Category: Open

1 Doctoral position in the Vessel Formation in Development and Disease group
1 Doctoral position in the Vessel Formation in Development and Disease group
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An ANR funded PhD position is available in the Vessel Formation in Development and Disease group at the iBV

The role of p16-dependent cellular senescence in healthy aging

 

Description :

Cellular senescence attracts attention as a key player contributing to organismal aging. The accumulation of senescent cells is dramatically increased with aging, however their precise contribution to aging-related phenotypes remains largely unclear. In collaboration with the team of D. Bulavin we showed p16-dependent senescent cells are required for healthy aging. We used different novel inducible mouse lines to characterise the role of p16 expressing cells in different organs. Currently, we focussed mainly on liver. The project aims at identifying the cell repertoire linked to aging-induced senescence and to investigate the impact of senescent cells on liver functions and to understand molecular pathways modulated by senescence. For these purposes we will use p16-Cre and p16-Cre-ERT2 mice crossed either with Rosa26-mTmG reporter or Rosa26-DTA ablator mice. The animals will be investigated by histological and immunohistological methods and RNA sequencing will be performed at different ages. This project will help to understand the molecular mechanism responsible for aging-induced activation of senescence and hopefully identify potential molecular targets to manipulate senescence through reprogramming and/or selective elimination of subsets of senescent cells.

Required Skills :        

The working language is English.
Experience in molecular biology, cellular biology and/or mouse genetics would be a plus.
Motivation to work with mouse models and team orientation are required. Animal experimentation training is part of the project.

Related publications:

Grosse, L, Wagner, N, Emelyanov, A, Molina, C, Lacas-Gervais, S, Wagner, KD et al.. Defined p16High Senescent Cell Types Are Indispensable for Mouse Healthspan. Cell Metab. 2020:. doi: 10.1016/j.cmet.2020.05.002. PubMed PMID:32485135 .

Wagner, KD, Du, S, Martin, L, Leccia, N, Michiels, JF, Wagner, N et al.. Vascular PPARβ/δ Promotes Tumor Angiogenesis and Progression. Cells. 2019;8 (12):. doi: 10.3390/cells8121623. PubMed PMID:31842402 PubMed Central PMC6952835.

Wagner, KD, El Maï, M, Ladomery, M, Belali, T, Leccia, N, Michiels, JF et al.. Altered VEGF Splicing Isoform Balance in Tumor Endothelium Involves Activation of Splicing Factors Srpk1 and Srsf1 by the Wilms' Tumor Suppressor Wt1. Cells. 2019;8 (1):. doi: 10.3390/cells8010041. PubMed PMID:30641926 PubMed Central PMC6356959.

Wagner, KD, Ying, Y, Leong, W, Jiang, J, Hu, X, Chen, Y et al.. The differential spatiotemporal expression pattern of shelterin genes throughout lifespan. Aging (Albany NY). 2017;9 (4):1219-1232. doi: 10.18632/aging.101223. PubMed PMID:28437249 PubMed Central PMC5425123.

Wagner, KD, Cherfils-Vicini, J, Hosen, N, Hohenstein, P, Gilson, E, Hastie, ND et al.. The Wilms' tumour suppressor Wt1 is a major regulator of tumour angiogenesis and progression. Nat Commun. 2014;5 :5852. doi: 10.1038/ncomms6852. PubMed PMID:25510679 .

El Maï, M, Wagner, KD, Michiels, JF, Ambrosetti, D, Borderie, A, Destree, S et al.. The Telomeric Protein TRF2 Regulates Angiogenesis by Binding and Activating the PDGFRβ Promoter. Cell Rep. 2014;9 (3):1047-60. doi: 10.1016/j.celrep.2014.09.038. PubMed PMID:25437559 .

Contacts:

Kay-Dietrich Wagner – kwagner@unice.fr
Nicole Wagner – nwagner@unice.fr

 

PhD Position - 3 years - Starting October 2020
PhD Position - 3 years - Starting October 2020
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Deciphering the regulation of the cell death receptor Fas by cell polarity molecules & adherens junctions in both tumoral and normal human epithelia

Key words: Receptor, Signaling, Cancer, Cell polarity, Cell-Cell jonctions

 

The PhD student will integrate the research group “death receptors signaling in cancer therapy” (iBV, http://ibv.unice.fr/research-team/hueber). at the Institute of Biology Valrose affiliated to the CNRS, Inserm and University Côte d’Azur (UCA).

Project proposal: Our team is investigating the functions of the cell death receptor Fas/CD95/TNFRSF6, a member of the TNFR superfamily. Fas is considered as a tumor suppressor thanks to its ability to eliminate cancer cells by engaging programmed cell death by apoptosis. However, Fas activation by its ligand (FasL) could also promote tumor development and immune disorders (1). Our group is studying the molecular mechanisms that control the Fas versatile signaling outcome in the context of both normal and cancer cells (2, 3). Our recent data show that formation of adherens junction, a cell-cell adhesion complex, and association with the Dlg1 polarity complex prevent the pro-apoptotic signaling of Fas (4, 5). This new Fas-regulatory mechanism is crucial to protect normal epithelial cells from apoptotic signals and to sense and eliminate abnormal cells from epithelial tissues to prevent pathological outcome such as cancer and chronic inflammatory diseases. The PhD student will pursue this project and decipher the regulation of Fas cell death and non- death signaling by the Cadherin-Dlg1 polarity complex notably by studying Fas receptor signaling/trafficking on both primary and tumoral epithelial human cells by using various cell biology approaches.

Bibliography of the team link to the project: 1- Rossin et al (2019) Cancers, 8;11(5):639. 2- NL t al (2018) Sci Rep, 20;8(1):12424. 3- Chakrabandhu K (2016), PLoS Biol, 4;14(3). 4- Gagnoux-Palacios, L.; et al (2018) Journal of Cell

Biology, 217, 3839-3852. 5- Gagnoux-Palacios L., Hueber AO (2019) Medecine/Sciences. 35(11):830-833.

Technical approaches: Human cell culture; cell death assays; receptor trafficking studies (cell surface labeling, endocytosis assay), protein expression quantification/localization (FACS, IP, IF, IB, ELISA, proteomic); microscopy techniques (confocal imaging, time-lapse).

Candidate profil: We are looking for a highly motivated student, independent and creative, with a Master’s Degree in Cellular, Cancer or Molecular Biology. Prior experience with cell culture and classical cellular and biochemical approaches will be appreciated.

HOW TO APPLY: Interested and motivated students should send as soon as possible a CV, a motivation letter, master scores/ranking and reference letters to both L. GAGNOUX (gagnoux@unice.fr) and A-O HUEBER (hueber@unice.fr).

1 Doctoral position - Deadline June 1st, 2020 (Optogenetics)
1 Doctoral position - Deadline June 1st, 2020 (Optogenetics)
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 Doctoral position at University Côte d’Azur: Fungal Cell Biology

Light-dependent regulation of cell polarity in a fungal pathogen

The fungus Candida albicans is normally a harmless commensal that is found on mucosal surfaces of the gastrointestinal and urogenital tract in most healthy individuals. This commensal organism can cause superficial as well as life-threatening systemic infections in response to alterations of its environment, and is particularly aggressive in immuno-compromised individuals. As an opportunistic pathogen it can colonize and infect different body sites and is responsible for one of the most predominant fungal nosocomial infections. The ability of this fungus to switch from an ovoid form to a filamentous form is critical for its pathogenicity, in particularly its ability to invade and penetrate into host tissues and evade and burst out of host immune cells.

The recent advent of light-dependent approaches to control protein subcellular localization has made possible the specific alteration of growth, circumventing classical genetic and chemical perturbations. We have optimized such a light-dependent protein targeting system for C. albicans, which gives us exquisite control of growth in this organism. In addition, new variants of these systems have been established which facilitate their use and response time. Furthermore, a number of new, spectrally distinct fluorescent proteins, which we have optimized for use in C. albicans, now make it possible to follow different cellular processes simultaneously during light-dependent perturbation of growth and cell polarity. The goal of this project is to use such a light-dependent protein targeting to probe filamentous growth as well as invasive filamentous growth in a human fungal pathogen. The project will use a combination of molecular biology, microbiology and live cell microscopy to probe filamentous growth and morphogenesis in this fungal human pathogen.

We are seeking highly motivated candidates with a background in Cell Biology and interest in live cell imaging. Experience in Microbiology would be a plus.

Interested candidates can contact R. Arkowitz (arkowitz@unice.fr) by June 1st

 

1) M Bassilana, C Puerner & RA Arkowitz. Curr. Opin. Cell Biol. 2020 62:150-158.
2) PM Silva, C Puerner, A Seminara, M Bassilana & RA Arkowitz. Cell Rep. 2019 28:2231–2245.
3) RA Arkowitz & M Bassilana. F1000 Res. 2019 8.
4) A Weiner, F Orange, S Lacas-Gervais, K Rechav, V Ghugtyal, M Bassilana & RA Arkowitz. Cell Microbiol. 2019 21: e12963
5) H Labbaoui, S Bogliolo, V Ghugtyal, NV Solis, SG Filler, RA Arkowitz & M Bassilana. Plos Pathog. 2017 13: e1006205

 

1 Doctoral position - Deadline June 1st, 2020 (SuperRes)
1 Doctoral position - Deadline June 1st, 2020 (SuperRes)
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Doctoral position at University Côte d’Azur: Fungal Cell Biology

Organelle dynamics in a human fungal pathogen at high temporal and spatial resolution

Worldwide, fungal infections cause significant morbidity and mortality and Candida species are the major etiological agent of such life-threatening infections and represent an emerging global microbial threat. A range of advances in medical treatment have increased life expectancy yet also dramatically increased the population of elderly as well as severely ill patients, highly susceptible to nosocomial infections, in particular those caused by fungi such as Candida albicans. C. albicans is normally a harmless commensal, found on mucosal surfaces of the gastrointestinal and urogenital tract in most healthy individuals that causes superficial as well as life-threatening systemic infections in response to alterations of its host environment. It is particularly aggressive in immuno-compromised individuals. The ability of this organism to switch from an ovoid to a filamentous form, concomitant with changes in cell surface antigens and enzyme production, is critical for its pathogenicity, in particular to invade host tissues and evade host immune cells. Many fungi, including C. albicans form elongated hyphal filaments that are tube-like cells in which growth is restricted to the tip. This dramatic yeast to filament cell shape change is a distinct advantage for studying the regulation of cell polarity and membrane traffic, critical for such morphogenesis. However, the hyphal apical zone is densely packed, with multiple membrane compartments including secretory vesicles below the light resolution limit and somewhat larger Golgi cisternae in a small volume at the filament tip and these compartments are highly dynamic making live cell imaging extremely challenging, in particular with high temporal and spatial resolution.

To understand the exquisite regulation of tip growth, the aim of this project is to quantitate the movement of membrane compartments in 3D with high spatial and temporal resolution. Conventional methods including fluorescence microscopy and electron microscopy suffer from either limited spatial or temporal resolution, whereas of super-resolution microscopy approaches, has made imaging with a resolution higher than that imposed by the diffraction limit of light possible. This interdisciplinary project (carried out with Laure BLANC‐FERAUD, I3S Laboratory – UMR CNRS 7271) will take advantage of fluorescent molecule blinking and their fluctuations over time, to generate super-resolved images with high temporal resolution. The goal of this project is to develop, optimize and apply such methods, specifically adapted to a multimodal microscope established at the iBV, to the investigate the reorganization of the membrane compartments during C. albicans filamentous growth, with high temporal and spatial resolution. This project will involve extensive state-of-the-art microscopy as well as optimization of image reconstruction and analyses computational algorithms.

We are seeking highly motivated candidates with a background in Cell Biology and interest in live cell imaging. Experience in Microbiology would be a plus.

Interested candidates can contact R. Arkowitz (arkowitz@unice.fr) by June 1st

 

1) M Bassilana, C Puerner & RA Arkowitz. Curr. Opin. Cell Biol. 2020 62:150-158.
2) PM Silva, C Puerner, A Seminara, M Bassilana & RA Arkowitz. Cell Rep. 2019 28:2231–2245.
3) RA Arkowitz & M Bassilana. F1000 Res. 2019 8.
4) A Weiner, F Orange, S Lacas-Gervais, K Rechav, V Ghugtyal, M Bassilana & RA Arkowitz. Cell Microbiol. 2019 21: e12963
5) H Labbaoui, S Bogliolo, V Ghugtyal, NV Solis, SG Filler, RA Arkowitz & M Bassilana. Plos Pathog. 2017 13: e1006205

1 PhD Position - 3 years - Starting October 2018
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Projet de thèse avec bourse, au sein de l’équipe de Stéphane Noselli à l’institut de Biologie Valrose’ (iBV), Université Côte d’Azur à Nice, FR.

Asymétrie droite-gauche et système nerveux : nouveaux gènes, nouvelles fonctions

L’asymétrie Droite-Gauche (DG) joue un rôle central dans l’organisation (positionnement, morphologie) et la fonction de nombreux organes (par ex : coeur, cerveau). Chez l’Homme, des défauts d’asymétrie DG des organes viscéraux entrainent de nombreuses malformations ou syndromes (situs inversus, malformation cardiaque, asplénie, syndromes de Kartagener, Ivemark, etc.), qui sont souvent associés à des maladies ciliaires et responsables d’un grand nombre de fausses-couches.

Le système nerveux présente également des asymétries DG à divers niveaux : anatomique, connectique (réseaux de connections neurales), et fonctionnel (comportements latéralisés, par ex. préférence main droite/gauche, et processus cognitifs complexes comme la mémoire). Illustrant son importance fonctionnelle chez l’homme, plusieurs troubles et syndromes sont fortement corrélés à des défauts de latéralité du système nerveux : Autisme, Schizophrénie, Hyperactivité et déficit d’attention, dyslexie etc.

De façon surprenante et intéressante, l’asymétrie des organes viscéraux et du cerveau est contrôlée par des mécanismes indépendants. Si les mécanismes contrôlant l’asymétrie des organes viscéraux est bien connue, nous ne savons en revanche rien de ceux contrôlant l’asymétrie du système nerveux, tant chez les mammifères que chez les invertébrés.

Notre projet vise à élucider les mécanismes d’asymétrie du système nerveux en utilisant le modèle drosophile, qui offre de très nombreux avantages méthodologiques. Par ailleurs, Il est estimé que 75% des gènes ayant un lien avec une maladie chez l’homme ont un équivalent chez la Drosophile. Mieux comprendre le contrôle génétique et la fonction des asymétries chez la Drosophile permettra la mise en évidence de mécanismes inédits conservés chez les vertébrés dont l’homme.

Notre laboratoire est pionnier dans l’étude de l’asymétrie DG chez le modèle drosophile. Le projet s’intéressera dans un premier temps à un circuit de neurones asymétriques présent uniquement du côté droit. De manière intéressante, ce circuit met en lumière chez la Drosophile l’existence, comme chez les vertébrés, d’un lien direct entre asymétrie cérébrale et cognition. En effet, une perte d’asymétrie de ce circuit neuronal provoque des défauts de mémoire à long terme.

Le laboratoire a entrepris un crible RNAi à grande échelle et identifié récemment les premiers gènes connus à ce jour affectant la mise en place de cette asymétrie chez la Drosophile. Les gènes et voies de signalisation identifiés sont fortement conservés chez l’homme. Le projet consistera à exploiter les nombreuses ressources et outils génétiques disponibles pour analyser le rôle des gènes/voies identifiés, en : 1) Caractérisant les défauts d’asymétries causés par les mutations, 2) Identifiant le réseau génique, le mécanisme d’action et les partenaires des gènes candidats, 3) Caractérisant le réseau neuronal impliqué et les défauts comportementaux/cognitifs provoqués par une altération de leur asymétrie, 4) Etudiant le rôle des gènes homologues dans le système nerveux de vertébrés modèles, en collaboration avec des laboratoires experts avec lesquels nous travaillons.

Ce projet pionnier débouchera sur la caractérisation des premiers gènes impliqués dans le contrôle de l’asymétrie du système nerveux et des fonctions cognitives associées.

Une large panoplie de techniques de laboratoire sera utilisée, incluant l’imagerie (microscopie confocale, 2-photon, reconstruction 3D de réseaux de neurones, etc.), la génétique (mendélienne, CRISPR, RNAi), expression contrôlée dans le temps et l’espace (système Gal4/UAS), toutes les techniques de biologie moléculaire et cellulaire, modélisation, etc..

 

N’hésitez pas à contacter le laboratoire pour de plus amples informations :

ibv.unice.fr/research-team/noselli

Stéphane Noselli : noselli@unice.fr
François Lapraz : lapraz@unice.fr

L‘institut de Biologie Valrose’ iBV, (28 équipes ; 310 personnes ; 25 nationalités) est un institut de recherche reconnu au niveau international disposant d’un environnement scientifique riche et dynamique, de nombreuses plateformes technologiques modernes et une atmosphère de travail collaborative et attractive. (ibv.unice.fr)

 

Selected Publications

Spéder et al., Nature 2006
Gettings et al., PLoS Biol 2010
Suzanne et al., Cur Biol 2010
Petzoldt et al., Development 2012
Coutelis et al., Dev Cell 2013
Géminard et al., Genesis 2014
Coutelis et al., EMBO Reports 2014
Gonzales-Morales et al., Dev Cell 2015
Van de Bor et al., Cell Reports 2015
Rousset et al., PLoS Genetics 2017
Roumengous et al., Cell Reports 2017
Juan et al, Nature Communications 2018
Tingler et al., Current Biology 2018
Ghiglione et al., Development 2018