WorldCat Identities

Centre Méditerranéen de Médecine Moléculaire (Nice)

Overview
Works: 75 works in 75 publications in 2 languages and 76 library holdings
Roles: Other
Publication Timeline
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Most widely held works by Centre Méditerranéen de Médecine Moléculaire (Nice)
Insectes hématophages : terrains, élevages, infections : études chez Cimex lectularius et Phlebotomus perniciosus by Arnaud Cannet( )

1 edition published in 2016 in French and held by 2 WorldCat member libraries worldwide

Les insectes hématophages impactent sur la santé humaine et animale par la nuisance et l'allergie induite par la piqûre ou par leur risque de transmission d'agents pathogènes. Les étudier permet de mieux prévenir, gérer ou traiter l'ensemble des pathologies induites. Au cours de cette thèse, nous avons étudié deux insectes que sont la punaise de lit et le phlébotome.- Pour les punaises de lit une revue de la littérature sur les méthodes d'élevage a été rédigée. Nous avons déterminé deux aspects que sont les facteurs physiques (température, humidité relative, photopériode) et physiologiques (type, fréquence des repas) à prendre en considération. Un travail de terrain de recueil de spécimens a permis d'étudier la génétique des spécimens par localités et d'évaluer le portage de pathogènes notamment la bactérie Wolbachia sp.- Pour le phlébotome, un élevage de l'espèce Phlebotomus perniciosus a été mis en place permettant d'évaluer deux modèles infectieux expérimentaux à Leishmania infantum sur souris BALB/c et sur gorgeur artificiel. Des captures de terrain ont été réalisées et une étude de la génétique de population de Phlebotomus ariasi a été publiée. Une revue de la littérature sur les principaux événements historiques et évolutifs des Leishmanies, des phlébotomes et des réservoirs animaux associés a été publiée.- Dans le cadre de cette thèse nous avons collaboré à un nouveau mode d'identification des diptères hématophages (dépôt d'un brevet).- Au cours de ces 3 années de thèse, nos activités entomologiques hospitalières ont permis la description de cas entomologiques originaux.Cette thèse a fait l'objet d'une bourse CIFRE financée par les Laboratoires VIRBAC
Impact de la metformine sur le métabolisme lipidique et mitochondrial dans les cellules cancéreuses de prostate by Camille Loubiere( )

1 edition published in 2014 in French and held by 1 WorldCat member library worldwide

Le cancer de la prostate est un véritable problème de santé publique qui se situe au premier rang des cancers incidents chez l'homme. Les cellules tumorales ont un métabolisme différent des cellules normales, et cibler le métabolisme des cellules cancéreuses est devenu une stratégie thérapeutique prometteuse. La metformine est un médicament couramment prescrit contre le diabète de type II, qui possède des propriétés anti-tumorales et affecte le métabolisme des cellules cancéreuses. L'augmentation de la lipogenèse est observée dans nombreux cancers dont le cancer de la prostate. Nous montrons que la metformine inhibe la lipogenèse dans les cellules cancéreuses de prostate via un déficit énergétique cellulaire. En effet, l'ATP est diminuée de façon dose dépendante par la metformine et cette diminution est significativement corrélée avec l'inhibition de la lipogenèse. De plus, la metformine induit un gonflement des mitochondries et une désorganisation des crêtes mitochondriales dans les cellules cancéreuses de prostate. De façon intéressante, nous observons que la metformine provoque une augmentation des flux calciques et un relargage du calcium du réticulum endoplasmique. Nous émettons l'hypothèse que ce calcium s'accumule dans la mitochondrie ce qui pourrait générer un gonflement de celles-ci. En réponse à ces signaux calciques ou à la diminution de la fonctionnalité des mitochondries, la metformine stimule la biogenèse mitochondriale dans les cellules cancéreuses de prostate. En conclusion, cette étude a permis de mieux comprendre les mécanismes moléculaires et cellulaires induits par la metformine dans le cancer de la prostate
Rôle du complexe Ro60/RNYs dans les macrophages chargés des lipides by Sofia Fazio( )

1 edition published in 2020 in English and held by 1 WorldCat member library worldwide

Ro60, an RNA-binding protein that associates with YRNAs, is a clinical target of the immune response in patients with systemic lupus erythematosus (SLE) and Sjogren's syndrome (SS). SLE and SS autoantibodies, including the anti-Ro60 autoantibody, penetrate inside the cells and localize in the nucleus. Interestingly, mice lacking Ro60 develop an autoimmune syndrome and pro-inflammatory status with features of SLE, indicating that Ro60 loss-of-function is involved in SLE pathogenesis. SLE and SS patients mainly die of premature inflammatory cardiovascular disorders caused by accelerated atherosclerosis. Based on these observations, we hypothesized that inflammation and cardiovascular accidents in SLE/SS patients would be caused by the dysfunction of Ro60 complex in the nucleus. During my PhD, we showed that in human and mouse primary macrophages and THP-1 cells (human monocytic cell line) stimulated with pro-inflammatory and pro-atherogenic stimuli (lipidladen macrophages), YRNA degradation allows Ro60 to bind chromatin in an RNA-independent fashion. To identify Ro60 binding sites on chromatin, we performed ChIP-seq analysis and found a significant increase of Ro60 binding upon palmitic acid (PA) treatment on promoters of coding genes, indicating that Ro60 could be involved in their transcription. By de novo motif discovery, we found two binding motifs that were significantly enriched in Ro60-binding sites. Next, to study the function of chromatin-associated Ro60 on its target genes, we performed RNA-seq in time course experiments on PA-treated and untreated THP1 cells, in presence or absence of Ro60. After, on the RNA-seq data obtained, we performed Exon-Intron Split analysis (EISA), a bioinformatic approach to quantify transcriptional and post-transcriptional regulation of gene expression from RNA-seq data of time course experiments. Our results indicate that Ro60 significantly promotes the transcription of 247 target genes that regulate inflammatory response upon 6h of PA treatment. We validated the direct control on three target genes (TRIM62, ZEB1 and CPT1A) by using a stably viral infected sh-Ro60-THP1 cells and control. On the other hand, by GO-term analysis performed on the RNA-seq data, we found that Ro60 knockdown overall promotes a pro-inflammatory phenotype in PA-treated Mo. Lastly, to identify Ro60 molecular partners that would contribute to this chromatin-associated function in lipid-laden macrophages, we performed a label-free quantitative LC/MS/MS analysis from the immunoprecipitated Ro60-containing complex in PA-treated and untreated THP-1 cells. We found that Ro60 interacts with components of the TREX (TRanscription and EXport) and nucleopore complexes, including THOC1, THOC4 and TPR. By performing co-IP experiments, we showed that THOC4 directly interacts with Ro60 on the chromatin and full cell extract. These results raised the possibility that Ro60 would directly regulate the transcription and export of transcripts involved in the inflammatory response in lipid-laden macrophages through its association with the TREX complex. We thus performed the EISA analysis in PA-treated and untreated THP-1 cells upon THOC4 knockdown and control and found that the synthesis of 25 transcripts, including TRIM62, ZEB1, and CPT1A, was downregulated in both THOC4 and Ro60 knockdown. In conclusion, we characterized a novel chromatin-associated function of Ro60, which associates with THOC4 to regulate the gene expression program of lipid-laden macrophages. The impairment of this new Ro60-dependent mechanism in SLE/SS patients by the nuclear penetration of anti-Ro60 autoantibodies in Mo/Ma could promote the overall inflammatory status of these patients and the higher cardiovascular accidents risk. In addition to provide new insights into regulated gene expression programs, the broader impact of this project resides in an opportunity to provide new etiological inputs for SLE and SS patients
<> by Déborah Vallée( )

1 edition published in 2019 in French and held by 1 WorldCat member library worldwide

Effets des antidiabétiques et de leurs dérivés sur le mélanome by Michaël Cerezo( )

1 edition published in 2014 in French and held by 1 WorldCat member library worldwide

Melanoma accounts for 8000 new cases each year and more than a thousand deaths. If diagnosed early enough, wide surgical excision may be sufficient to treat. However, at the onset of metastasis, the prognosis becomes very bad due to the ineffectiveness of all treatments. Finally, although encouraging results were recently obtained with B-Raf inhibitors and immunotherapy, these responses are insufficient. So identification of new candidate molecules is an essential element for melanoma treatment. During the first part of my PhD, I was interested in metformin, the most commonly used molecule for the treatment of type 2 diabetes mellitus. It had been shown in our laboratory that metformin reduces melanoma cells viability in vitro and in vivo. Melanoma is a highly metastatic cancer, so I focused on the potential effect of metformin on melanoma cells invasion. We observed a decrease of melanoma cells invasion dependent on the activation of AMPK / p53 axis in vitro and in vivo. So we have shown for the first time that metformin can be used to inhibit melanoma cells invasion.During the second part of my PhD, I have been interested in other antidiabetic drugs, thiazolidinediones (TZD). Through a structure / activity screening we identified a molecule, HA15, derived from TZD and having a very strong anti-melanoma activity in vitro and in vivo. We showed that HA15 induced unfolded protein response (UPR), via the chaperone protein Bip, leading to autophagy and apoptosis activation, and resulting in cell death. This study identified a new molecule potentially effective against melanoma and reinforces the idea that UPR could be a therapeutic target for melanoma treatment
Nouvelles altérations métaboliques des cancers bronchiques non à petites cellules : rôle de l'efflux du cholestérol et de la mitophagie by Emma Guilbaud( )

1 edition published in 2021 in French and held by 1 WorldCat member library worldwide

Étude de l'implication de la protéine matricellulaire SPARC et des fibroblastes du microenvironnement lymphatique dans la résistance thérapeutique des mélanomes by Anaïs Pottier( )

1 edition published in 2015 in French and held by 1 WorldCat member library worldwide

Melanoma is the most dangerous form of skin cancer due to its high metastatic potential and its resistance to both classical chemo- and radiotherapies. New targeted therapies directed against the V600E oncogenic form of BRAF found in about 60% of patients have demonstrated spectacular efficacy both in terms of progression free and overall survival. However most patients invariably relapse after a few months due to resistance mechanisms. Cancer cells are anchored and interact constantly with their microenvironment. Both soluble factors and the extracellular matrix produced by stromal cells have been shown to contribute to cancer cell resistance to therapies. SPARC is a matricellular protein that orchestrates interactions between normal and/or cancer cells and their microenvironment. While it is absent in melanocytes, SPARC expression increases in melanoma and is correlated with both tumoral progression and a bad prognosis. When SPARC is secreted by melanoma cells, it activates the AKT kinase, destabilizes the p53 tumor suppressor and promotes proliferation and survival. Here we identify the couple SPARC/AKT as a new actor contributing to both innate and acquired resistance to BRAFV600E inhibitors. In addition, we demonstrate that targeting SPARC in melanoma cells increases their sensitivity to both BRAF and MEK inhibitors. Finally we show that lymph node fibroblasts share features of activated fibroblasts and confer resistance to BRAF inhibitors to melanoma cells through the production of a permissive extracellular matrix
Rôle de la kinase inflammatoire Tpl2 dans l'inflammation du tissu adipeux lors de l'obésité by Franck Ceppo( )

1 edition published in 2014 in French and held by 1 WorldCat member library worldwide

During obesity a chronic low grade inflammation is developed in adipose tissue and contributes to its malfunction and participating in the development of insulin resistance. This inflammation is due to the infiltration and activation of various immune cells in adipose tissue, such as macrophages. Saturated fatty acids and LPS are involved in immune cell activation and leading to the production of inflammatory cytokines, all of which are involved in the malfunction of adipose tissue and insulin resistance. The inflammatory TPL2 kinase activated by LPS and cytokines, has recently been identified as a novel kinase, whose expression is increased in obese tissue. Its role in the inflammation of this tissue and in the insulin resistance is a major area of research in the search for new therapeutic targets for the treatment of obesity and metabolic complications associated. Our results suggested that TPL2 is involved in the deleterious effects of macrophages activated by fatty acids or LPS on the biology of adipocytes. Similarly, the pharmacological inhibition of TPL2 or use of interfering RNA impairs chemotactic potential secretome of adipocytes versus the macrophages. Our results indicate that the TPL2 kinase is activated by hypoxia in adipocytes and macrophages, and its inhibition leads to a reduction of the expression and production of inflammatory factors. These studies suggested thatTPL2 is a potential therapeutic target in the treatment of obesity and diabetes
L'hypoxie et le métabolisme comme approche thérapeutique dans le médulloblastome by Julie Contenti-Liprandi( )

1 edition published in 2022 in French and held by 1 WorldCat member library worldwide

Medulloblastoma is a cancerous brain tumor that affects mostly children. It is rarely found in adults. Among the 4 groups defined according to molecular characteristics, group 3 is the least favorable with a survival rate of 50%. Current treatments, based on surgery, radiotherapy and chemotherapy, are however not sufficiently adapted to the different characteristics of the tumor, which are still not understood. In this study, we addressed the problem of medulloblastoma from a metabolic perspective in an oxygen-deficient microenvironment. Tumor hypoxia and consequent metabolism have been little studied in MB. In this study, we show that Group 3 MB have either a post-translational modificationor mutations in the PAS-A domain of HIF-1a blocking association with HIF-1b, resulting in a completely inactive HIF-1. Only HIF-2 is then present to replace HIF-1 in the activation of metabolic pathways. In vitro and in vivo data showed that pharmacological inhibitor of HIF-2a, the PT2385 , coupled with Metformin, a specific inhibitor of the mitochondrial complex I, can efficiently block and kill Group 3 MB compared to Non-Group 3 MB.We also established that cells in group 3 are more sensitive to Phenformin, a complex 1 inhibitor, than cells in other groups. Furthermore, we showed that this subgroup differentially utilizes the two shuttles, mitochondrial glycerophosphate dehydrogenase (mGPDH) and malate-aspartate shuttle (MAS), which allow NADH to move from the cytoplasm to the mitochondria. The use of phenformin and iGP1, a specific inhibitor of mGPDH, as well as the combination of the two specific inhibitors of the two shuttles, iGP1 and AOAA, clearly showed a greater ability to decrease cell proliferation and induce cell death specifically for cells in group 3 compared to cells in other groups.Our study reinforces the idea of not only molecular but also metabolic heterogeneity in the different groups that constitute medulloblastoma and provides a potential new therapeutic solution for patients in group 3 whose tumors are more aggressive
Le cluster pro-fibrotique miR-143/145 favorise la plasticité phénotypique associée à la résistance des mélanomes aux thérapies ciblées by Serena Diazzi( )

1 edition published in 2021 in English and held by 1 WorldCat member library worldwide

Le mélanome est le cancer de la peau le plus agressif de par sa grande plasticité phénotypique, son potentiel métastatique et sa résistance aux traitements. Malgré la percée des thérapies ciblant la voie oncogénique MAP kinase, la résistance du mélanome a ces traitements demeure un obstacle majeur qui limite le bénéfice pour les patients porteurs de la mutation BRAFV600E. Les cellules de mélanome peuvent transiter vers un état de type mésenchymateux dédifférencie en fonction des pressions du microenvironnement et des traitements. Cette plasticité cellulaire phénotypique adaptative a été décrite comme un facteur essentiel de résistance aux thérapies ciblées. Mon équipe de recherche travaille sur ce type de résistance non-génétique définie comme ≪ mésenchymateuse ≫, dans lequel les cellules tumorales présentent un comportement invasif et acquièrent des caractéristiques observées typiquement dans les fibroses telles que la capacité à accumuler et à remodeler la matrice extracellulaire et activer les voies de mécanotransduction. Dans ce contexte, mon projet a consiste à caractériser un cluster compose de deux ≪ FibromiRs ≫, microARN impliques dans les mécanismes de fibrogènes et qui sont fortement exprimes dans les mélanomes résistants. Mes résultats obtenus à l'aide d'approches in vitro et in vivo démontrent le rôle du locus miR-143/-145 dans la régulation de la résistance non-génétique en raison de sa capacite à remodeler la matrice et façonner une niche de protection et de tolérance pour la tumeur face aux inhibiteurs de la voie MAP kinase. MiR-143 et miR-145 contribuent également au passage d'un phénotype cellulaire différentié prolifératif a un phénotype mésenchymal plus invasif et résistant. Au niveau moléculaire, j'ai identifié parmi les nombreuses cibles potentielles du cluster, la FSCN1 comme un gène clé cible de miR-143 et -145. Ces travaux ont permis de dévoiler le rôle du cluster miR143/-145 dans le comportement agressif des cellules de mélanome dédifférenciées résistantes et de proposer miR-143 et miR-145 comme nouvelles cibles thérapeutiques pour vaincre la résistance mésenchymateuse et mieux combattre la maladie métastatique réfractaire
Le rôle de la mécanotransduction dans la plasticité, la progression et la résistance thérapeutique du mélanome by Margaux Lecacheur( )

1 edition published in 2021 in French and held by 1 WorldCat member library worldwide

Melanoma is the most aggressive and deadliest form of skin cancer due to its heterogeneity, high metastatic potential, and therapeutic resistance. Despite existing therapies, including targeted therapies against the BRAF/MEK pathway or immunotherapies, patients may still undergo therapeutic failure. This occurs in part due to the onset of resistance to therapies. Melanoma intra-tumoral heterogeneity and melanoma cell plasticity contribute to therapeutic resistance. Melanoma cell plasticity is the ability of cells to switch between different cell phenotypes. For example, melanoma cells can switch from a differentiated state, where they express the melanocytic marker MITF, to a more dedifferentiated state, thereby creating tumor heterogeneity. This cell plasticity can be induced by targeted therapies. In this context, the acquisition of a dedifferentiated mesenchymal phenotype has also been described as an escape mechanism in response to therapies. The ability of cells to disseminate and to resist treatment is based on their ability to adapt to their microenvironment. Within the tumor, tumor cells interact with a complex environment composed of stromal cells and extracellular matrix (ECM). The ECM, mainly produced by fibroblasts, is a dynamic web that is constantly remodeled and its physiochemical properties can influence tumor architecture. Tumor cells can sense the tension from the ECM and respond to it by a process called mechanotransduction. Previous studies have shown the role of ECM stiffening in the progression and therapeutic resistance of several solid cancers. However, the role of ECM stiffening and the role of mechanotransduction in melanoma is not fully understood. My thesis project investigated the influence of ECM stiffening modifications on melanoma progression, plasticity and resistance to targeted therapies. In the first part of my thesis, results showed that targeted therapies against the BRAF/MEK pathway stimulate in vitro and in vivo melanoma cells to produce and assemble a collagen rich ECM that contributes to tumor stiffening and therapeutic escape. In the second part of my thesis, we analyzed melanoma cell response to substrate stiffness modifications, which melanoma cells might encounter during disease progression and in response to targeted therapies. We demonstrated that melanoma cells harboring a differentiated mesenchymal-like phenotype are more sensitive to changes in ECM stiffness, as depicted by an increase in their proliferation, migration/invasion and resistance to therapy on a stiff substrate. Interestingly, we identified that the collagen receptors DDR1 and DDR2 are responsible for this mechanophenotype, through the activation of the mechanosensory protein YAP, which was dependent on the actomyosin cytoskeleton. This work highlights the role of DDR in melanoma mechanotransduction and progression and unveils a novel weakness of dedifferentiated cells. This work could therefore lead to future developments of new therapeutic strategies that target the interaction between melanoma cells and their ECM microenvironment
Ingénierie génétique d'organoïdes à l'aide de nanoblades et étude du rôle d'UBTD1 comme modulateur de la force d'adhésion cellulaire dans les organoïdes de prostate by Victor Tiroille( )

1 edition published in 2021 in English and held by 1 WorldCat member library worldwide

During my thesis, I worked on the 3D organoid model following two main objectives: i) developing genetic tools to modify the genome of organoids and ii) deciphering the role of ubiquitin domain-containing protein 1 (UBTD1) in the development of prostate organoids . Genome engineering has become in the last few years more accessible thanks to the RNA programmable endonucleases such as the CRISPR-Cas9 system. However, using this editing technology in synthetic organs called 'organoids' is still very inefficient. This is mainly due to the delivery methods used for the CRISPR-Cas9 machinery, which are predominantly performed by electroporation of RNPs containing the CAS9-gRNA complex, a procedure toxic for the organoids. Here we describe the use of the 'Nanoblade' technology to accomplish genome editing in organoids. Nanoblades outperformed by far knockout (KO) levels achieved with other techniques used to date for delivery of the gene editing machinery. We reached up to 80% of gene knockout in organoids after treatment with nanoblades. We achieved high-level nanoblade-mediated KO for the androgen receptor (AR) encoding gene and the cystic fibrosis transmembrane conductance regulator (CFTR) gene with single gRNA or dual gRNA containing nanoblades. Most importantly, in contrast to other gene editing methods, this was obtained without toxicity for the organoids. Moreover, it requires only four weeks to obtain stable lines KO for a gene in organoids and no obvious unwanted INDELS in off-target site in the genome were detected. In conclusion, nanoblades simplify and allow rapid genome editing in organoids with little to no side-effects.Morphogenesis and tissue remodeling are finely regulated processes governed by cell-cell adhesions. However, the spatial and temporal control of adhesion molecules remains partially unexplored. Here we studied the role of UBTD1 as a modulator of the strength of adherens in the prostate epithelium. We showed that down-regulation of UBTD1 disrupted the self- organization of cells in three dimensions. Conversely, we demonstrated that overexpression of UBTD1 induced more regular epithelial monolayers and increased cell surface tension. Transcriptomic analyses revealed a gene expression profile of proteins involved in cell junctions affected by UBTD1 modulation. Using the prostate organoid model, we showed that UBTD1 expression in luminal cells disrupted cyst formation in mouse prostate organoids. Finally using a co-immunoprecipitation approach coupled to mass spectrometry, we showed that UBTD1 interacts with partners involved in cell-cell junctions and that these interactants have their expression modulated by UBTD1 deregulation. Our results show that a protein involved in protein degradation processes regulates the strength of adherens junctions
Rôle du facteur de transcription circadien Krüppel-Like Factor 10 (KLF 10) dans le développement des complications hépatiques de l'obésité by Pierre Leclère( )

1 edition published in 2019 in French and held by 1 WorldCat member library worldwide

Échapper à la mort cellulaire dans le cancer : mitophagie et régulation de la mort indépendante des caspases by Elodie Villa( )

1 edition published in 2017 in French and held by 1 WorldCat member library worldwide

Une des caractéristiques des cellules tumorales est leur habileté à échapper à la mort cellulaire. Pour y parvenir, elles ont développé une stratégie consistant à éliminer sélectivement les mitochondries endommagées par un processus de mitophagie. L'acteur principal de la mitophagie est l'ubiquitine ligase Parkin ; mais elle est mutée ou absente dans la majorité des cancers. Nous avons découvert qu'une autre ligase, ARIH1, appartenant à la même famille des RBR ligases que Parkin, est capable d'induire la mitophagie en réponse à un stress. Contrairement à Parkin, ARIH1 est surexprimée dans de nombreux cancers, notamment dans les cancers du poumon permettant ainsi une augmentation de la mitophagie conférant ainsi à ces cellules une résistance au stress induit par des agents chimiothérapeutiques. La mort cellulaire la mieux caractérisée est l'apoptose qui est directement liée à l'activation de caspases. Il a pourtant été établi qu'une inhibition des caspases ne permet pas d'empêcher la mort cellulaire car il existe la « mort cellulaire indépendante des caspases » ou CICD. Cependant, sa définition moléculaire précise reste toujours inconnue. Ainsi dans ce but, un criblage siRNA pan génomique a révélé l'importance de la voie ubiquitine/protéasome. Nous avons pu identifier en particulier une enzyme E3 ligase comme étant protectrice de la CICD. Cette enzyme est surexprimée dans de nombreux cancers et pourrait permettre aux cellules cancéreuses de résister à la CICD et favoriser la progression tumorale. En résumé, ce travail a permis de souligner l'importance des ubiquitines ligases dans les mécanismes d'échappement à la mort cellulaire mis en place par les cellules cancéreuses
Identification de composés immuno-stimulateurs anti-microbiens de nouvelle génération by Alissa Majoor( )

1 edition published in 2021 in French and held by 1 WorldCat member library worldwide

La Leishmaniose est une maladie tropicale négligée que l'on retrouve dans plus de 88 pays à travers le monde. On compte par an jusqu'à 1 000 000 de nouveaux cas, menant à près de 30 000 morts. Chez l'homme, il existe plusieurs formes de la maladie, allant d'une forme cutanée pouvant guérir spontanément, à la forme viscérale la plus grave.La leishmaniose viscérale est conférée par plusieurs espèces de leishmanies, dont L. infantum dans le pourtour du bassin Méditerranéen. Ce parasite dimorphique envahit les macrophages de ses hôtes notamment l'humain et le chien où il est responsable de la maladie. En l'absence de traitement, la leishmaniose viscérale est mortelle et les traitements existants aujourd'hui sont toxiques, coûteux, et font face à l'apparition croissante de résistances.Trouver de nouveaux traitements est donc aujourd'hui une priorité, et ce projet de thèse vise à identifier des alternatives naturelles aux molécules anti-Leishmania. En prenant une approche écologique, nous récupérons des déchets de la parfumerie et des plantes issues de la biodiversité locale et nous en testons les extraits sur les parasites afin d'identifier des composés immunostimulateurs, qui permettraient de favoriser une élimination du parasite par l'hôte. Afin de pouvoir suivre l'évolution au cours du temps d'une infection in vitro et/ou in vivo, nous avons également cherché à créer de nouveaux outils pour visualiser la présence du parasite Leishmania en développant de nouvelles souches rapportrices fluorescentes et bioluminescentes.Au cours de ma thèse, nous avons identifié une plante dont l'extrait favorise l'élimination de la forme amastigote intracellulaire retrouvée dans les macrophages hôtes. A l'aide de nos collaborateurs à l'Institut de Chimie de Nice (ICN), nous avons réalisé un fractionnement bioguidé et obtenu des sous-fractions de cette plante ainsi que des molécules pures capables d'éliminer le parasite Leishmania infantum.Une seule molécule, dont le nom est soumis à confidentialité pour des raisons de dépôt de brevet, a montré un effet sur le parasite intracellulaire, sans montrer de toxicité. Cette dernière module la sécrétion de cytokines de la cellule hôte. Actuellement, l'étude de 20 dérivés structuraux de cette molécule est en cours. Des études préliminaires chez la souris ont permis de montrer que la prise de cette molécule par voie orale, de façon préventive, pouvait diminuer la charge parasitaire dans l'animal.Nous avons en parallèle développé la construction de nouvelles souches rapportrices de Leishmania exprimant la luciférase teLuc, le fluorophore rouge mRuby ou rouge lointain mMaroon1, et des souches exprimant fluorescence et bioluminescence, eFFly-mCherry. Cette dernière construction a été intégrée dans 3 espèces différentes de leishmanies : L. infantum, responsable de leishmaniose viscérale, L. major responsable de leishmaniose cutanée, et L. tarentolae qui est une souche non pathogène pour l'homme
Rôle de MITF et du métabolisme des sphingolipides dans le mélanome cutané by Justine Leclerc( )

1 edition published in 2019 in French and held by 1 WorldCat member library worldwide

Recherche de nouvelles stratégies thérapeutiques ciblant le métabolisme des cellules cancéreuses à l'aide d'un modèle murin de lymphome T déficient pour PTEN by Célia Rosilio( )

1 edition published in 2014 in French and held by 1 WorldCat member library worldwide

Les leucémies aiguës lymphoblastiques et les lymphomes de type T sont des cancers très agressifs, génétiquement hétérogènes. Les pronostics sont globalement défavorables et la survie après rechute n'est que de 10%. Les plus fréquentes mutations ont pour conséquence l'activation constitutive de l'axe PI3K/AKT/mTOR favorisant la progression tumorale. La compréhension des mécanismes de la transformation cancéreuse, à l'aide d'un modèle murin (invalidation spécifique de PTEN dans les lymphocytes T), va permettre de proposer de nouvelles cibles potentielles et de futurs traitements ciblés qui peuvent agir seuls ou en combinaison avec les médicaments chimiothérapeutiques et améliorer le pronostic et la survie des patients. Dans un premier temps, je me suis intéressée au fait de cibler à la fois le métabolisme leucémique élevé et l'activation oncogénique de la voie mTOR en utilisant des activateurs du senseur de stress AMPK : metformin, phenformin et AICAR. Puis, comme il est connu que la concentration en acides aminés intracellulaire influe sur la voie mTOR je me suis intéressée à interférer avec l'action du transporteur d'acides aminés LAT-1, dont le gène slc7a5 est fortement surexprimé dans un grand nombre de cancers dont notre modèle de lymphome T tPTEN-/-. Enfin, je me suis intéressée aussi au rôle de la surrexpression du récepteur de la transferrine (CD71) par les cellules tPTEN-/-, qui suggère que ces cellules cancéreuses pourraient avoir développé une addiction au fer, co-facteur essentiel de nombreux processus métaboliques. Globalement, les résultats présentés dans ce mémoire de thèse démontrent l'intérêt de cibler le métabolisme reprogrammé des cellules cancéreuses
Implication de la voie p53 et du microARN miR-34a dans la résistance à l'insuline adipocytaire by Pierre-Jean Cornejo( )

1 edition published in 2014 in French and held by 1 WorldCat member library worldwide

Dysfunction of adipose tissue in obesity is involved in the development of insulin resistance. Activation of p53 in adipocytes has recently been implicated in insulin resistance in obesity, by unknown mechanisms. MicroRNA miR-34a is involved in the cellular response induced by p53 in different cell types. Among its targets, VAMP2 and Sirt1are two proteins involved respectively in the translocation of glucose transporters (Glut4) and the insulin sensitivity. We show that p53 expression is increased in adipocytes of obese mice. We are seeing an increased number of fat cells with DNA damage and also more damage in adipocytes from obese mice. The induction of DNA damage by doxorubicin and stabilization of p53 by Nutline inhibits glucose transport induced by insulin and the insulin signaling in murine and human adipocytes in vitro. Consistent with the p53 activation in adipocytes in obesity, we show that the expression of miR-34a is increased in the TA and obese mice adipocytes. Overexpression of miR-34a in 3T3-L1 adipocytes inhibits glucose transport in response to insulin, insulin signaling, lipolysis, and increases expression of the mRNA of leptin. We show that the inhibition of the insulin signaling is due to induction of the mRNA and the tyrosine phosphatase PTP1B by miR-34a. Inhibition of lipolysis is accompanied by inhibition of expression of ATGL, the rate-limiting enzyme in lipolysis. Common to all of these effects is the control of the expression of these proteins by Sirt1, a NAD + dependent deacetylase. However, inhibition of expression of miR-34a by Sirt1 can not account for all the observed effects
Implication du facteur de transcription E2F1 dans le mélanome by Florian Rouaud( )

1 edition published in 2015 in French and held by 1 WorldCat member library worldwide

Melanoma is the most deadly form of skin cancer. It originates from malignant transformation of melanocytes and quickly disseminates as metastasis through the body. At this stage, this cancer is refractory to almost all therapies. Thus, new therapeutic target identification is needed for setting up specific biotherapies against melanoma. In this context, we focused on E2F1 transcription factor which plays a critical role in cell cycle. Recently, it was also implicated in several cell functions. So we aimed at characterizing its implication in melanoma. We observed that E2F1 is weakly expressed in normal skin cells. On the contrary, it is strongly expressed in melanoma and its expression correlates with a bad clinical prognosis. We also showed that E2F1 inhibition decreased melanoma cell viability in vitro and in vivo, as a result of cell cycle arrest, senescence and apoptosis. These processes seem to depend on p53 pathway. With this work we characterized E2F1 as a potential therapeutic target in non-mutated p53 melanoma. In parallel, we initiated a collaboration with Dr Slama-Schwok for studying NS1 compound, a NO-synthase inhibitor. This compound presents an in vitro anti-melanoma activity. Indeed, it induces endoplasmic reticulum stress, which leads to partial autophagy and cell death by apoptosis. This work opens new perspectives for metastatic melanoma treatment
 
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Alternative Names
C3M

INSERM U1065

INSERM U895 : Environnement, reproduction et cancers hormonodépendants

INSERM Unité 1065 : Equipe 5 "Environnement, reproduction et cancers hormonodépendants"

Languages
French (17)

English (3)