Dissertationen zum Thema „Cxcr1-2“
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Sitaru, Sebastian [Verfasser], und Markus [Akademischer Betreuer] Sperandio. „CXCR1/2 inhibition in neutrophil recruitment / Sebastian Sitaru ; Betreuer: Markus Sperandio“. München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2021. http://d-nb.info/1236502159/34.
Der volle Inhalt der QuelleMateo, Lou. „Synthèse et évaluation de nouveaux antagonistes des récepteurs CXCR1-2 pour cibler conjointement l’angiogenèse et l’inflammation dans les pathologies cancéreuses“. Thesis, Université Côte d'Azur, 2021. http://www.theses.fr/2021COAZ4006.
Der volle Inhalt der QuelleCancer is one of the main causes of death in the world. Angiogenesis and inflammation represent two essential hallmarks in the development and progression of tumors and are essential for the survival of the cancer cells. Better knowledge of cellular mechanisms has enabled the development of targeted anti-angiogenic therapies. However, the emergence of resistance constitutes the main limitation of these current anti-angiogenics targeted therapies, as you may know the anti-VEGF therapies. But in parallel to the VEGF pathway, another crucial pro-angiogenic and pro-inflammatory axis in cancers is required: the CXCL-ELR+/CXCR pathway, particularly in metastatic kidney cancer. The aim of this work was to develop original small organic molecules able to inhibit the ligand/receptor interaction (CXCL-ELR+ / CXCR1-2) in order to have both anti-inflammatory and anti-angiogenic activities. The 2-aminobenzothiazinone pattern was chosen for the preparation of 3 new classes of inhibitors. Divergent synthesis strategies were used to obtain the members of families 1 & 2, although the conditions have been adapted according to the reactivity of each substrate. The last family of molecules was prepared according to a linear synthesis. However, this latter strategy displayed some limitations during the cyclisation step. Thereafter, biological evaluations revealed a promising compound exhibiting an IC50 of 0.6 μM on the 786-O cell line compared with our reference molecule (IC50 = 2 μM). Other result highlighted that this compound also exerted an inhibition of the chemotaxis of cells expressing CXCR1-2 receptors. Further studies on zebrafish are planned with this compound in order to study its ability to interfere with the angiogenesis phenomenon in vivo
Penco-Campillo, Manon. „Le VEGFC et les récepteurs CXCR1/2 : des cibles pertinentes pour le traitement des médulloblastomes pédiatriques“. Electronic Thesis or Diss., Université Côte d'Azur, 2022. http://www.theses.fr/2022COAZ6025.
Der volle Inhalt der QuelleMedulloblastoma (MB) is the most common and aggressive pediatric brain tumor. Despite aggressive multimodal treatment, resulting in significant side effects, 30% of patients develop resistance and relapse following the appearance of metastases within 5 years. Recurrences cannot be controlled by conventional (radio- and chemotherapy) or targeted (anti-angiogenic, anti-inflammatory, anti-immune checkpoint) treatments. The objective of my thesis is therefore to discover new targets and relevant therapeutic strategies for these patients at diagnosis or after a relapse.MBs are highly vascularized tumors. The phenomenon of resistance is, in part, linked to the development of blood (angiogenesis) and lymphatic (lymphangiogenesis) vessels in the tumor, which constitute the main routes of metastatic dissemination. The lymphatic growth factor, VEGFC, and its receptors/co-receptors are the major players in lymphangiogenesis. In the first part of my thesis, I showed that VEGFC is inversely correlated to MB cell growth and aggressiveness. Indeed, VEGFC decreases the proliferation and migration of MB cells, as well as their ability to form pseudo-vessels in vitro, by an autocrine signalization. Cells resistant to radiotherapy show elevated levels of VEGFC and lose their ability to migrate and form pseudo-vessels. Irradiation reduces the aggressiveness of MB cells by a VEGFC-dependent process. VEGFC-overexpressing cells and radiation-resistant cells form smaller experimental tumors in nude mice. Thus, VEGC appears to be a negative regulator of MB growth. These results pave the way for the development of pro-VEGFC therapies in these cancers.In the second part of my thesis, I correlated the expression of the ELR+CXCL/CXCR1-2 pro-angiogenic and pro-inflammatory signaling pathway to shorter survival in patients with MB. I showed that a novel pharmacological inhibitor (C29) of CXCR1-2 receptors inhibits proliferation, CXCL8/CXCR1-2-dependent migration, invasion and pseudo-vessel formation by susceptible or resistant MB cells to radiotherapy. C29 reduces the growth of experimental MBs in an ex vivo organotypic mouse model and crosses the blood-brain barrier. Thus, targeting CXCR1-2 represents a promising strategy for the treatment of pediatric MB, at first line or at relapse.Key words: pediatric medulloblastoma, VEGFC/VEGFR, CXCR1-2, ELR+CXCL cytokines, targeted therapy, lymphangiogenesis, angiogenesis
Fabre, Marie. „Conception, synthèse et optimisation de nouveaux antagonistes des récepteurs CXCR1/2 pour le traitement de la DMLA exsudative“. Thesis, Université Côte d'Azur, 2021. http://www.theses.fr/2021COAZ4044.
Der volle Inhalt der QuelleIn western countries, exudative age-related macular degeneration (AMD) is one of the leading causes of blindness in the elderly. This disease is characterized by an abnormal vascularization of the choroid and a strong intraocular inflammation. Currently, only anti-VEGF symptomatic treatments exist, which rely on humanized monoclonal antibodies (mAbs) and recombinant fusion glycoprotein targeting pro-angiogenic factors. Moreover, only 30% of the patients present a durable response to this treatment.The blockage of the ERL+ CXCL cytokines signaling pathway has been proposed as a promising alternative to target simultaneously choroid vascularization and inflammation. Indeed, this sub-family of cytokines is specifically involved both in inflammation and in the early stage of the pro-angiogenic signal.Two compounds of diarylurea family, MCK133 and MCK140, have established a proof of concept in vitro and in vivo. Therefore, a new series of compounds has been designed that features the same pharmacophore bearing a triazole core, to enhance the activity, the physicochemical and pharmacological properties.Four series based on the pharmacophore were considered: two with an imidazole core and two with a triazole core. Synthetic pathways to each of these families have been studied. A triazole family has been particularly explored, and 63 analogs have been synthesized to determine the structure-activity relationships, by varying key positions of the molecule. All synthesized compounds were evaluated on several in vitro models of angiogenesis, inflammation, migration, and cell proliferation to assess their potential against exudative AMD. A promising lead compound has been identified. The perspectives of this thesis are the evaluation of this compound on several in vivo models of exudative AMD.Finally, the last part of this manuscript presents two annexe projects: (i) the study of the biamidines transfer to biguanides and (ii) the stability study of NRPa-308
Abdelouahab, Hadjer. „Etude des mécanismes impliqués dans l'hématopoièse extra-médullaire dans les myélofibroses primaires et secondaires“. Paris 7, 2014. http://www.theses.fr/2014PA077212.
Der volle Inhalt der QuellePrimary and secondary myelofibrosis (MF) are rare and complex myeloproliferative neoplasms (MPN). They are characterized by medullary fibrosis and constitutive mobilization of stem cells and hematopoietic progenitors (HSPC), associated with extramedullary hematopoiesis in the liver and spleen. MF are also characterized by a complex mutational profile with JAK2V617F and MPLW515 being the main mutations in signaling molecules, leading to constitutive activation of signaling pathways. During this work, we have studied the role of CXCL12/CXCR4 in the constitutive HSPC mobilization and in the progression of the EMH in MF. Our results have shown that CD34+ MF patient cells are characterized by a strong chemotactic response to CXCL12 in vitro. This strong migration did not correlate with a high CXCR4 membrane expression, but seems correlated with activation of signaling pathways. Our results further demonstrated that the signaling pathways of CXCL12/CXCR4 and cytokines/cytokine receptors were synergistic in the chemotactic responses of cells to CXCL12. Furthermore, treatment MF patients with JAK2 inhibitors mobilizes CD34+ cells in peripheral blood. Finally, CXCR4 inhibition reduced the migration of MF CD34 cells in response to CXCL12 and induced a decrease in EMH in two mouse models of MF. Altogether, these resulb suggest that the constitutive HSPC mobilization and EMH in MF depend on CXCL12/CXCR4 signaling
Shi, Yu. „Coreceptor usage and sensitivity to neutralization of HIV-1 and HIV-2 /“. Stockholm, 2004. http://diss.kib.ki.se/2004/91-7140-093-1/.
Der volle Inhalt der QuelleLiebick, Marcel [Verfasser], Martin [Akademischer Betreuer] Oppermann, Susanne [Akademischer Betreuer] Lutz und Dieter [Akademischer Betreuer] Kube. „Chemokine receptors CXCR4 and CCR5: Cell surface expression, signaling and modulation by β-arrestin 2 / Marcel Liebick. Gutachter: Susanne Lutz ; Dieter Kube. Betreuer: Martin Oppermann“. Göttingen : Niedersächsische Staats- und Universitätsbibliothek Göttingen, 2015. http://d-nb.info/1067626565/34.
Der volle Inhalt der QuelleFrange, Pierre. „Caractérisation virologique des virus VIH-1 isolés en primo-infection en France“. Thesis, Paris 5, 2013. http://www.theses.fr/2013PA05T022.
Der volle Inhalt der QuelleHigh genetic diversity is a major characteristics of HIV-1. In France, although subtype B strains are still predominant, the proportion of non-B viruses isolated in patients at the time of primary HIV-1 (PHI) infection increases over time. Between 1997 and 2007, 28.4% of patients were infected with non-B subtypes strains. Forty-nine viruses showed different phylogenies between the pol and env genes, indicating that recombinations have occurred in 8.3% of cases. These recombinants were isolated both in patients from Sub-Saharan Africa (28.3%) and in white subjects (6.3%).The phenotypic analysis of viral tropism of 131 non-B strains showed a very low (0.8%) proportion of CXCR4-tropic strains (X4 strains) at the time of PHI. Compared to phenotypic tests, genotypic predictions can overestimate (12.2% versus 0.8%) the proportion of X4 strains in non-B subtypes.The phylogenetic analysis of 987 strains isolated in 1999-2010 showed that 12.7% of PHI cosegregated into 56 transmission chains. PHIs are a significant source of onward transmission, especially in men having sex with men, with increasing frequency during the recent years (10.2% in 1999-2006 versus 15.2% in 2006-2010, p=0.02).The comparison of the viral quasispecies isolated in plasma and PBMC samples from 8 patients at the time of PHI ("recipients") and their transmitting partners ("donors") suggested that a severe genetic bottleneck occurrs during HIV-1 heterosexual and homosexual transmission. Indeed, we observed in all cases the transmission of a single variant, which was derived from an infrequent variant population within the blood of the donor. The proportion of X4 quasispecies in donors were higher in case of X4 versus CCR5-tropic viral transmission, suggesting that X4 transmission may be associated with a threshold of X4 circulating quasispecies in donors
Fortier, Yasmina. „Étude de la dynamique des lymphocytes TFH et B au niveau de la rate et des ganglions mésentériques et impact d'un traitement anti-apoptotique sur la dynamique de ces populations et de la réponse humorale chez le macaque rhésus infecté par le VIS“. Thesis, Sorbonne Paris Cité, 2019. http://www.theses.fr/2019USPCB034.
Der volle Inhalt der QuelleHIV infection is characterized by a viral spread in the host body and a progressive destruction of CD4+ T cells, leading to a defect in the immune system. The memory T cells apoptosis and exhaustion induced by the virus leads the outcome of an AIDS. It was showed that germinal centers (GCs), specialized anatomical structures present in the B follicles of the secondary lymphoid organs, represent privileged viral reservoir. Among secondary lymphoid organs, spleen and mesenteric lymph nodes would be viral sanctuaries because of their role in the generation of the immune response. Spleen is the main organ of the B cell response, and mesenteric lymph nodes are essentials in the establishment of the mucosal immune response. GCs are mainly composed by B cells but also by TFH cells, a sub-population of effector memory CD4+ T cells, crucial for the generation of the B cell response, especially for the maturation of the highly efficient antibodies. Previous works from our laboratory showed that the defect of the B cell response during HIV infection is due to a loss and a defect of the TFH cells. Recently, it was showed that GCs are also composed of follicular memory CD8+ T cells, expressing the chemokine receptor CXCR5. Recent works suggested that those cells are implicated in the control of HIV infection. Thus, the aim of my thesis was to study the dynamic of follicular T cells in these two organs, spleen and mesenteric lymph nodes, and to set how well the administration of a pan-caspase inhibitor during acute phase of SIV infection help to restore effective functions as the antibody production. Those works were done in rhesus monkeys infected with the strain SIVmav251. My results show that the persistent infection of mesenteric lymph node is associated with a loss and a defect of B follicles and with a defect of TFH cells. They also show a defect in the expression of the CXCL13 chemokine, ligand of the CXCR5 receptor, potentially capable of creating a bad environment for B cell differentiation. My results show also that the administration of a pan-caspase inhibitor during the acute phase of infection leads to a decrease in the CD4+ T cells apoptosis as expected, a decrease in the inflammatory cytokines expression and in a better specific systemic B cell response in treated monkeys. These could help in the control of the viral replication. Finally, my results show that in the spleen, there's an increase of the follicular CD8+ T cells filtering the B follicles, which mainly doesn't express the CXCR5 receptor in infected monkeys, especially the progressor ones. They also show that there's an increase in the expression of the MIP1b chemokine, possibly responsible of the recruitment of conventional CD8+ T cells in the infected monkeys, and an increase in the expression of cytotoxic markers in the non-progressors monkeys compared to the progressors ones. Thus, these work seems to show that follicular CD8+ T cells of progressor monkeys fail to control SIV infection. Thus, SIV infection induce an altered B cell response, associated to a defect of B follicles, a defect of TFH cells, and an increase in follicular CD8+ T cells potentially inefficient. Altogether, my works focused on the study of follicular T cells show and confirm the strength the importance of these T cells in the host-pathogen relationship
Drwal, Veronika [Verfasser], und Thomas [Akademischer Betreuer] Wex. „Die Bedeutung der Expression der G-Protein-gekoppelten-Rezeptoren BRS 3, CCKA, CXCR 4, GHRH, GRPR, NK 1, NMBR, NT 2, PAC 1, VPAC 1 und VPAC 2 bei kolorektalen Tumoren in Abhängigkeit von Tumorstadium und Differenzierungsgrad / Veronika Drwal. Betreuer: Thomas Wex“. Magdeburg : Universitätsbibliothek, 2012. http://d-nb.info/1054135525/34.
Der volle Inhalt der QuelleQuettier, Maude. „Etudes des altérations fonctionnelles de la signalisation dépendante du récepteur à l’antigène dans les cellules B de la Leucémie Lymphoïde Chronique“. Thesis, Sorbonne Paris Cité, 2015. http://www.theses.fr/2015USPCD055/document.
Der volle Inhalt der QuelleAltered B-cell antigen receptor (BCR) signaling pathways play a key role in chronic lymphocytic leukemia(CLL) pathophysiology. Our lab has previously shown that ex-vivo antigenic stimulation of CLL-B cells led todifferential cell survival and cell migration, which allowed the distinction between two groups of patients. Basedon these results, we evidenced that the cell survival advantage in response to BCR engagement from one groupdepends on 1) a critical threshold mediated by the early effector expression levels (BCR, Syk et Zap70), a BCR competency of the leukemic cells translated by Syk phosphorylation, PLCƳ2 activation, intracellular Ca2+mobilization and the transcription factor NFAT2 activation; this activated BCR/NFAT signaling cascade, which is reflected by the ex-vivo measurement of CLL cell survival, was correlated to the overall survival from CLLpatients; 2) increased levels of global and specific Syk phosphorylation, phospho-Syk subcellular distribution, Sykability to interact with positive and negative effectors and to activate them. Moreover, study of BCR stimulation mediated decreased migration in CLL B cells showed that it relied on CXCR4 internalization levels that were regulated by activated PI3Ks acting upstream of the PKDs; activation of the latters allowed CXCR4 phosphorylation and then its endocytosis. Altogether, these data allowed us to better understand the molecular mechanisms underlying the survival advantage and the decreased migration of CLL B cells in response to antigenic stimulation, to evidence eventual functional biomarkers of stratification (pSyk and pPLCƳ2), to point out potential therapeutic targets (NFATs and PKDs), and to partially explain how Fostamatinib and Idelalisib function as therapeutic drugs in CLL
Lai, Wan-Tzu, und 賴宛姿. „A novel CXCR1/2 antagonist (pT12S) as a potent anticancer drug“. Thesis, 2017. http://ndltd.ncl.edu.tw/handle/ca98k4.
Der volle Inhalt der QuelleLee, Wei-Chen, und 李韋蓁. „The Effect of Novel CXCR1/2 Antagonist (RP4) in Pancreatic Cancer“. Thesis, 2018. http://ndltd.ncl.edu.tw/handle/84wa83.
Der volle Inhalt der QuelleWang, Hsin-Yu, und 王欣裕. „The molecular mechanism of homocysteine induced COX-2 and CXCR4 expression in monocytes“. Thesis, 2009. http://ndltd.ncl.edu.tw/handle/03622540790793112549.
Der volle Inhalt der Quelle國立嘉義大學
生化科技研究所
97
Homocysteine is a sulfur-containing amino acid formed during the metabolic demethylation of methionine. Homocysteine is recycled to methionine by the remethylation pathway. In excess of methionine, homocysteine is covered via transsulfuration pathway to Cysteine. The association between homocysteine and athrosclerosis has been extensively studied. There is no complete consistency across the study; however, increasing evidence has shown that even mild to moderate elevation in homocysteine concentrations may be a risk factor for athrosclerosis. The graded effect of homocysteine concentrations on the severity of coronary athrosclerosis remains constroversial. The early stage of athrosclerosis involves adhesion of monocytes to endothelial cells (ECs), which are located in close proximity to smooth muscle cells (SMCs). Growth factor and cytokine contribute to progression of atherosclerotic lesions. The aims of this study are to investigate the molecular mechanisms of homocysteine-induced COX-2 expression of U937 monocytes. The effect and signal transduction of homocysteine on monocyte COX-2 expression was examined in vitro. The results from this study may provide insights into the mechanisms contributing to inflammatory response in patients with hyperhomocysteinemia.
Liebick, Marcel. „Chemokine receptors CXCR4 and CCR5: Cell surface expression, signaling and modulation by β-arrestin 2“. Doctoral thesis, 2014. http://hdl.handle.net/11858/00-1735-0000-0022-5DD3-C.
Der volle Inhalt der QuelleHe, Pei-Jiun, und 何姵君. „Helicobacter pylori-derived Heat shock protein 60 could enhance angiogenesis through CXCR-2 signal pathway“. Thesis, 2009. http://ndltd.ncl.edu.tw/handle/56378587362820469560.
Der volle Inhalt der Quelle國立交通大學
生物科技系所
97
Helicobacter pylori, the microbe has been discovered it can promote the malignant process of gastric cancer. Heat shock protein 60 of H. pylori (HpHSP60) was previous identified as a potent immunogen. This study aims to study the role of HpHSP60 on gastric cancer carcinogenesis. First, the results of patients’ anti-HpHSP60 antibodies in sera were correlated to gastric cancer. According to these finding, this pathogen-derived component was speculated it may play a role in tumor malignant process. Sequentially, we investigated the effect of HpHsp60 on the cell proliferation, anti-death activities, angiogenesis, and metastasis. The results showed HpHSP60 could enhance migration of gastric cancer cells and promote angiogenesis it had no effect on proliferation and rescuing cell death of gastric cancer cells. Moreover, the results showed HpHSP60 could stimulate THP1 monocytic cells, AGS gastric cancer cells, and umbilical vein endothelial cells (HUVECs) to express the angiogeneic factors. In addition, HpHSP60 could also enhance tube formation, migration and indirectly promote proliferation of HUVECs. Furthermore, inhibition of CXCR2 signal decreased the tube formation. Therefore, these results propose HpHSP60 may trigger angiogeneic factor releases and enhance the angiogenesis via CXCR2-dependent pathway.
Espírito, Santo Maria. „Estudo da susceptibilidade do VIH-2 à inibição por moléculas inibidoras do co-recptor CCR5“. Master's thesis, 2010. http://hdl.handle.net/10451/2384.
Der volle Inhalt der QuelleAté à data deste trabalho, poucos estudos têm sido feitos para determinar a susceptibilidade do VIH-2 aos antagonistas dos co-receptores (CoR). Estes pertencem a um grupo de inibidores de entrada com um novo mecanismo de acção, agindo fora da célula, ligam-se ao CoR, impedindo a sua utilização durante a entrada viral, ao contrário dos outros inibidores já existentes, que têm por alvo, proteínas do HIV. Neste estudo, determinou-se a susceptibilidade do HIV-2 aos inibidores do CCR5 (TAK-779, MVC, PF-2221753 e mAb2D7) e do CXCR4 (SDF-1alpha e o mAb12G5), usando seis estirpes VIH-2 isoladas e caracterizados no nosso laboratório, e utilizando a estirpe HIV- 1BaL como controlo. Para os ensaios de inibição, utilizou-se a linha celular humana obtida dum osteossarcoma (GHOST) que expressa o receptor CD4 e o co-receptor CCR5 ou CXCR4. A replicação viral foi monitorizada pela detecção do Ag p24 nos sobrenadantes da cultura. Os resultados demonstraram que o TAK-779, MVC e o PF-227153 inibiram eficientemente todas as estirpes HIV-2 enquanto o mAb2D7, inibiu apenas a estirpe HIV-2ALI. Verificou-se ainda que o SDF-1alpha inibiu três das quatro estirpes estudadas, enquanto o mAb12G5 teve um efeito inibitório menor quando comparado com o SDF-1alpha. Estes resultados permitem-nos concluir que: os antagonistas do CCR5 analisados são mais eficientes para o HIV-2 do que para o HIV-1BaL e que o SDF-1alpha é mais eficaz quando comparado com o mAb12G5 para a inibição das estirpes. Estes resultados sugerem assim novas direcções e soluções terapêuticas no combate à infecção por HIV-2.
Until the date of this work, little is known about HIV-2 susceptibility to coreceptor (CoR) antagonists (CCR5 and CXCR4 antagonists). These belong to a group of entry inhibitors with a novel mechanism of action, acting outside the cell by binding to CoR and preventing its use during viral entry, unlike the other existing drugs that target HIV proteins. In this study we determine the susceptibility of HIV-2 to CCR5 (TAK-779, MVC, PF- 2221753, mAb2D7) and CXCR4 (SDF-1alpha and mAb12G5) inhibitors using six strains previously isolated and characterized in our laboratory. HIV-1BaL was used as control. Inhibition assays, were done using human osteosarcoma cell line (GHOST) coexpressing CD4 and the CoR CCR5 or CXCR4 and viral replication was monitored by Ag p24 detection in culture supernatant. The results indicated that TAK-779, MVC and PF-227153, efficiently inhibited all HIV-2 strains. Regarding mAb2D7, only inhibited the HIV-2ALI strain. It was also possible to demonstrate that SDF-1alpha inhibited three of the four strains studied, while mAb12G5 had lower inhibitory effect when compared to the SDF-1alpha. These results enable us to conclude that the CCR5 antagonists under study are more efficient for HIV-2 than for HIV-1BaL and that SDF-1alpha is more effective when compared with mAb12G5 to the inhibition of these strains. Finally, these findings also suggest new directions and therapeutic solutions to the control of HIV-2 infection.
Dröge, Arnold Paul Bernhard [Verfasser]. „Evaluation von Metallothionin 3, CXCR4, X-IAP und IAP-2 als Progressionsmarker des invasiv duktalen Mammakarzinoms / vorgelegt von Dröge, Arnold Paul Bernhard“. 2009. http://d-nb.info/993372430/34.
Der volle Inhalt der QuelleCalado, Ana Marta Carvalho 1980. „O receptor das quimiocinas CCR8 : sua relevância como co-receptor alternativo para isolados primários de HIV-1 e HIV-2“. Master's thesis, 2012. http://hdl.handle.net/10451/6289.
Der volle Inhalt der QuelleO ciclo de replicação do HIV na célula do hospedeiro começa com a ligação da glicoproteína de superfície viral ao receptor CD4 e aos receptores das quimiocinas (co-receptores) presentes na membrana das células. Com este trabalho pretendemos avaliar a contribuição do CCR8 como co-receptor alternativo para os isolados de HIV-1 e HIV-2 e caracterizar a capacidade para infectar macrófagos derivados de monócitos (MDM), por parte dos isolados que venham a revelar capacidade para utilizar este co-receptor. Tentou-se ainda estabelecer uma correlação entre o co-receptor utilizado e os dados imunológicos e clínicos dos indivíduos a partir dos quais os vírus foram isolados. Os resultados obtidos demonstraram que o CCR8 é eficientemente utilizado não apenas por isolados de HIV-2, mas particularmente por isolados de HIV-1. Observámos também que o uso do CXCR4, isoladamente ou em conjunto com o CCR5 e/ou CCR8, foi mais frequentemente observado em isolados de HIV-1 do que de HIV-2. Directamente relacionado com isso é a constatação de que a não utilização do CXCR4 é significativamente mais comum em isolados HIV-2; ambos os resultados podem ser associados com a progressão mais lenta para a doença, geralmente observada em indivíduos infectados com HIV-2. A capacidade de alguns isolados virais para utilizarem co-receptores alternativos, para além do CCR5 e CXCR4, pode ter impacto na eficácia da terapêutica com inibidores de entrada e possivelmente também na patogénese do HIV. A caracterização da capacidade de estirpes de HIV-1 e HIV-2, com diferentes perfis de utilização de co-receptores, infectarem MDM, permite-nos concluir que não existe uma relação entre o biotipo dos isolados estudados e a infecção produtiva destas células. No entanto, apesar de não ter sido possível detectar actividade da RT nas culturas de MDM, constatamos que houve integração do DNA viral no genoma celular. Concluímos que isto se pode dever ao limiar de sensibilidade do método de quantificação de RT, ou pode ser consequência de algum factor de inibição que esteja a actuar pós-transcrição reversa e integração, ou ainda pode ser devido à ausência de algum factor celular necessário à conclusão do ciclo de replicação. Não nos foi possível estabelecer uma correlação entre os co-receptores usados e os dados imunológicos e clínicos dos indivíduos infectados.
The HIV replication cycle in the host cell begins with the binding of the viral surface glycoprotein with the CD4 receptor and coreceptors present on the cell membrane. With this work we intend to evaluate the contribution of CCR8 as alternative coreceptor for HIV-1 and HIV-2 isolates and characterize the ability to infect monocyte-derived macrophage (MDM) by strains that reveal capacity to use this coreceptor. We also tried to establish a correlation between the coreceptor usage and the immunological and clinical data of the patients from which the virus was isolated. The results showed that CCR8 was efficiently used not only by HIV-2 isolates, but particularly by HIV-1 isolates. We also demonstrate that CXCR4 usage, alone or together with CCR5 and/or CCR8, was more frequently observed in HIV-1 than in HIV-2 isolates. Directly related to this is the finding that the non-usage of CXCR4 is significantly more common in HIV-2 isolates; both features could be associated with the slower disease progression usually observed in HIV-2 infected patients. The ability of some viral isolates to use alternative coreceptors besides CCR5 and CXCR4 could further impact on the efficacy of treatment with entry inhibitors and possibly also in HIV pathogenesis. The ability of HIV-1 and HIV-2 strains, with different profiles of coreceptors usage, to infected MDM, allows us to conclude that there isn’t a relationship between the biotype of the isolates and productive infection of these cells. However, despite we were unable to detect RT activity in MDM cultures, we observe integration of viral DNA in cell genome. We conclude that this may be due to the sensitivity threshold of the RT quantification method, or may be the result of some inhibitory factor that is acting after reverse transcription and integration, alternatively, it may be due to the absence of some cellular factor that allows the completion of replication cycle. We were unable to establish a correlation between the coreceptor usage and the clinical and immunological data.
Sauvé, Karine. „Régulation de l’activité transcriptionnelle des récepteurs des estrogènes (ER) par le récepteur à chimiokine CXCR4 et les récepteurs à activité tyrosine kinase ErbB2 et ErbB3“. Thèse, 2013. http://hdl.handle.net/1866/10885.
Der volle Inhalt der QuelleInduction of estrogen-regulated gene transcription by estrogen receptors ERα and ERβ plays an important role in breast cancer development and growth. High expression of the chemokine receptor CXCR4 and its ligand CXCL12/SDF-1 has also been correlated with aggressive breast tumor phenotypes. Here, we describe a positive regulatory loop between CXCR4/SDF-1 signaling pathway and ER transcriptional competence in human breast cancer cells. Treatment of breast carcinoma MCF-7 cells with SDF-1 increased ER transcriptional activity and expression of ER target genes, including SDF-1 itself. These effects were blocked by the antiestrogen ICI-182780 and by CXCR4 silencing, and conversely, estrogen-induced gene expression and growth of MCF-7 cells were impaired upon CXCR4 inhibition. Growth factor signaling also plays an important role in breast cancer. Overexpression and deregulated signaling of receptor tyrosine kinase ErbB2 correlate with aggressive breast tumor phenotype and poor outcomes. However, how ErbB2 and CXCR4 signaling is functionally related to regulate ER response in breast cancer cells is not known. Here we show that steady-state levels of ErbB2 and its dimeric partner ErbB3, as well as ErbB2 tyrosine phosphorylation were negatively regulated with the expression of CXCR4. CXCR4 downregulated ErbB2/ErbB3 dimer activation of the PI3-K/Akt pathway in response to ErbB3 ligand heregulin-β, whereas addition of SDF-1 restored activation levels. We found that heregulin-β promoted CXCR4 phosphorylation at serine 339, an important site for CXCR4 internalization and signaling. In addition, ErbB2 recruitment to CXCR4 was enhanced by ErbB3 and heregulin-β. Transcriptional activity and gene expression measurement showed that the hormonal repression of ER was relieved with the expression of CXCR4 and partially recuperated with the addition of SDF-1. Together, these results show that CXCR4 recruitment to ErbB2 alters ErbB2/ErbB3 signaling pathway and downstream regulation of ER hormonal activity in in breast cancer cells. Our work has enabled us to identify and characterize the impact of membrane receptors signaling on ER transcriptionnal response in breast cancer cells. Membrane signaling is one of the factors involved in endocrine therapy resistance and targeting the receptors implicated could be benificial to improve existing treatments and to work on the creation of new ones.
Rhainds, David. „Exploration des mécanismes responsables de la dichotomie entre la chimiotaxie et la division cellulaire“. Thèse, 2017. http://hdl.handle.net/1866/20412.
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