.lt/obj/LT-eLABa-0001:E.02~2014~D_20140616_103439-46413.
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Vibracijos žalingam poveikiui į žmogaus organizmą lemia daug įvairių veiksnių. Tyrimai šioje srityje koncentruojasi į mašinos virpesių energijos dydį ir jos mažinimo galimybes, tačiau aktualu ir žmogaus-mašinos analizavimas kaip bendros sistemos. Tokios sistemos virpesių energijos perdavimas į žmogaus kūną priklauso ir nuo sistemos standumo savybių, kurias galima apibūdinti kontaktinėmis jėgomis tarp mašinos ir žmogaus kūno dalies. Tokių tyrimų Lietuvoje nebuvo atlikta, o užsienio autorių tyrimai negausūs, todėl tyrimas yra labai aktualus. Tiriamajame darbe analizuojama kitų autorių tyrimų medžiaga apie vibracijos poveikį žmogui, sudaryta tyrimų metodika ir atlikti tyrimai, kaip nešiojamųjų ar rankomis valdomų mašinų įrankių jėgos pasiskirsto rankos plaštakoje ir kokią įtaką per rankas veikiančios vibracijos perdavimui turi rankos ir darbo priemonės sąlyčio jėgos. Nustatyta, kad didėjant sąlyčio jėgoms tarp vibruojančios darbo priemonės (įrankio) ir rankos nuo 3 N iki 29 N bendroji vibracijos vertė veikianti operatoriaus ranką didėjo nuo 2,7 m/s2 iki 3,7 m/s2.Hazardous affects of vibration against a human’s organism are caused by various factors. Researches in this field are concentrated into the energy size of machine vibration and possibilities to decrease it; however, analysis of a human-machine as a general system is also relevant. Transfer of vibration energy by such system into a human’s body depends on properties of system rigidity, which may be described as contact forces between a machine and a human’s body part. Such researches were not carried out in Lithuania and the studies of foreign authors are not numerous, thus such analysis is very relevant. The study thesis analyses research materials by other authors on vibration impact on humans. There were developed research methods and performed tests on how strengths of mobile and manually operated tools distribute over the hand and what impact hand - tool contact strengths have on transfer of vibration acting through hands. It was determined that increase in contact strength between a vibrating tool and a hand from 3 N to 29 N total vibration value on the operator’s hand increase from 2,7 m/s2 to 3,7 m/s2.
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Medin, Carey L. "Chemokine Induction by Dengue Virus Infection: Mechanisms and the Role of Viral Proteins: a Dissertation". eScholarship@UMMS, 2005. https://escholarship.umassmed.edu/gsbs_diss/30.
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The focus of this thesis is the role of dengue virus in the induction of chemokines. Dengue virus (DENV) occurs as four distinct serotypes, called DENV 1,2,3,and 4. Symptomatic DENV infection ranges from a self limited febrile illness, dengue fever (DF), to a more severe disease, dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS). DHF is characterized by increased capillary permeability resulting in decreased plasma volume, which may be accompanied by hemorrhagic manifestations. Many factors including T cell cross reactivity, viral burden, antibody dependent enhancement and induction of chemokines and cytokines have been reported in DHF and may play a role in the pathogenesis of DENV infection.
Cytokines have been shown to modulate endothelial cell permeability [1-3]. Recent studies have shown that DENV-infected endothelial cells secrete the chemokine, interleukin (IL)-8 in vitro [4]. In addition, the permeability of an endothelial cell monolayer was found to be increased by interleukin-8 (IL-8) in vitro[5]. This thesis examines the effects of DEN2V infection on the induction of chemokines, and specifically, which DEN2V viral protein(s) are involved in the induction of IL-8.
The chemokine induction profile following DEN2V infection was initially assessed in various cell lines that may represent potential targets in vivo, including monocytes, liver cells and endothelial cells. We hypothesized that distinct profiles of chemokine secretion can be induced by DEN2V infection of various cell types in vitro. We found RANTES (Regulated upon Activation, Normal T cell Expressed and Secreted) and IL-8 were induced in two of the five cell lines. DEN2V infection of primary monocyte-derived dendritic cells induced RANTES and IL-8 along with macrophage inflammatory protein-1α (MIP-1α), MIP-1β and monocyte chemoattractant protein-1 (MCP-1) but at an earlier time post infection than in the cell lines. These results showed that DEN2V infection induces distinct chemokine profiles in many cell types. In addition, monocytic-derived DCs can secrete chemokines upon infection with DEN2V.
Characterization of the signaling pathways induced by DEN2V revealed that DEN2V induction of chemokines in human embryonic kidney (HEK293A) cells is mainly through the nuclear factor kappaB (NFκB) pathway, as previously reported for endothelial cells and 293T cells [4,6]. Alternatively, the liver cell line (HepG2) activated mainly activator protein (AP)-l. In addition, DENV infection can induce the activation of the interferon-stimulated response element (ISRE) driven promoter.
IL-8 has been shown to have multiple effects on the immune system ranging from recruiting cells to the site of infection to countering the antiviral effects of type I interferon (IFN) [7,8]. Previous reports have shown that viral proteins can induce chemokines such as seen with IL-8 induction with the nonstructural protein 5A (NS5A) and core proteins from hepatitis C virus [9,10]. We hypothesized that protein(s) from DENV could induce chemokine production. The expression of DENV proteins was analyzed for effects on IL-8 and RANTES production in HEK293A cells. The effects of viral replication on IL-8 and RANTES induction were also analyzed using a DENV replicon that contains genes for the capsid protein and the nonstructural proteins. Transfection of plasmids expressing NS5 or the DEN2V replicon induced the expression and secretion of IL-8 but not RANTES. We attributed the lack of RANTES induction to the inability of NS5 or the DEN2V replicon to induce transcription from the ISRE driven promoter. We also found that NS5 and the DEN2V replicon induced IL-8 mainly through the CCAAT/enhancer binding protein (c/EBP) and AP-1 pathways. The profile of transcription factor activation is different from what was seen with DENV infection of HEK293A cells and suggests that the transient expression of the NS5 protein and the replication and/or translation of the DEN2V genome use different pathways than viral infection to induce IL-8.
In addition, we found that the expression of prM-E, known to produce virus-like particles, could induce IL-8 secretion and activate transcription from the IL-8 promoter. As with the expression of NS5, RANTES was not induced. Analysis of the transcription factors involved in IL-8 induction using luciferase reporter constructs indicated that expression of prM-E induced transcription of IL-8 through NFκB, AP-1 and c/EBP, similar to what was seen with DEN2V infection of HEK293A cells. These results suggest that production of virions or virus-like particles induce IL-8 but that another mechanism in the viral life cycle is responsible for the induction of RANTES expression by DEN2V infection.
We were also interested in the effects of drugs that have been used previously to inhibit cytokine or chemokine production on chemokine induction during DEN2V infection. We hypothesized that pharmacological inhibitors of cytokines will inhibit secretion of chemokines in DEN2V infected cells. We found that the pharmacological inhibitors SB203580 and rolipram enhanced chemokine production in a DEN2V infected liver cell line (HepG2), whereas dexamethasone had the same effect in a kidney epithelial cell line (HEK293A). We conclude that drugs that inhibit signaling pathways involved in cytokine production in other experimental systems can have variable effects on chemokine induction in different cell types during DEN2V infection.
The data generated in this thesis extend our understanding of how DEN2V manipulates the host cell during viral infection to produce chemokines and perhaps enhance viral propagation and dissemination through the induction of IL-8. In addition, this study provides insight into the variable effects pharmacological drug treatment may have on disease progression during DENV infection. These results increase our understanding of DENV pathogenesis and may be helpful in finding better strategies for treatment and prevention.
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Zhou, Zhicheng. "HIV-1 entry at the foreskin : crosstalk between the HIV-1 infected cells and the inner foreskin mucosa". Thesis, Paris 5, 2014. http://www.theses.fr/2014PA05T027.
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Les épithéliums muqueux se présentent comme porte d’entrée majeure du virus de l’immunodéficience humaine (VIH) et jouent un rôle critique dans la transmission sexuelle du virus. Les cellules épithéliales et les cellules dendritiques dans les muqueuses pluristratifiés, sont des cibles initiales pour la transmission virale. Il a été déjà montré, sur les muqueuses génitales chez l’homme, que la circoncision réduit plus de 60% acquisition du virus chez l’homme. Les mécanismes d’entrée du VIH au niveau du tractus génital chez l’homme sont tres mal connus et pratiquement pas étudiés. Nous avons émis l’hypothèse selon laquelle le prépuce, qui est enlevé lors de la circoncision, pourrait être une porte d’entrée majeure du virus. Nous avons d’abord montré que le VIH peut pénétrer effectivement au niveau du prépuce ex vivo, la partie interne du prépuce présente plus permissive que la partie externe. De plus, le virus pénètre uniquement dans le prépuce après formation d’une synapse virologique entre la cellule infectée, présente dans les secrétions génitales et la surface muqueuse du prépuce. La formation de la synapse virologique induit le bourgeonnement massif et polarisé de virions dans la fente synaptique; ceux ci pénètrent dans l’épiderme du prépuce. À l’inverse, l’entrée du VIH sous forme de virus libre dans le prépuce est inefficace. Nous avons ensuite caractérisé la séquence des événements initiaux mis en place lors de l’entrée du VIH dans le prépuce interne. La première cellule cible immune est la cellule de Langerhans (LCs), dont le rôle physiologique est de protéger la muqueuse contre les pathogènes qui l’envahissent. Après la capture du virus les LCs migrent vers le derme pour former des conjugués cellulaires avec les cellules T CD4+ du derme. La dynamique de migration de LCs est régulée par de sécrétion de cytokines et chimiokines (RANTEs et MIP- 3alpha) induites par la pénétration du virus dans le tissu. Nous avons ensuite caractérisé les mécanismes de l’immunité mis en jeu au niveau des kératinocytes de l’épiderme lors de la formation de la synapse virologique et évalué comment ces signaux contribuent à l’entrée efficace du virus dans la muqueuse du prépuce interne chez l’homme, ex vivo. À l’aide d’un modèle cellulaire de muqueuse simplifiée basé sur des kératinocytes primaires humains ex vivo, nous avons montré que les protéines d’enveloppe du VIH , gp120 mais pas gp41, et les molécules d’adhésion (intégrines LFA-1, leurs ligands ICAM-1 and -3) contrôlent la formation de la synapse virologique. La synapse virologique induit au niveau des kératinocytes l’activation de la voie NF- B indépendentmmment de MyD88 après activation du Toll-like-receptor 4 (TLR4) exprimé par les kératinocytes. En recherchant quelle cytokine pouvait être induite par cette signalisation, nous avons montré que la synapse virologique induit la sécrétion par les kératinocytes d’une cytokine produite par les cellules non-hématopoïétiques, la thymic stromal lymphopoietin (TSLP). La TSLP est un chemoattracteur des cellules myéloïdes comme les cellules LCs et peut induire leur maturation. Nous avons ensuite montré que, sur des explants de prépuce humain ex vivo, la synapse virologique induit bien la sécrétion de TSLP, laquelle en premier lieu attire les LCs qui expriment le TSLP-récepteur vers la surface du tissus induisant leur maturation. Les LCs peuvent ensuite migrer dans l’autre sens vers le derme. La sécrétion des cytokines comme RANTEs, MIP-3alpha, qui sont impliquées lors de la pénétration effective du virus dans les tissus n’a pas de rôle dans la signalisation induite par la formation de la synapse virologique proprement dite. Les kératinocytes de l’épiderme du prépuce interne, grâce à leur réponse innée TSLP induite par la synapse virologique ont un rôle déterminant dans l’entrée du VIH dans le prépuce. Ainsi, en réponse de la synapse virologique, les kératinocytes secrètent du TSLP après activation de la voie de NF- B dépendante de MyD88. (...)The mucosal epitheliums are presented as a major portal of HIV-1, and play a critcal role for the sexual transmission of HIV-1. Epithelial cells, and dendritic cells in the pluristratified mucosa, are the initial targets of viral transmission. It has already been shown, in the genital mucosa in men, circumcision reduces by more than 60 % of virus acqusition by men. The entry mechanisms of HIV-1 in the male urogenital tracts are poorly understood and not pratically studied. We suggested that foreskin, removal by circumcision surgery, could be a major portal of HIV-1 entry. We first showed that HIV-1 could enter efficiently ex vivo inner foreskin mucosa, the inner part of foreskin which is more permissive than the outer part. More over, virus penetrates only after the viral synapse (VS) formation between HIV-1-infected cells and foreskin epidermis, in the presence of genital secretion on the surface of foreskin mucosa. The formation of VS induces massive and polarized budding of HIV-1 particles within the synaptic cleft. The virions therefore penetrate into the foreskin epidermis. Inversely, cell-free virus entry is inefficient in the foreskin. Next, we characterized the initial events of HIV-1 VS formation in the inner foreskin. The first cell type that HIV-1 encounters is Langerhans cells (LCs), whose physiological role is to protect the mucosa against invasive pathogens. After capture of virus, LC migrates towards the dermis to form intercellular conjugates with dermal CD4+ T cells. The dynamic of LC migraiton is regulated by the secretion of cytokines in the mucosa, induced by HIV-1 entry, including RANTEs and MIP-3alpha. We then characterized the mechanisms of foreskin epidermal keratinocyte (KC), activated innate immunity during the VS formation and the signaling pathway contributed to the efficient entry of HIV-1 via inner foreskin mucosa. Using a simplified mucosal model based on human primary foreskin keratinocytes, we demonstrated that HIV-1 envelope protein, gp120, but not gp41 and the adhesion molecules (integrins LFA-1, ICAM-1/-3), contribute to the VS formation. VS induces at the KC level the activation of NF- B pathway by I B and p65 molecules, after activation of TLR4 expressed on KCs. By searching for which cytokine could be induced by this signalisation, we then showed that VS induced the secretion by KC of one cytokine, which is produced by the non-hematopoetic cells, thymic stromal lymphopoietin (TSLP). TSLP is an chemoattractant for myeloid cells like LCs, and could induce LC maturation. We then showed, using the foreskin explants that, VS induces the secretion of TSLP, which first attracts LC expressing constitutively TSLP receptors to the apical surface of foreskin, inducing its maturation. These matured LCs then migrate to another direction towards the dermis. The secretion of cytokines such as RANTEs and MIP-3alpha, involved in the HIV-1 efficient entry has no roles in the signaling induced by VS formation as mentioned above. The Inner foreskin keratinocytes, due to the innate response of TSLP induced by VS, have a determinant role in the HIV-1 entry into the foreskin. Likewise, in response to VS, KCs secrete TSLP after NF- B activation dependent on regulator MyD88. The secreted TSLP, in addition to four different proinflammatory cytokines and chemokines (IL-6, IL-8, MIG, and MMP-9) allows virus to attract LCs to the foreskin surface, to capture the virus present in the synaptic cleft in order to facilite efficient transmission at the level of foreskin mucosa. Likely to the conventional immune cells, KCs, in one hand protects the foreskin mucosa and in another, is hijacked to facilitate HIV-1 transmission
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Gray, David R. Captain. "The "first" rangers in Korea: the Eighth Army Ranger Company in combat August 1950-March 1951". The Ohio State University, 1990. http://rave.ohiolink.edu/etdc/view?acc_num=osu1341502956.
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Wagenhofer, Markus. "Block numerical ranges". [S.l.] : [s.n.], 2007. http://deposit.ddb.de/cgi-bin/dokserv?idn=98404972X.
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Jin, Jun. "Study of the multiple conformations of the HIV-1 co-receptor CCR5". Sorbonne Paris Cité, 2016. http://www.theses.fr/2016USPCC053.
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Les récepteurs couples aux protéines G représentent la majorité des récepteurs cibles en thérapie. Différentes conformations de ces récepteurs semblent coexister à la surface cellulaire. Toutefois, leur caractérisation moléculaire et l'impact de ses conformations sur la fonction des récepteurs restent peu connus. Nous nous sommes intéressés à cette question, en prenant comme modèle le récepteur de chimiokines CCR5. En plus de son rôle physiologique, CCR5 est utilisé par la majorité des souches VIH -1 primaires dites « R5 ». Elles sont responsables in vivo de la transmission et du maintien de l'infection. Des individus qui n'expriment pas CCR5, à cause d'un polymorphisme naturel, sont protégés contre l'infection et ne souffrent pas du manque de CCR5. Ce récepteur représente donc une cible de choix pour une stratégie antivirale. Nous avons d'abord montre dans un article publié en 2014 (Jin, JBC 2014) l'existence de conformations particulières de CCR5 à la surface cellulaire, nommées « spare receptors» pour « récepteurs de réserves ». Nous avons exploite les caractéristiques de l'analogue de chimiokine psc-rantes, qui présente une puissante activité antivirale et induit une séquestration intracellulaire des récepteurs à long terme. Nous relevons l'existence d'une population de récepteurs « de réserves » (non reconnues par les chimiokines natives) dans des expériences de compétition de liaison, d'internalisation et de désensibilisation. Nous montrons en particulier que les chimiokines natives sont incapables d'inhiber la liaison de psc-rantes, l'internalisation induite par psc-rantes ou l'induction d'une réponse calcique médiée par psc-rantes. La capacité de cet analogue à cibler une large quantité de récepteurs explique le recrutement massif de B-arrestine2 observe a la membrane plasmique et l'internalisation importante du récepteur, a l'origine de son fort pouvoir antiviral. Ces récepteurs de réserves pourraient être ceux cibles par les VIH pour échapper à la barrière des chimiokines. Ils représentent des lors une cible prioritaire pour inhiber l'infection. Nous nous sommes ensuite intéressés à l'organisation moléculaire de ses conformations. Différents travaux indiquent d'une part que les récepteurs de chimiokines s'organiseraient sous forme d'oligomères constitutifs et, d'autre part, que cette organisation serait nécessaire au transport des récepteurs vers la surface cellulaire, à la liaison des ligands, à la signalisation et au trafic intracellulaire après stimulation. Cette propriété structurale des récepteurs, sujette à controverse pour les GPCR de classe A, pourrait aussi influencer l'entrée des VIH -1 dans certaines conditions, mais cet effet reste mal connu. Par homologie avec les structures cristallographiques récemment décrites de cxcr4 et du récepteur mu opioïde, nous avons proposé en collaboration avec Esther Kellenberger (Strasbourg) un nouveau modèle de dimérisation de ccr5. A partir de ce modèle, nous avons identifié les résidus impliques dans plusieurs interfaces de dimérisation par des approches biochimique et biophysique. En ciblant ces interfaces par mutagénèse dirigée et en utilisant un test original de suivi de l'export des protéines, nous montrons l'importance de la dimérisation de ce récepteur pour son transport a la surface cellulaire. Ce travail nous a également permis de révéler de nouvelles caractéristiques du compose maraviroc, unique antiviral ciblant CCR5 actuellement sur le marché. Celui-ci par interaction avec CCR5 au niveau du reticulum endoplasmique induit une nouvelle conformation de CCR5 qui favorise son export. Ces résultats bientôt soumis pour publication, révèlent plusieurs conformations de CCR5 et montrent leur rôle fonctionnel. A travers cette thèse, nous abordons l'enjeu d'avoir aujourd'hui une vision des conformations des GPCRS, et discutons l'impact qu'elles pourraient avoir sur la fonction de ces récepteurs et leur ciblage thérapeutiqueCCR5 (c-c chemokine receptor type 5), a seven-transmembrane receptor, exhibits multiple conformations at the cell surface based on interactions with ligands, heterotrimeric G proteins, B-arrestins, neighboring gpcrs and membrane lipids, and also based on the location and trafficking of the receptor. These conformations play an important role in receptor functions including ligand binding, cell signaling and trafficking. CCR5 also serves as a co-receptor for r5-tropic human immunodeficiency virus, type 1 (HIV-1) entry. The native chemokines ccl3, ccl4, and ccl5 can compete with HIV-1 gp120 for binding CCR5, and are supposed to form a natural barrier against HIV-1. However, their antiviral activity is limited by a pool of CCR5 adopting conformations that have low-chemokine affinity at the cell surface. We demonetrated that this pool of CCR5 that is not stabilized by chemokines could represent a target for inhibiting HIV-1 infection. We exploited the characteristics of the chemokine analog psc-rantes, which displays potent anti-HIV-1 activity. We show that native chemokines fail to prevent high-affinity binding of psc-rantes, analog-mediated calcium release (in desensitization assays), and analog-mediated CCR5 internalization. These results indicate that this pool of spare CCR5 may bind psc-rantes but not native chemokines. Improved recognition of CCR5 by psc-rantes may explain why the analog promotes higher amounts of b-arrestin2/ccr5 complexes, thereby increasing CCR5 down-regulation and HIV- 1 inhibition. Together, these results highlight that spare CCR5, which might permit HIV-1 to escape from chemokines, should be targeted for efficient viral blockade. Numerous studies also showed that gpcr form dimers or larger oligomers, a process that is involved in gpcr conformational changes. The molecular and functional relevance as well as the interaction interfaces of this organization are still poorly understood. To this aim, by using the HIV-1 coreceptor CCR5, we defined by chemical cross-link and molecular modeling two non-exclusive dimer interfaces, and a third one stabilized by the inverse agonist maraviroc, which indicates that CCR5 could also exhibit multiple conformations through homo-dimerization. We then showed, by site directed mutagenesis combined with saturation time-resolved fluorescence resonance energy transfer and a novel export assay, the essential role of dimerization in receptor transport to the cell surface. These results produce a consensual picture of the interfaces between protomers of class a dimers and reveal the impact of dimerization during biogenesis. They also provide new features of the marketed drug maraviroc highlighting both pharmacological chaperone and allosteric inhibitor activities. Overall, distinguishing multiple CCR5 conformations and their corresponding receptor functions has implications for understanding the selective use of CCR5 by HIV-1 and the development of improved strategies to block CCR5 use by HIV-1