Conférences 2015

Les Conférences : Année 2015
 

Mercredi 16 décembre 2015 à 10 h 00
Salle de conférences de la Plateforme Génomique Fonctionnelle

Pr Richard Bonnet
Bactériologie – Université de Clermont Ferrand

“Le cancer colorectal : Escherichia coli, l’ ennemi de l’intérieur ?”

Escherichia coli est une bactérie commensale du microbiote intestinal surreprésentée au niveau des tumeurs colorectales. Un lien a été observé entre sa présence et des facteurs de mauvais pronostic. Les souches E. coli observées au niveau de ces tumeurs produisent fréquemment une génotoxine appelée Colibactine, qui favorise la carcinogenèse dans des modèles murins prédisposés. Cette croissance pourrait être soutenue par une sénescence cellulaire responsable de la production de facteurs de croissance induite par les bactéries. En conséquence, il est possible de prévenir la carcinogenèse induite par E. coli avec des molécules « drug-like » ciblant la production de la Colibactine et ainsi, de réduire le nombre de tumeurs colorectales dans un modèle murin de cancer colorectal colonisé par des E. coli producteurs de Colibactine. Au total, ces données suggèrent un nouveau paradigme de la cancérogenèse colique dans lequel E. coli serait un acteur important susceptible d’être pris en compte dans une stratégie de traitement ciblé.

Invitation : Francis Mégraud – Inserm U 853

 

Vendredi 4 décembre 2015 à 11 h 00
Salle de conférences de la Plateforme Génomique Fonctionnelle

Isabelle Maridonneau-Parini
Institut de Pharmacologie et de Biologie Structurale, CNRS UMR5089, Université Toulouse, France

Podosomes: mechanosensory protrusive structures involved in macrophage 3D migration”

Macrophages are immune cells able to migrate in all body tissues. In wounded and infected tissues, they are involved in tissue repair and bactericidal activity. In several pathologies including chronic inflammatory diseases and cancers, tissue infiltration of macrophages stimulates disease progression. It is therefore necessary to identify the molecular and cellular mechanisms that control this process, a step towards identification of pharmacological targets.
Although tissue migration takes place in constrained 3D environments, most of the studies on cell migration have been carried out in 2D environments. We have reported that macrophages can use two 3D migration modes. The choice of the migration mode is dictated by the architecture of the extracellular matrix (ECM): the amoeboid mode (ROCK-dependent) takes place in porous ECM, a migration mode shared by all leukocytes, and the mesenchymal mode (protease-dependent), which takes place in dense matrices, is mostly macrophage-specific.
Podosomes are actin-rich structures with adhesion and proteolytic activities constitutively formed in a few cell types including macrophages. We have obtained evidence that podosomes play a critical role in the mesenchymal migration while they do not form in the amoeboid migration. Actually, interfering with podosome effectors specifically inhibits the mesenchymal migration. We have shown that podosomes exert localized protrusive forces on the ECM through actin polymerization and actomyosin contractility. The rigidity of the ECM influences the force generated by podosomes and the density of podosomes, indicating that these cell structures are mechanosensors. The role of podosome components in the process of force generation and their respective positioning at nanoscale range are under investigation with the aim to determine the force/architecture relationship.

Invitation : Frédéric Saltel et Julie di Martino – GREF Inserm U 1053

 

Jeudi 26 Novembre 2015 à 11 h 00
Salle de conférences de L’IBGC

Thibaud Renault
Helmholtz Center for Infection Research Infection Biology of Salmonella
Braunschweig, Germany

“BAX, mitochondries et apoptose : une question de taille…”

La voie mitochondriale de l’apoptose, déclenchée par exemple en réponse à un stress cellulaire, atteint un point de non-retour lors de la perméabilisation de la membrane mitochondriale externe. Cette étape, principalement régulée par les protéines de la famille BCL-2, est également dépendante de facteurs intrinsèques à la mitochondrie, parmi lesquels on peut citer la composition lipidique de la membrane externe. L’étude systématique de la perméabilisation mitochondriale dans un modèle de stress du réticulum endoplasmique a permis de mettre en évidence que le déclenchement de l’apoptose requiert une taille optimale des mitochondries.
En utilisant des approches complémentaires (modèles animaux, cellulaires, mitochondries isolées et vésicules) nous avons démontré que la courbure de la membrane mitochondriale externe influence directement l’activation de BAX, un membre pro-apoptotique de la famille BCL-2.
Cette découverte revêt un intérêt particulier dans la compréhension des mécanismes de résistance à l’apoptose des cellules cancéreuses présentant un réseau mitochondrial hyper-fragmenté. Nos résultats indiquent qu’en modulant pharmacologiquement la taille des mitochondries de ces cellules, il est possible de restaurer l’activation de BAX, et le déclenchement de l’apoptose.

Invitation : Stephen Manon – IBGC CNRS UMR 5095

 

Mardi 24 Novembre 2015 à 14 h 00
Salle de conférences de l’IBGC

Victor Appay
Immunity and Infectious Diseases Research Center (CIMI-Paris), INSERM U1135, Pierre et Marie Curie University, DHU FAST, Paris, France

Causes and Consequences of Cellular Immune Aging in Humans”

Life expectancy in Europe has nearly doubled over the last century, however aging is associated with impaired vaccine efficacy and increased susceptibility to infectious and malignant diseases. This is most likely related to the decline of the immune system with age, or immunosenescence. A better understanding of the causes and consequences of immune aging is therefore a public health priority. In recent years, we have characterized cellular immune compartments in the elderly, exploring putative causes of their decline in relation to elevated inflammation and chronic viral infections, and studying potential consequences on cellular immune competence with advanced age. Elderly humans exhibit a skewed distribution of ab T-cell, gd T-cell as well as NK cell subsets, with increased proportions of highly differentiated old cells. Systemic and chronic inflammation emerges as a major driver of these alterations. Some of these immunological changes are in part related to CMV infection and the induction of strong CMV-specific cellular responses, independently of age. Old individuals display also an altered hematopoiesis and decreased lymphocyte replenishment associated with an exhaustion of primary immune resources (down to the level of hematopoietic progenitors). Although the naïve T-cell compartment undergoes increased homeostasis with old age, this is insufficient to sustain a quantitatively and qualitatively adequate naïve T-cell compartment in the elderly. Using an original in vitro approach to examine CD8+ T-cell priming efficacy in humans, we actually show that old individuals consistently mount impaired de novo CD8+ T-cell responses against a melanoma antigen, which likely reflects reduced pre-immune competence against cancer.

Invitation : Julie Dechanet-Merville – CIRID CNRS UMR 5164

 

Mardi 17 novembre 2015 à 11 h 00
Salle de conférences de la Plateforme Génomique Fonctionnelle

Bruno Lemaître
Global Health Institute, Ecole Polytechnique Fédérale of Lausanne, Lausanne, Switzerland

Drosophila immunity: an overview”

The application of Drosophila genetics to these mechanisms has generated insights into insect immunity and uncovered general principles of animal host defense. These studies have shown that Drosophila has multiple defense “modules” that can be deployed in a coordinated response against distinct pathogens. Today, Drosophila can be considered as having one of the best-characterized host defense systems among the metazoan. This seminar will provide an overview of the Drosophila immune responses underlining new findings and questions.

Invitation : Thomas Pradeu – CIRID UMR CNRS 5164


Mardi 10 Novembre 2015 à 11 h 00

Salle de conférences de la Plateforme Génomique Fonctionnelle

Brooke Moriswood
Department of Cell and Developmental Biology, Würzburg – Germany

“The real flux capacitor? A putative molecular valve in trypanosomes”

The African trypanosome is a unicellular monoflagellated parasite that dwells in the bloodstream of infected mammalian hosts, in continuous exposure to the adaptive immune response. It relies on an extremely high rate of endocytosis in order to take up and degrade antibodies bound to the glycoproteins that shield its surface. All endocytic traffic occurs however at only a single point on its plasma membrane – an invagination containing the base of the flagellum termed the flagellar pocket. Clustered around the neck of the flagellar pocket on its cytoplasmic face are a number of cytoskeletal complexes, one of which (the hook complex) is the focus of this presentation. Depletion of the hook complex component TbMORN1 results in a striking phenotype in which protein access to the flagellar pocket is apparently impaired, suggesting that it may function as a kind of molecular valve.

Invitation : Derrick Robinson – CNRS UMR 5234

 

Vendredi 6 novembre 2015 à 11 h 00
Salle de conférences de l’IBGC

Régis Meyer
Research Assistant Member, Oklahoma Medical Research Foundation, Cell Cycle and Cancer Biology Department, Oklahoma CIty, USA

“Understanding the chromosome segregation machinery and genomic instability using yeast as a model”

Most solid tumors share two hallmarks that could be targets for cancer therapy: Chromosomal instability (CIN) and aneuploidy, with tumor cell karyotypes ranging from 40 to 90 or more chromosomes. CIN is defined by elevated frequencies of whole-chromosome missegregation that can lead to aneuploidy, an abnormal number of chromosomes. The cause of the observed chromosome imbalances is still unknown, but can likely be found in defects in the processes that control chromosome segregation during cell division. Studies of chromosome segregation machinery have already uncovered a plethora of novel proteins that have some of which have already been used as early markers of cancer and/or are targets for anti-tumor drug development programs. Among those actors, the conserved kinases Mps1 and Aurora-B, which is one of the most commonly over-expressed proteins in tumors with aneuploidy/CIN, are both promising target for cancer therapy. Both are implicated in several aspects of chromosome segregation in mitosis and meiosis. In particular, these two kinases are involved in promoting the proper alignment of chromosomes (bi-orientation) on the spindle. This process is achieved during a multistep process that involves the release and reattachment of kinetochore-microtubule connections that would lead to chromosome segregation errors. Although both kinases are known to be required to bi-orient chromosomes, their precise functions and relationship was unclear when I started my project. In order to elucidate the functions of Aurora-B and Mps1 in chromosome alignment (prometaphase), I developed a unique and simple system that takes advantage of specific features of budding yeast, the power of its genetics, and sophisticated live cell imaging. I identified a previously under appreciated aspect of the chromosome-kinetochore attachment process and for the 1st time, I clearly separated the function of Aurora-B and Mps1 in this process: Aurora-B is required for releasing incorrect attachments, whereas Mps1 is required to promote new force-generating attachments. These findings give us the opportunity to refine the search for future cancer therapies that will target the chromosome re-orientation process in somatic cells.

Invitation : Bertrand Daignan-Fornier

 

Jeudi 22 octobre 2015 à 11 h 00
Salle de conférences de l’IBGC

Fabrice Gouilleux
Génétique, Immunothérapie, Chimie et Cancer  (GICC)  – Equipe LNox  CNRS : UMR7292, Université François Rabelais – Tours

“STAT5 signalling and oxidative stress in leukemia cells : a Ying/Yang effect ?”

STAT5 transcription factors are frequently activated in hematopoietic neoplasms and are targets of various tyrosine kinase oncogenes. Evidences for a crosstalk between STAT5 and Reactive Oxygen Species (ROS) metabolism have recently emerged but conflicting roles of STAT5 as a ROS regulator have been reported. Using leukemia cell lines and mouse models, we provide evidence that tyrosine phosphorylation acts as a switch to convert a non-phosphorylated STAT5 with antioxidant properties to a phosphorylated and pro-oxidant molecule. We demonstrate that sustained activation of STAT5 in Chronic Myeloid Leukemia (CML) cells promotes ROS production by repressing expression of two antioxidant enzymes, catalase and glutaredoxin1. Catalase was shown not only to reduce ROS levels in CML cells but also to induce quiescence. Quiescence was also evidenced when CML cells were co-cultured with bone marrow stromal cells used as an in vitro microenvironment model and was accompanied by a reduction of STAT5 phosphorylation and upregulation of catalase and glutaredoxin1. These data support a dual role of STAT5 in the regulation of ROS production and highlight the repression of antioxidant defenses as an important regulatory mechanism.

Bourgeais, J., Gouilleux-Gruart, V., & Gouilleux, F. (2013).Oxidative metabolism in cancer: A STAT affair? Jak-Stat, 2(4), e25764
Cholez, E. et al. (2012). Evidence for a protective role of the STAT5 transcription factor against oxidative stress in human leukemic pre-B cells. Leukemia, 26(11), 2390–7.
Bourgeais, J. et al. Oncogenic STAT5 signalling promotes oxidative stress by repressing antioxidant defenses (submitted)

Invitation : Vincent Praloran – CIRID UMR CNRS 5164

 

Mardi 13 octobre 2015 à 11 h 00
Salle de conférences de l’IGBC

Milos R. Filipovic
Friedrich-Alexander University Erlangen-Nuremberg and
IBGC UMR5095, Université de Bordeaux

“Hydrogen sulphide is a new gasotransmitter in control of health and disease”

Signalling by gasotransmitters started attracting a lot of attention three decades ago, when nitric oxide (NO) was initially discovered. Recently another gaseous molecule produced in our body, hydrogen sulphide (H2S), started emerging as important regulator of different physiological functions. Made by the action of at lest three enzymes, H2S constitutes essential part of vasodilatory mechanisms but it also acts as immune-modulator and neurotransmitter, among other functions. Furthermore its pharmacological potential in treating a plethora of disease models has been documented. The mechanisms of its action(s), however, remained largely unidentified. Using a multidisciplinary approach of combining chemistry with physiology we characterized the three main reaction pathways by which H2S can affects cellular processes: (i) cross-talk with nitric oxide and other reactive oxygen and nitrogen species, (ii) reaction with important metalloenzymes and (iii) reversible modification of cysteine residues. We provide evidence for the formation of new redox-active signalling molecules formed in the cross-talk of NO and H2S, which then activate transient receptor potential A1 (TRPA1) channels expressed in sensory nerve endings. This activation leads to the release of calcitonin gene-related peptide (CGRP) and neuro-regulation of local and systemic blood pressure. Furthermore, we developed a new chemical tool to label and detect the H2S-induced oxidative post-translational modifications of cysteine, widely called as S-sulfhydration of persulfidation. Our studies identify the mechanisms and conditions under which S-sulfhydration in the cells can occur. More importantly we identified the enzyme which can act as “de-persulfidase”, controlling the levels of protein persulfidation. This makes regulation of cell signalling through “persulfidation/depersulfidation” quite similar to the phosphorylation/dephosphorylation. Heme centers in mitochondria, in particular cytochrome c, have shown potential to act as mediators of protein S-sulfhydration where in combination with cytochrome c oxidase they form a pseudo-enzymatic complex that acts as a “persulfidase”. Finally, the role of protein persulfidation in progressive neurodegenerative disease, spinocerebellar ataxia 3 (SCA 3) has been addressed. Our study indicates that in the Drosophila model of SCA 3, levels of persulfidation drop dramatically and can be rescued by overexpressing H2S producing enzyme. As a result, this overexpression also leads to partial rescuing of SCA 3 phenotype in these flies. Broader consequences of all these pathways and their physiological and pharmacological significance will be discussed.

Invitation : Bertrand Daignan-Fornier – IBGC UMR 5095


Séminaire Philosophie & Biologie
Organisé par Thomas Pradeu & Cédric Brun
Avec le soutien du programme HEADS (http://heads.u-bordeaux.fr/en/)

MKenneth Gemes
Professor of Philosophy Birkbeck College, University of London

http://www.bbk.ac.uk/philosophy/our-staff/academics/gemes

Nietzsche’s Notion of Health”

 It is widely known that Nietzsche take himself to present a tremendous challenge to conventional morality.  Many of his interpreters have been exorcised in trying to make precise the nature of that challenge.  Here the attention has focused largely on the question of how his genealogical accounts of morality amount to a genuine challenge, rather than an instance of the genetic fallacy.  Less attention has been paid to Nietzsche’s claim that morality involves a kind of pathology.  This talk aims to expose some of the bases of Nietzsche’s idea  about health and how they relate to his attacks upon morality and how they connect with his own positive values.  Beyond Nietzsche scholarship this project aims to show us perspectives from which we might question are own accounts of health and values, both individual and social.

Invitation : Andreas Bikfalvi – Inserm U 1029


Mercredi 8 juillet 2015 à 14 h 00
Salle de conférences de la Plateforme Génomique Fonctionnelle

Walid Rachidi
Univ. Grenoble Alpes / CEA Grenoble, INAC-LCIB-LAN

Laboratoire Lésions des Acides Nucléiques

“Conséquences des lésions à l’ADN induites par différents agents génotoxiques et réponses des systèmes de réparation.”

Les conséquences biologiques des lésions de l’ADN dépendent de plusieurs facteurs : la nature de l’agent génotoxique (pro-oxydant ou non), de sa dose, de la nature des cellules cibles (proliférantes, différenciées, souches, hors cycle cellulaire…), de la capacité de réparation des cellules cibles et de leur état physiologique (vieillissement, stress oxydant…). En effet, une cellule qui subit l’action d’un agent génotoxique, va essayer de maintenir l’intégrité de son ADN par une augmentation ou une stimulation ciblée des capacités de réparation des dommages induits par l’agent génotoxique en question. Diverses voies sont impliquées selon la nature du dommage : l’élimination des lésions volumineuses induisant une distorsion de l’ADN (dimères de pyrimidines…) nécessite l’intervention de la voie NER (réparation par excision des nucléotides) alors que les petites lésions oxydatives ou les cassures simple brin sont prises en charge par le système BER (réparation par excision de base)..Cependant, certains types de dommages peuvent échapper à la réparation et conduire, après plusieurs divisions cellulaires, à des mutations au niveau des gènes clés (proto-oncogènes ou gènes suppresseurs des tumeurs) et par conséquent à l’apparition des cancers. Enfin, si le taux de dommages est très important et que les systèmes de réparation sont débordés, l’apoptose sera mise en place afin d’éliminer les cellules lésées. L’excès de l’apoptose peut conduire à un vieillissement accéléré ou encore à des maladies neurodégénératives.
Dans cette conférence, Je vous parlerai des conséquences biologiques des dommages à l’ADN induits par différents agents génotoxiques (rayonnements ionisants, UVA, UVB…) au niveau des populations cellulaires spécifiques (cellules souches qui sont les cibles majeures des cancérigènes, cellules âgées avec une faible capacité de réparation, cellules hypersensibles aux agents genotoxiques…). Ces modèles nous ont permis d’amplifier  les réponses cellulaires aux agents génotoxiques. De plus, je vous exposerai les méthodes spécifiques et les outils innovants développées au sein de notre laboratoire, « Lésions des acides nucléiques » pour quantifier et les dommages à l’ADN (chromatographie liquide haute performance couplée à la spectrométrie de masse en mode tandem (CLHP-SM/SM)) et mesurer les activités de réparation de l’ADN dans les extraits tissu
laires et cellulaires (biopuces fonctionnelles).

Invitation : Hamid Rezvani (Inserm U 1035)


Jeudi 18 juin 2015 de 09 h 00 à 18 h 00
Salle de conférences de la Plateforme Génomique Fonctionnelle

Journée Jeunes Chercheurs

Pour la neuvième année, les doctorants de la FR TransBiomed (TBM Doc’s) organisent la Journée Jeunes Chercheurs (JJC) de la FR TransBioMed le 18 juin 2015 à la plateforme Génomique Fonctionnelle. Cette journée basée sur le thème de la convivialité permet aux étudiants en master, doctorat, post doctorat et aux statutaires de se retrouver et de discuter autour des projets des jeunes chercheurs de la FR. Cette année le thème abordé en conférence plénière sera les brevets. Pour cela deux intervenants Lucile Tran, travaillant à Aquitaine Science Transfert, et Hamid Reza Rezvani, chercheur à l’unité Inserm U1035 ayant récemment déposé un brevet, viendront parler de leurs parcours et de leurs expériences sur les brevets.

Le comité d’organisation lance un appel à participation (communications orales et posters) pour les masters, doctorants et post-doctorants. La participation aux communications orales vous offre la possibilité de présenter vos travaux à un public de jeunes chercheurs ainsi qu’aux statutaires. Vous pouvez également choisir de présenter vos résultats sous forme de poster lors de sessions qui y seront dédiées. Comme chaque année, nous décernerons le prix de la meilleure communication orale et du meilleur poster.

Si vous souhaitez participer à cette JJC et proposer une communication orale ou un poster, cliquez sur le lien suivant pour vous inscrire (Inscription gratuite mais obligatoire) et nous vous transmettrons rapidement le programme de la journée.


Mardi 16 juin 2015 à 11 h 30
Salle de conférences de l’IBGC

Arnaud Jacquel
Mediterranean Center for Molecular Medicine,

C3M/INSERM U1065 / Cell Death, Differentiation, Inflammation and Cancer Team, Nice, France

“A role for autophagy in the differentiation of human monocytes into macrophages”

The differentiation of human blood monocytes into macrophages is a caspase-dependent process when triggered ex vivo by Macrophage Colony Stimulating Factor / Colony Stimulating Factor 1 (M-CSF/CSF-1). Autophagy is the process by which long-lived, superfluous or damaged macromolecules and organelles are degraded by the lysosome for recycling. Pharmacological and genetic evidence indicate that autophagy plays pleiotropic functions in development, cellular homeostasis, survival, cell death and differentiation. It has been also reported that many differentiation processes including megakaryocyte and erythrocyte differentiation require both caspase activation and autophagy induction. However, the role of autophagy in the differentiation of monocyte into macrophages, while suspected, has not been investigated in detail. In this context, we have previously shown, using pharmacological inhibitors, si-RNA approaches and Atg7-/- mice, that autophagy initiated by ULK1 is required for CSF-1-driven differentiation of human and murine monocytes into macrophages. We have also unraveled a major role for autophagy in macrophage acquisition of phagocytic functions. At this meeting, I will present evidence that the CaMKKb-AMPKa1-ULK1 pathway is required for CSF-1-induced autophagy and human monocyte differentiation and that this pathway links P2Y6 receptor engagement to the induction of autophagy. I will also depict the signalling network that connects the CSF-1 receptor to P2Y6-mediated autophagy and monocyte differentiation. Finally, I will show that the physiological P2Y6 ligand UDP and P2Y6 agonists can restore efficient monocyte differentiation through re-induction of autophagy in primary myeloid cells from Chronic Myelomonocytic Leukemia (CMML) patients. Collectively, our findings highlight an essential role for P2Y6-mediated autophagy during differentiation of human monocytes into macrophages and pave the way for future therapeutic interventions for CMML.

Invitation : Mojgan Mergny (Inserm U 916)


Jeudi 11 juin 2015 à 11 h 00
Salle de conférences de l’IBGC

Eric Muraille
Laboratoire de Parasitologie

Faculté de Médecine/Université Libre de Burxelles – Belgique

“Le système immunitaire: pierre angulaire de l’auto-organisation du vivant”

Les métazoaires, des plus simples aux plus complexes, abritent une importante flore commensale, la microbiota. Celle-ci est souvent indispensable au métabolisme de l’hôte, à ses défenses immunitaires et parfois même à sa reproduction. Si l’hôte est indissociable de sa microbiota et forme avec elle un consortium, comment s’opère la distinction entre le soi et le non soi au sein de ce consortium? Comment la coopération entre les éléments du consortium peut-elle être stabilisée et protégée de l’exploitation par des parasites? Quelles sont les conséquences de la gestion de la coopération sur l’organisation du vivant ? Telles sont les nouvelles questions fondamentales auxquelles doit répondre la biologie moderne.

Invitation : Sven Saupe (IBGC CNRS UMR 5095)


Jeudi 4 juin 2015 à 14 h 00
Salle de conférences de la Plateforme Génomique Fonctionnelle

Carlo Chizzolini
Immunologie – Genève

“Contribution of the immune response to the pathogenesis of systemic sclerosis”

Systemic sclerosis (SSc) or scleroderma is a rare disease of unknown origin characterized by fibrosis (thickening) of the skin and internal organs associated with abnormalities of the blood vessel and the immune system. No cure is available for SSc and its prognosis varies according to disease subset, being relatively benign in SSc with limited skin involvement and worse in individuals with diffuse skin, lung and cardiac involvement. In these patients the quality of life is severely reduced and life expectancy is shortened. SSc carries high direct and indirect costs and profoundly impact on the social life of affected persons and their relatives. The dysregulated interplay between several cell types including endothelial cells, fibroblasts and cells of the immune system is thought to lead to the cardinal features of the disease. It is likely that inflammatory events participate to SSc physiopathology and in particular to fibrosis development. This could be achieved by an excessive activity of factors that enhance fibrosis and/or by defective inhibitory mechanisms. In recent years we have focused our attention to the contribution of T lymphocytes (cells of the immune system) to SSc pathogenesis and have found that profound alterations in the function of T cells characterize SSc. Some of the altered function we described may directly lead to enhanced fibrosis. Others remain more obscure. In particular, we have observed that T cells producing the inflammatory mediators named interleukin-17 (IL-17) and IL-22 are increased in SSc. Their impact on fibroblast metabolism is the current focus of our interest.

Invitation : Marie-Elise Truchetet (CNRS UMR 5164)

 

Programme du réseau Hôte-Pathogène

Réunion du Vendredi 29 mai 2015 à 14 h 00

Salle de réunion de l’U 1026 INSERM Bioingéniérie tissulaire de Joëlle Amédée, 3A-4A  2ème étage

 « La protéine d’inclusion cylindrique (CI): un facteur viral clé dans l’adaptation du virus de la mosaïque de la laitue à la résistance conférée par eIF4E ». Sylvie German-Retana – UMR BFP 1332 – INRA Biologie du Fruit et Pathologie, Equipe de Virologie.

« Perturbation d’une interaction hôte-pathogène commune: Ubiquitine ligase Nedd4 – motif viral PPxY». Sisley AustinUMR 5234 – Dynamique intracellulaire des structures sous virales.

 « Etude de la séquence d’insertion IS1294 et de son implication dans la dissémination des gènes de résistance aux antibiotiques chez les entérobactéries ». Haytham Yassine –  UMR 5234 – Variabilité, réplication et mobilité des génomes viraux et bactériens.

« Rôle de la voie Hippo dans la signalisation oncogenique induite par H. pylori dans la carcinogenèse gastrique ». Silvia Molina-Castro – Inserm U853 – Infection à Helicobacter, inflammation et cancer.

 

Jeudi 21 mai 2015 à 11 h 00
Salle de conférences de la Plateforme Génomique Fonctionnelle

Franck Gallardo, PhD.
CEO, NeoVirTech SAS
Advanced Technological Institute for Life Sciences
1 place Pierre Potier, Oncopole TOULOUSE

“From visualization of DSB dynamics to viral DNA replication in vivo, use of the ANCHORTM technology for next generation High Content Screening and deep in-cell localization”.

           
Currently available DNA visualization tools are based on the use of numerous clustered bacterial operator repetitions bound by a specific repressor-fluorescent protein fusion to detect the position of a specific DNA sequence. Even if these systems allow detection of chromosome dynamics in vivo, they present major practical and biological constraints (size, repetitive nature, gene silencing reinforcement, fragile site creation).
We have developed a new system, called ANCHORTM, that allows for the first time direct visualization of DNA metabolism and replication.  We have successfully used this system to detect DNA double strand break (DSB) resection following the induction of a single DSB. Moreover, proof of concept experiment has shown that this system can be used to detect highly replicative and highly mobile structures such as viruses. The ANCHORTM technology has been optimized over the last years to convert various viral DNAs into replicative autofluorescent viruses. ANCHORTM labeled viruses allow for the first time visualization and quantification of the viral cycle in living cells. Applications for HCS campaign and deep in cell localization will be presented, which pave the way for rapid and robust next generation screening for the discovery or repositioning of active antiviral molecules.

Invitation : Harald Wodrich (CNRS UMR 5234)


Mardi 19 mai 2015 à 11 h 00
Salle de conférences de la Plateforme Génomique Fonctionnelle

Steeve Boulant
Department of Infectious Diseases,
Virology Heidelberg University Schaller research group at CellNetworks German Cancer Research Center (DKFZ)
Heidelberg Germany

“Viral infection of human intestinal epithelial cells, a battle between viral and cellular strategies.”

Intestinal epithelial cells (IECs) constitute the primary barrier that separates us from the outside environment. IECs are structurally polarized, with an apical side facing the lumen of gut containing the microbiota and a basolateral side facing the “sterile“ lamina-propia. Interestingly, instead of generating an inflammatory response against the commensal flora, IECs have developed mechanisms to tolerate the presence of these microorganisms. This complex interaction between the microbiota and the IECs appears to be key to maintain gut homeostasis and functions. However the mechanisms remain to be characterized.

In this seminar, I will present recent unpublished data from the lab showing that IECs are able to distinguish between enteric virus infections emanating from the apical vs. basolateral side adapting their innate immune response. If infection emanate from the luminal side, moderate response is generated. On the contrary, if infection initiates from the basal membrane side, indicative of loss of epithelial barrier function, response of IECs leads to stronger inflammatory response. I will propose a model where by evaluating the quality of the epithelial barrier, IECs can tailor their innate immune response and this mechanism would be the foundation of gut homeostasis establishment and maintenance.

Invitation : Harald Wodrich (CNRS UMR 5234)


Mardi 12 mai 2015 à 11 h 00
Salle de conférences de la Plateforme Génomique Fonctionnelle

Pr Stephane Dedieu
UMR CNRS 7369, Unité MEDyC, Matrice Extracellulaire et Dynamique Cellulaire,
Campus Moulin de la Housse, BP1039, 51687 Reims Cedex 2, France.

“The endocytic receptor LRP-1 as a versatile integrator of extracellular signals from tumor microenvironment”.

Low-density lipoprotein receptor-related protein-1 (LRP-1) is a large multifunctional endocytic receptor mediating the clearance of various biological molecules from the extracellular matrix (ECM). In the tumor context, LRP1-mediated endocytosis was first reported to decrease the accumulation of extracellular proteinases (matrix metalloproteinases, serine proteases) and to reduce the excessive remodeling of the ECM. LRP-1 was then widely associated to anti-tumor properties during the past decade and suggested as an attractive receptor for targeting the invasive behavior of malignant cells. However, the real functionalities connected to LRP-1 appear now much more complex and multifaceted. Using a long-term vector-based short hairpin RNA strategy against LRP-1, we indeed demonstrated that LRP-1 silencing prevents carcinoma cell invasion, despite the high accumulation of proteolysis events associated to the tumor microenvironment. Evidence is now accumulating to consider an emerging model in which LRP-1 could constitute a subtle sensor of tumor environment that may coordinate the adhesion-deadhesion balance of malignant cells to support tumor progression. Through this seminar, I will present the main results from my research group that have increased our understanding on how LRP-1 contributes to cancer-related events and have strengthened the molecular knowledge of the integrated functional relationships between LRP-1-mediated endocytosis and signaling to control cell-matrix interactions.

Invitation : Clotilde Billotet (Inserm U 1029)

 

Mercredi 6 mai 2015 à 11 h 00
Salle de conférences de l’IBGC

Bram Flahou
Department of Pathology, Bacteriology and Avian Diseases, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium

“Pathogenesis and significance of gastric non-H. pylori Helicobacter infections in animals and humans.”

Besides the well-known gastric pathogen Helicobacter pylori, other helicobacters with typical spiral morphology have been detected in a minority of human patients presenting for upper gastrointestinal endoscopy. This group of non-H. pylori helicobacters (NHPH) includes gastric Helicobacter species colonizing the stomach of carnivores and H. suis, naturally colonizing the stomach of pigs. In this animal species, infection causes chronic inflammation and a decrease of the daily weight gain. Moreover, it predisposes animals to the development of ulcers of the non-glandular pars oesophagea of the stomach. Besides pigs, several nonhuman primate species harbour H. suis, and they are most likely the ancestral source of H. suis infection in pigs.
H. suis infection causes a Th17/Treg response in rodent models of human gastric disease, accompanied by a Th1/Th2 component in Mongolian gerbils and mice, respectively. In addition, a strong upregulation of CXCL-13 is observed, which may in part be responsible for the development of MALT lymphoma(-like lesions), indeed observed in long-term infected Mongolian gerbils as well as humans infected with gastric non-H. pylori Helicobacter species. This contrasts to more pronounced epithelial-cell related dysplastic changes seen during H. pylori infection, finally leading to the development of gastric adenocarcinoma.
Besides a pronounced inflammatory response, H. suis and other gastric NHPH have a remarkable tropism for acid-secreting parietal cells, which may show signs of degeneration and dysfunction. Often, this leads to alterations in gastric acid secretion. H. suis and other gastric NHPH lack homologues of several known H. pylori virulence factors such as the cagPAI and VacA. Recently, we have identified H. suis GGT as one of the key cell death-inducing factors, mainly trough degradation of 2 important substrates: glutamine and glutathione. Through degradation of reduced glutathione into its degradation products, H. suis (and H. pylori) GGT causes an increase of extracellular H2O2 concentrations, leading to cell death, including apoptosis and necrosis/oncosis. Recent research in our department has shown that H. suis GGT is also a key factor in the generation and modulation of host immune responses, by influencing lymphocyte proliferation, cytokine secretion and homeostasis of the mucosal epithelium. In vivo supplementation to Helicobacter-infected animals of the GGT substrates glutamine and glutathione strongly affects the outcome of the infection.
In conclusion, the possible involvement of NHPH, including H. suis, should not be neglected in humans and animals suffering from gastric disease.

Invitation : Philippe Lehours (Inserm U 853)

 

Mardi 5 mai 2015 à 11 h 00
Salle de conférences de l’IBGC

Emma Josefsson
Laboratory Head – The Walter and Eliza Hall Institute of Medical Research
Cancer & Haematology Division – Australia

“Regulation of Megakaryocyte and Platelet Survival”

Platelets play essential roles in haemostasis, wound healing and a range of other processes. Their number is tightly controlled within narrow physiological ranges through a dynamic balance between platelet production and consumption/clearance rates. Megakaryocytes in the bone marrow produce around 100 billion platelets per day. Since the majority of platelets are not being consumed in haemostatic processes in a healthy individual, the regulation of their survival time is critical. Recent work has demonstrated that BCL-2 family proteins control the survival of megakaryocytes and platelets. We recently challenged a prevalent paradigm to show that neither intrinsic nor extrinsic apoptosis in megakaryocytes are required for platelet production, but rather need to be restrained in order for them to develop and survive. We have identified megakaryocyte survival to be co-ordinately regulated by pro-survival proteins Mcl-1 and Bcl-xL and our studies have provided the first clear view of the morphological features of acute apoptotic death in megakaryocytes in vivo. Importantly, the apoptotic death machinery can be triggered in megakaryocytes by chemotherapy treatment and by viral infection, providing mechanistic insights into chemotherapy- and virus-induced thrombocytopaenia.

Invitation : Muriel Priault (CNRS UMR 5234)

 

Mardi 21 avril 2015 à 14 h 00
Salle de conférences de la Plateforme Génomique Fonctionnelle

Olga Dolnik
Dr. rer. physiol Institut für Virologie – Marburg

“Host cell factors involved in Marburg virus nucleocapsid transport”

Filoviruses, including Ebola (EBOV) and Marburg viruses (MARV), are endemic in central Africa and cause hemorrhagic fever in humans and non-human primates, with high lethality. Since the first documented outbreak 1968 of MARV in Europe we are faced now the biggest EBOV outbreak in West Africa with more than 25.000 cases and 10.000 death. Presumably, the disease severity primarily depends on the response of host-cell factors interacting with viral proteins. The understanding of this interactions is therefore fundamental for the development of antivirals. We used therefore reverse genetics to generate a recombinant MARV encoding a nucleoprotein (NP), a major component of the viral nucleocapsid, with a mutated PSAP late domain motif, which has previously been shown to mediate interaction with the cellular ESCRT protein Tsg101. We found that the PSAP-mediated interaction with Tsg101 was important at several steps of MARV assembly before viral fission. Interestingly, IQGAP1, an actin cytoskeleton regulator which interacts with Tsg101, was also recruited to nucleocapsids in dependence of the PSAP late domain. Using live cell imaging we show that the interaction of NP with Tsg101 not only impacts viral budding at the plasma membrane but also nucleocapsid transport through the cytoplasm.

Invitation : Harald Wodrich (CNRS UMR 5234)

 

Mercredi 15 avril 2015 à 15 h 00
Salle de conférences de la Plateforme Génomique Fonctionnelle

Amélie Bigorgne
Centre d’Immunologie et des Maladies Infectieuses (CIMI), UPMC Inserm U1135
Faculté de Médecine Pierre et Marie Curie, Pitié-Salpétrière

“Structure et fonction des cellules épithéliales du foie et de l’intestin :
Partir de l’immunologie pour comprendre l’interaction avec les composants bactériens
Ou le maintien de la polarité apico-basale”

Les cellules épithéliales constituent une première ligne de défense entre le milieu extérieur et le milieu intérieur, et un déséquilibre de l’homéostasie met en péril leurs nombreuses fonctions (barrière, transport, sécrétion).
L’inflammation du foie au cours de l’obésité et les maladies inflammatoires chroniques de l‘intestin, prédisposant notamment au cancer, représentent des priorités en terme de santé publique. Dans la survenue de ces maladies, le déséquilibre immunologique et le remodelage des cellules épithéliales sont des éléments clé qui impliquent des régulations encore mal connues.

En partant d’une part d’un modèle d’inflammation du foie au cours de l’obésité et d’autre part d’un déficit immunitaire combiné associé à une atrésie intestinale multiple (MIA-CID), j’ai pu identifier des mécanismes qui sous-tendent l’interaction des cellules épithéliales du foie avec les composants bactériens du tube digestif, et le maintien de la polarité apico-basale de l’intestin, respectivement.

Bigorgne AE, Farin HF, Lemoine R, Mahlaoui N, Lambert N, Gil M, Schulz A, Philippet P, Schlesser P, Abrahamsen TG, Oymar K, Davies EG, Ellingsen CL, Leteurtre E, Moreau-Massart B, Berrebi D, Bole-Feysot C, Nischke P, Brousse N, Fischer A, Clevers H, de Saint Basile G. TTC7A mutations disrupt intestinal epithelial apicobasal polarity. J Clin Invest. 2014 Jan;124(1):328-37.

Bigorgne AE, Bouchet-Delbos L, Naveau S, Dagher I, Prévot S, Durand-Gasselin I, Couderc J, Valet P, Emilie D, Perlemuter G. Obesity-induced lymphocyte hyperresponsiveness to chemokines: a new mechanism of Fatty liver inflammation in obese mice. Gastroenterology. 2008 May;134(5):1459-69.

Mots-clé : Obésité, inflammation, chimiokines, foie, intestin, LPS, antibiotiques. Maladie génétique rare, déficit immunitaire, organoides intestinaux, polarité apico-basale

Invitation : Jean Rosenbaum (U 1053)

 

Mardi 7 avril 2015 à 11 h 00
Salle de conférences de la Plateforme Génomique Fonctionnelle

Pr Catherine Muller-Staumont
Equipe Microenvironnement, Cancer et Adipocytes – Institut de Pharmacologie et de Biologie Structurale, CNRS
UMR 5089, 205 route de Narbonne, BP 64182, F-31077 Toulouse, France

“Adipocytes et cancer : une relation risquée !”

Invitation : Jean-Max Pasquet (U 1035)


Mardi 31 mars 2015 à 11 h 00
Salle de conférences de l’IBGC

Emmanuelle Fabre
Chromosome Biology and Dynamics Group
Hôpital Saint Louis – UMR INSERM 944, CNRS 7212, IUH – Paris

“Chromosome dynamics in budding yeast : what roles for actin ?”

During vegetative growth, chromosomes undergo movements that have implications for functions, such as DNA repair, but whose origin remains unclear.

Fluorescence microscopy, image analyses and chromosome conformation capture have helped us to decipher the contribution of actin on chromosomal movements and organization in budding yeast. I will also discuss some functional outcomes of chromosome dynamics.

Invitation : Isabelle Sagot (IBGC CNRS UMR 5095)


Jeudi 19 mars 2015 à 11 h 00
Salle de conférences de l’IBGC

Iban Seiliez
INRA, UR1067 Nutrition, Métabolisme, Aquaculture (NuMeA)
F-64310 Saint Pée sur Nivelle, France

“Nutritional regulation of autophagy: insights from fish”

Autophagy functions as an important catabolic mechanism by mediating the turnover of intracellular organelles and protein complexes, through a lysosome dependent degradative pathway. Although the induction of autophagy by nutrient starvation (especially amino acids and glucose) has been extensively studied in cell culture experiments, we still know very little about the role of nutrients and their interactions in vivo in the regulation of this degradative route. In this context, and by using the carnivorous rainbow trout (Oncorhynchus mykiss) as a study model, we demonstrated that autophagy is not only sensitive to the nutritional status (starved/fed) but also to the nature of the consumed diets. More precisely, we showed that autophagosomal formation but also the expression of the related genes are not inhibited by refeeding when the proteins/carbohydrates ratio decreased. Similarly, we demonstrated that a deficiency of only one essential amino acid (methionine) in the diet induce both the formation of autophagosomes and the expression of the related genes. Together, these results demonstrate the specific role of nutrient as well as that of their interactions in the regulation of autophagy and highlight the interest to consider the macronutrient composition of the diets in the control of this degradative pathway. Our current research aim at understanding the metabolic consequences of these nutritional modulations of autophagy.

Invitation : Muriel Priault (IBGC CNRS UMR 5095)

 

Jeudi 12 mars 2015 à 11 h 00
Salle de conférences de l’IBGC

Raul V. Duran
Institut Européen de Chimie et Biologie
VINCO U916 Unit
Pessac, France

“Linking metabolic transformation and cell signaling deregulation in cancer”

During last years, a particular attention has been dedicated to examining the crosstalk between metabolism and cell signaling, with especial emphasis in cancer cells. Our investigations focused on how cells sense nutrient availability and how this signal is transduced towards mTOR, a master regulator of cell growth. Our results showed that glutamine, a critical amino acid for the metabolism of many types of cancer cell, upregulates mTORC1 pathway through glutaminolyis. Glutaminolysis is the double deamination of glutamine to form α-ketoglutarate. Intracellular α-ketoglutarate stimulates PHD activity, necessary for the activation of mTORC1 by Rag proteins. Therefore, our results established that the glutamine/PHD/mTORC1 pathway constitute a central signaling cascade which regulates cell growth in response to nutrient availability. In addition, glutamine-mediated mTORC1 activation inhibits autophagy. Our results also showed that the anomalous activation of mTORC1 by glutaminolysis during starvation causes apoptotic cell death, probably due to autophagy inhibition and metabolic collapse. Rapamycin treatment prevented this effect, suggesting that in these circumstances, mTORC1 is behaving as a tumor suppressor, rather than as a tumor promoter. These results might have implications to explain the modest result of rapamycin as an anticancer drug.

Invitation : Muriel Priault (IBGC CNRS UMR 5095)

 

Jeudi 26 février 2015 à 11 h 00
Salle de conférences de la Plateforme Génomique Fonctionnelle

Konstantin Stark
Munchen, Germany

“Stasis induced venous thrombosis as an inflammatory disease”

Although venous thrombosis is a common disease, the processes initiating clot formation are not well understood. We could show that venous thrombosis shares many similarities to sterile inflammation and this mechanism is essential to trigger activation of the coagulation system in this setting. Using intravital microscopy in a mouse model of reduced venous blood flow we could characterize the recruitment of myeloid leukocytes and platelets to the developing thrombus. The interplay of these cell types is essential to trigger the activation of the coagulation cascade resulting in fibrin formation and vessel occlusion. However, these processes are context dependent and other mechanisms control venous thrombogenesis in the setting of malignancy.

Invitation : Chloé James (Inserm U 1034)

 

Jeudi 12 mars 2015 à 11 h 00
Salle de conférences de l’IBGC

Raul V. Duran
Institut Européen de Chimie et Biologie
VINCO U916 Unit
Pessac, France

“Linking metabolic transformation and cell signaling deregulation in cancer”

During last years, a particular attention has been dedicated to examining the crosstalk between metabolism and cell signaling, with especial emphasis in cancer cells. Our investigations focused on how cells sense nutrient availability and how this signal is transduced towards mTOR, a master regulator of cell growth. Our results showed that glutamine, a critical amino acid for the metabolism of many types of cancer cell, upregulates mTORC1 pathway through glutaminolyis. Glutaminolysis is the double deamination of glutamine to form α-ketoglutarate. Intracellular α-ketoglutarate stimulates PHD activity, necessary for the activation of mTORC1 by Rag proteins. Therefore, our results established that the glutamine/PHD/mTORC1 pathway constitute a central signaling cascade which regulates cell growth in response to nutrient availability. In addition, glutamine-mediated mTORC1 activation inhibits autophagy. Our results also showed that the anomalous activation of mTORC1 by glutaminolysis during starvation causes apoptotic cell death, probably due to autophagy inhibition and metabolic collapse. Rapamycin treatment prevented this effect, suggesting that in these circumstances, mTORC1 is behaving as a tumor suppressor, rather than as a tumor promoter. These results might have implications to explain the modest result of rapamycin as an anticancer drug.

Invitation : Muriel Priault (IBGC CNRS UMR 5095)

 

Jeudi 26 février 2015 à 11 h 00
Salle de conférences de la Plateforme Génomique Fonctionnelle

Konstantin Stark
Munchen, Germany

“Stasis induced venous thrombosis as an inflammatory disease”

Although venous thrombosis is a common disease, the processes initiating clot formation are not well understood. We could show that venous thrombosis shares many similarities to sterile inflammation and this mechanism is essential to trigger activation of the coagulation system in this setting. Using intravital microscopy in a mouse model of reduced venous blood flow we could characterize the recruitment of myeloid leukocytes and platelets to the developing thrombus. The interplay of these cell types is essential to trigger the activation of the coagulation cascade resulting in fibrin formation and vessel occlusion. However, these processes are context dependent and other mechanisms control venous thrombogenesis in the setting of malignancy.

Invitation : Chloé James (Inserm U 1034)

 

Jeudi 19 février 2015 à 11 h 00
Salle de conférences de l’IBGC

Frédéric BARRAS
Laboratoire Chimie Bactérienne, CNRS, Aix-Marseille Université, Institut Microbiologie de la Méditerranée, Marseille, France

“Fe-S clusters in biology : biogenesis and role in aminoglycoside sensitivity”

Iron-sulphur (Fe-S) clusters are ubiquitous cofactors present in a myriad of proteins controlling processes as diverse as DNA replication and repair, gene expression, photosynthesis, respiration and central metabolic pathways. Fe-S clusters assembly and delivery into apo-proteins are catalysed by multi-protein systems conserved throughout prokaryotes and eukaryotes. Escherichia coli possesses ISC and SUF Fe-S biogenesis systems, which are also present in mitochondria and chloroplasts, respectively. In addition, “non-ISC, non-SUF” components arise that constitute a diversified delivery network allowing Fe-S clusters to be targeted to different client proteins under fluctuating growth conditions, some of them being unfavourable for Fe-S biosynthesis and/or stability. By using the E. coli model, I will discuss the underlying factors that control Fe-S cluster homeostasis, including genetic regulation that allows cells to change Fe-S assembly/delivery pathways. The maturation of the complex I (Nuo), the consequences on p.m.f.-dependent processes such as aminoglycoside antibiotics will be presented. Last recent results on the long standing question of the importance of frataxin in bacterial Fe-S biogenesis will be discussed.

Related papers
Roche B. et al. (2013) Iron/sulfur proteins biogenesis in prokaryotes: formation, regulation and diversity. B.B.A. Bioenergetics 1827:455-469
Ezraty B., et al. (2013) Fe-S cluster biosynthesis controls uptake of aminoglycosides in a ROS-less death pathway. Science 340:1583-1587.
Roche B., et al., (2014) The iron-binding CyaY and IscX proteins assist the ISC-catalyzed Fe-S biogenesis in Escherichia coli. Mol. Microbiol. in press
Py B and Barras F (2015) Genetic approaches of the Fe-S cluster biogenesis process in bacteria: Historical account, methodological aspects and future challenges. B.B.A. in press

Invitation : Bertrand Daignan-Fornier (IBGC UMR 5095)


Vendredi 13 février 2015 à 11 h 00
Salle de conférences de l’IBGC

Valérie Vouret-Craviari
Institute for Research on Cancer and Aging, Nice
Team 3 « Inflammation and carcinogenesis »

“A non-canonical role for HIF1 in the etiopathogenesis of Crohn Disease”

The prevalence of Crohn disease (CD), an incurable form of inflammatory bowel disease, increases word wild; in France it affects around 200000 persons. Extensive studies in the last decades have suggested that the etiology of CD involves environmental and genetic factors that lead to dysfunction of the epithelial barrier with consequent deregulation of the mucosal immune response to gut microbiota. In this lecture, I will summarize our recent discoveries on the role of the hypoxic transcription factor 1 (HIF1) in CD etiopathology.

“HIF1A et étiopathogénie de la maladie de Crohn”

La maladie de Crohn (MC) est une maladie inflammatoire chronique intestinale (MICI). Son incidence et sa prévalence sont en constante augmentation à travers le monde et plus particulièrement dans les régions industrialisées; En France cette pathologie concerne 200000 personnes. Malgré les nombreuses découvertes réalisées ces dix dernières années, les solutions thérapeutiques restent insatisfaisantes. Au cours de ma présentation, je dresserai un état des lieux des connaissances actuelles de la maladie de Crohn et je vous présenterai nos résultats sur le rôle du facteur de transcription hypoxique (HIF1) dans l’étiologie de cette maladie.

Invitation : Nadine Camougrand (IBGC UMR 5095)

 

Mardi 27 janvier 2015 à 11 h 00
Salle de conférences de la Plateforme Génomique Fonctionnelle

Nicolas Joly
Equipe “Nanomanipulation de biomolécules” Institut Jacques Monod – UMR7592 CNRS – Université Paris Diderot

Enhancer dependent transcription: new insights on the role of the AAA+ activator”

Invitation : José-Eduardo Gomes (IBGC UMR 5095)

 

Mardi 20 janvier 2015 à 11 h 00
Salle de conférences de la Plateforme Génomique Fonctionnelle

Claudine Kieda
CNRS UPR 4301 “Centre de Biophysique Moléculaire » Orléans

“New angiogenesis-based therapeutic strategies to compensate tumor hypoxia  towards a  stable vessel normalization provide the means to transform the tumor microenvironment and potentiate cancer treatment”

Claudine Kieda’scientific interest focuses on the mechanisms of cell recognitions and cross talks during the normal biological processes (immunological response) and in diseases as cancer. Oxygen partial pressure (pO2), is a key parameter of organ physiology, it characterizes tissue “normoxia” called: “physioxia”.  This is decreased in pO2-associated pathologies as cancer where hypoxia turns on angiogenesis. Tumor vessels O2-delivery is impaired and contributes to tumor growth, metastasis and hypoxia-selection of aggressive cancer stem-like cells. Consequently, the anticancer strategies directed to pathological angiogenesis destruction are being revisited towards normalization and vessel functionalization. This is reached by several pO2 control strategies which are able to change the tumor microenvironment and the immune tolerance into efficient immune response.
Clinical strategies attempt to regulate vessels structure and re-establish their function. But vessels tend to be normalized only transiently, for periods during which other cancer therapies can be beneficially applied. Thus stabilization of vasculature normalization is the challenge that we could reach by several concordant approaches:

  • directly enhancing O2 delivery by red blood cells using an allosteric effector of hemoglobin;
  • target the tumor site by therapeutic gene expressed in a hypoxia-restricted manner;
  • tumor targeting by endothelial cells, incorporating the developing blood vessels;
  • ROS activation with cold plasma (Plasma-Gun) impacting tissue pO2.

These methods allowed the demonstration that hypoxia compensation is the key for efficient radiotherapy and/or chemotherapy, reverting pathologic angiogenesis, immune tolerance, selection of resistant cancer stem cells and blocking metastasis.

Invitation : Christophe Grosset (Inserm U 1053)


Mercredi 14 janvier 2015 à 11 h 00
Salle de conférences de la Plateforme Génomique Fonctionnelle

John Creemers
Laboratory of Biochemical Neuroendocrinology Center for Human Genetics. KU Leuven

“Proprotein processing in health and pathology”

Proprotein processing is a fundamental process in eukaryotic cells. It facilitates the activation, inactivation and modulation of activity of many secretory proteins like hormones, neuropeptides, enzymes, adhesion molecules and serum factors. Correct temporospatial control of processing of these factors is of the utmost importance to maintain homeostasis and impairment can contribute to many pathologies like cancer, neurodegeneration and obesity.
My research group is interested in understanding pathophysiological functions of proprotein convertases (PCs), a seven-member family of serine endoproteases involved in the cleavage of proproteins. We use human patients and genetically modified mouse models to study proprotein processing in health and disease.
We use the Cre-Lox recombination system to generate tissue-specific knockout mouse models. However, we have recently discovered a major flaw in the basic transgenic construct that is used a large variety of commonly used Cre-driver lines, necessitating the re-evaluation of a large volume of published work.

Invitation : Majid Khatib (Inserm U 1029)

 

Jeudi 8 Janvier à 11 h 00
Salle de Conférences de l’IBGC

Florian Georgescauld
Department of Cellular Biochemistry, Max Planck Institute of Biochemistry, Martinsried, Germany

“Rôle des chaperonnes Hsp70 et GroEL/GroES dans le repliement des protéines”

Afin d’acquérir leur conformation fonctionnelle, 30% des protéines cytosoliques bactériennes transitent à travers les chaperonnes Hsp70 et/ou GroEL/GroES. En utilisant l’échange hydrogène/deutérium suivi en spectrométrie de masse, nous avons pu caractériser à une résolution peptidique l’effet de ces chaperonnes sur le repliement de deux protéines substrat. Nous avons montré que Hsp70 maintient ces substrats dans un état entièrement déplié, avant transfert à GroEL. Suit une encapsulation du substrat dans le nano-compartiment formé par GroEL/GroES où, le repliement du substrat est accéléré 30 fois et est partiellement modifié par rapport au repliement spontané (1). Nous suggérons qu’un ensemble de protéines requiert une accélération de leur repliement par GroEL/GroES, afin de devenir fonctionnelles à une échelle de temps biologiquement pertinente et éviter l’agrégation ou la dégradation.
(1) Georgescauld et al, 2014, Cell, 157,922-934

Invitation : Michel Rigoulet (UMR 5095 – IBGC)

LOGO-UNIVERSITE-BORDEAUX inserm57x16mmHD logo cnrs chu bergoni
Mentions Légales