MASTER BIOLOGY and HEALTH SCIENCE of LILLE Research Projects 2021-2022 - Master Biologie Santé
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MASTER BIOLOGY and HEALTH SCIENCE of LILLE Research Projects 2021-2022
p. Projects Supervisors – Research Units Cellular Integrative and Translational Neuroscience Role of talin mechanotransduction in synaptic plasticity Devrim KILINC - Inserm U1167 RID-AGE – tel : 03 20 87 78 01 - 9 devrim.kilinc@pasteur-lille.fr Molecular Mechanisms of Hypothalamic Wiring Sébastien G. BOURET, Inserm UMR-S 1172, Development and 9 Plasticity of the Neuroendocrine Brain, Lille Neuroscience & Cognition Research Center. 03-5950-7551. sebastien.bouret@inserm.fr Qualitative aspects of memory processing in Alzheimer's disease and Maxime BERTOUX - équipe “Troubles cognitifs dégénératifs et 10 related disorders Vasculaires” de l’Institut Lille Neuroscience & Cognition, Université de Lille, Inserm, CHU de Lille. e-mail: maxime.bertoux@inserm.fr Modelling in vitro brain networks involved in early stages of Sophie HALLIEZ - sophie.halliez@inserm.fr - 03 20 29 75 53 - 10 Alzheimer’s disease Alzheimer & Tauopathies, UMR-S 1172, LilNCog Therapeutic potential of neuroprotection of anti-ferroptotic drugs in David DEVOS, Jean-Christophe DEVEDJIAN - University of Lille, Lille 11 Parkinson's disease. Neuroscience & Cognition, Inserm, UMR-S1172 - TEL: 0320445449 david.devos@chru-lille.fr Benefits of precise visual tasks and laser pointing tasks to improve Arnaud DELVAL ; Cédrick BONNET (to be contacted) – SCALab – 11 postural control in patients with Charcot-marie Tooth cedrick.bonnet@univ-lille.fr ; https://pro.univ-lille.fr/cedrick- bonnet/ Tel: 06 16 89 41 75 Study of the transgenerational transmission of maternal stress in rat: Sara MORLEY FLETCHER - Team GlycoStress - UMR 8576 CNRS 12 molecular and behavioral approaches «Glycobiologie Structurale et Fonctionelle » - Université de Lille, Villeneuve d’Ascq - 03.20.33.6402; sara.morley-fletcher@univ-lille.fr Maternal stress programs the sex mediated-increased sensitivity to Stefania MACCARI - Team GlycoStress - UMR 8576 CNRS 12 cocaine reward in the offspring «Glycobiologie Structurale et Fonctionelle» - Université de Lille, Villeneuve d’Ascq - 03.20.33.6402; stefania.maccari@univ-lille.fr Influence of mammary tumor extracellular vesicles on the microglial Christophe LEFEBVRE - christophe.lefebvre@univ-lille.fr - tel : 03 20 13 response in the development of brain metastases. 43 41 27 ; Faculté des Sciences et Technologies, Laboratoire PRISM U1192 Inserm
Diabetes and Cardiovascular diseases Circadian regulation of the glycolytic pathway Philippe LEFEBVRE, Université de Lille, UMR Inserm 1011. E-mail : 15 philippe-claude.lefebvre@inserm.fr Transcriptional control of hepatic cell phenotypic plasticity Jérôme EECKHOUTE – INSERM U1011 « Récepteurs nucléaires, 15 maladies cardiovasculaires et diabète » - Faculté de Médecine - Bd du Pr. Leclerc, Bâtiment JK, Lille - jerome.eeckhoute@inserm.fr - 03.20.97.42.19 Characterization of cardiac remodeling during the development of Laura BUTRUILLE / David MONTAIGNE - INSERM U1011, Récepteurs 16 NAFLD (Non Alcoholic Fatty Liver Disease): focus on the role of nucléaires, maladies métaboliques et cardiovasculaires - 03 20 44 52 myocardial immune cells. 30 laura.butruille@pasteur-lille.fr / david.montaigne@chru-lille.fr Impact of time of day on perioperative immuno-inflammatory David MONTAIGNE / Laura BUTRUILLE - INSERM U1011, Récepteurs 16 response and myocardial remodeling after cardiac surgery nucléaires, maladies métaboliques et cardiovasculaires - 0320445230 david.montaigne@chru-lille.fr / laura.butruille@pasteur-lille.fr Pathophysiological role of amino acids involved in the one carbon Guillaume GRZYCH, AHU CHU Lille - guillaume.grzych@chru-lille.fr 17 metabolosm in NAFLD: analysis of the molecular mechanisms of the - UMR 1011. Pasteur Institute of Lille. 1 rue du Pr Calmette. Lille. variations observed in a cohort of patients FASTRIP- Targeting strategy for the inhibition of FAT10/PPAR Réjane PAUMELLE-LESTRELIN. INSERM- UMR 1011 « Nuclear 17 interaction to treat NASH receptor, metabolic and cardiovascular diseases” Laboratoire JK - Faculté de médecine, Bd Pr Leclerc, Lille - Tel : 03 20 97 42 09 - rejane.lestrelin@univ-lille.fr Characterization of dendritic cell (DC) and T cell (T) interactions in David DOMBROWICZ – david.dombrowicz@pasteur-lille.fr - UMR 18 non-alcoholic steatohepatitis (NASH) 1011. Institut Pasteur de Lille. 1 rue du Pr Calmette. Lille. 0320877967 Characterisation of the metabolic effects of TGR5 activation in the Anne TAILLEUX-Inserm UMR 1011-Institut Pasteur de Lille-Université 18 gut: study in a murin model using a pharmacological tool de Lille anne.tailleux@univ-lille.fr Role of intestinal epithelial nuclear receptor FXR in the Non Alcoholic Sophie LESTAVEL - UMR 1011 INSERM - Laboratoire J&K, Pôle 19 Fatty Liver Disease complication of Type 2 Diabetes Recherche Faculté de Médecine, Boulevard du Pr Jules Leclercq Lille - Email: sophie.lestavel@univ-lille.fr - +33 3 20 97 42 13
Role of the mitochondrial protein import machinery in angiogenesis Anna Rita CANTELMO - U1011 - Récepteurs Nucléaires, Maladies 19 in health and disease Métaboliques et Cardiovasculaires, Institut Pasteur de Lille - 1 Rue du Pr Calmette - Lille - 03 20 33 70 78 - anna-rita.cantelmo@univ-lille.fr The nuclear receptor Rev-Erbα: a new player in intestinal dietary lipid Olivier BRIAND – INSERM U1011 – EGID - Laboratoire JK, Pôle 20 metabolism? recherche Faculté de médecine, boulevard du Pr Jules Leclercq Lille - Phone : +33 3 20 97 42 11 – olivier.briand@univ-lille.fr Brown adipose tissue from embryo to adult: implications in metabolic Alicia MAYEUF-LOUCHART -Institut Pasteur de Lille, Université de 20 diseases Lille, Unité 1011 - Equipe 5 - 03.20.87.77.75 - alicia.mayeuf- louchart@inserm.fr Pathophysiological role of glucose-induced metabolism pathways in Chantal FRADIN - RID-AGE UMR1167, équipe 5, Faculté de Médecine, 21 Caenorhabditis elegans Pôle Recherche, Lille - 03 20 62 34 86, chantal.fradin@univ-lille.fr Effects of maternal obesity on glucose homeostasis and susceptibility Christophe BRETON, UMR 1283-8199 INSERM/CNRS. Faculté de 21 to type 2 diabetes in offspring Médecine - Pôle recherche, 2ème étage (aile ouest), place de Verdun, Lille. Tel : 03 20 62 68 28. Mail : Christophe.breton@univ-lille.fr Role of cell cycle and inflammation regulators in the dedifferentiation Jean-Sébastien ANNICOTTE – INSERM U1283/CNRS UMR 8199 EGID – 22 of pancreatic β cells during type 2 diabetes and aging. Faculté de Médecine - Pôle Recherche, 2ème étage Ouest- place de Verdun - Lille – 03 20 97 42 54 – jean-sebastien.annicotte@inserm.fr Epigenomic reprogramming of pancreatic β cells during type 2 Jean-Sébastien ANNICOTTE – INSERM U1283/CNRS UMR 8199 EGID – 22 diabetes. Faculté de Médecine - Pôle Recherche, 2ème étage Ouest- place de Verdun - Lille – 03 20 97 42 54 – jean-sebastien.annicotte@inserm.fr Investigations of the molecular mechanisms involved in the lipid- Alexandrine DURING - Marrow Adiposity and Bone Laboratory - 23 associated bone loss during early stages of osteoporosis development MABLab ULR 4490, Université de Lille, France - Tel: +33 3 20 16 79 89- in the rat OVX model Email: alexandrine.during@univ-lille.fr Fundamental and clinical oncology EMT mechanism and stem cell state in pancreatic cancer and their Kaja BALCER - Kaja.balcer@gmail.com - 06.79.16.47.39 - Laboratoire 25 implication in chemo resistance to FOLFIRINOX. accueil : Canther UMR9020 CNRS - U1277 Inserm
Paucimannose glycan recognition by antibodies : structure and Julie BOUCKAERT – Campus CNRS Haute Borne, 50 Avenue de Halley, 25 specificity Villeneuve dAscq, France - UGSF – UMR 8576 – Université Lille – (0)3 62 53 17 29, julie.bouckaert@univ-lille.fr Role of the mitochondrial protein import machinery in angiogenesis Anna Rita CANTELMO - U1011 - Récepteurs Nucléaires, Maladies 26 in health and disease Métaboliques et Cardiovasculaires, Institut Pasteur de Lille - 1 Rue du Pr Calmette - Lille - 03 20 33 70 78 - anna-rita.cantelmo@univ-lille.fr Influence of mammary tumor extracellular vesicles on the microglial Christophe LEFEBVRE - christophe.lefebvre@univ-lille.fr – tel 03 20 43 26 response in the development of brain metastases. 41 27 ; Faculté des Sciences et Technologies, Université de Lille, PRISM U1192 Inserm Immunity, Inflammation, Infection Dissecting key factors for apicomplexan parasite proliferation using Mathieu GISSOT - CIIL – CNRS UMR8204 - Institut Pasteur de Lille – 28 Toxoplasma gondii as a model. Equipe BAP, Laboratoire de Biologie cellulaire et moléculaire du Toxoplasme, Lille. Tel : 0359317430 - mathieu.gissot@pasteur-lille.fr Molecular study of the encystment/excystment process of the Eric VISCOGLIOSI, Institut Pasteur of Lille, Center for Infection and 28 intestinal parasite Blastocystis Immunity of Lille, Inserm U1019, UMR CNRS 9017, University of Lille, CHU of Lille – tel (+33) 03 20 87 79 61 - eric.viscogliosi@pasteur-lille.fr Characterization of a new Toxoplasma gondii protein family essential Emmanuel ROGER - emmanuel.roger@univ-lille.fr - CIIL – CNRS UMR 29 for parasite proliferation. 8204 - Institut Pasteur de Lille – Equipe BAP (Bureau : 03 59 31 74 30) Establishement of a new model of long term 3D inverted organoid for Silvia SPECA - Inserm U1286 – INFINITE - Institute for Translational 29 better characterizing UC-associated intestinal fibrosis Research in Inflammation - Tel: (+33) 320 97 42 31 - e-mail: silvia.speca2@univ-lille.fr Role of miRNAs in COVID-19 Ilka ENGELMANN, Laboratoire de Virologie ULR3610, CHU Lille, 30 Université de Lille. ilka.engelmann@chru-lille.fr - Tel : +33 (0)320444880 Characterization of dendritic cell (DC) and T cell (T) interactions in David DOMBROWICZ – david.dombrowicz@pasteur-lille.fr - UMR 30 non-alcoholic steatohepatitis (NASH) 1011. Institut Pasteur de Lille. 1 rue du Pr Calmette. Lille. Tel : 0320877967
Precision Health Advanced glycation end-product receptor RAGE as a therapeutic Isabelle LANDRIEU, isabelle.landrieu@univ-lille.fr, 0362531712 - 32 target in ageing-diseases Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167 - RID- AGE, Lille - CNRS ERL9002 Integrative Structural Biology Lille, France Role of talin mechanotransduction in synaptic plasticity Devrim KILINC; Inserm U1167 RID-AGE – tel : 03 20 87 78 01 - 32 devrim.kilinc@pasteur-lille.fr Transcriptional control of hepatic cell phenotypic plasticity Jérôme EECKHOUTE – INSERM U1011 Récepteurs nucléaires, 33 maladies cardiovasculaires et diabète - Faculté de Médecine de Lille – Bd du Pr Leclerc, Bâtiment J&K, Lille - Tel: 03.20.97.42.19 - jerome.eeckhoute@inserm.fr Characterization of cardiac remodeling during the development of Laura BUTRUILLE / David MONTAIGNE - INSERM U1011, Récepteurs 33 NAFLD (Non Alcoholic Fatty Liver Disease): focus on the role of nucléaires, maladies métaboliques et cardiovasculaires - 03 20 44 52 myocardial immune cells. 30 laura.butruille@pasteur-lille.fr / david.montaigne@chru-lille.fr Impact of time of day on perioperative immuno-inflammatory David MONTAIGNE / Laura BUTRUILLE - INSERM U1011, Récepteurs 34 response and myocardial remodeling after cardiac surgery nucléaires, maladies métaboliques et cardiovasculaires - 03 20 44 52 30 david.montaigne@chru-lille.fr / laura.butruille@pasteur-lille.fr Pathophysiological role of amino acids involved in the one carbon Guillaume GRZYCH, AHU CHU Lille - guillaume.grzych@chru-lille.fr 34 metabolosm in NAFLD: analysis of the molecular mechanisms of the - UMR 1011. Pasteur Institute of Lille. 1 rue du Pr Calmette. Lille. variations observed in a cohort of patients FASTRIP- Targeting strategy for the inhibition of FAT10/PPAR Réjane PAUMELLE-LESTRELIN. rejane.lestrelin@univ-lille.fr - Tel : 03 35 interaction to treat NASH 20 97 42 09 - INSERM- UMR1011 « Nuclear receptor, metabolic and cardiovascular diseases” Laboratoire JK - Faculté de médecine - Bd Pr Leclerc - Lille Brown adipose tissue from embryo to adult: implications in metabolic Alicia MAYEUF-LOUCHART - Institut Pasteur de Lille, Université de 35 diseases Lille, Unité 1011-Pr B. Staels, Equipe 5-Dr. H. Duez) 03.20.87.77.75 alicia.mayeuf-louchart@inserm.fr Characterization of dendritic cell (DC) and T cell (T) interactions in David DOMBROWICZ – david.dombrowicz@pasteur-lille.fr - UMR 36 non-alcoholic steatohepatitis (NASH) 1011. Institut Pasteur de Lille. 1 rue Pr Calmette. Lille. 0320877967
Characterisation of the metabolic effects of TGR5 activation in the Anne TAILLEUX-Inserm UMR 1011-Institut Pasteur de Lille-Université 36 gut: study in a murin model using a pharmacological tool de Lille - anne.tailleux@univ-lille.fr Role of intestinal epithelial nuclear receptor FXR in the Non Alcoholic Sophie LESTAVEL - UMR 1011 INSERM (Dir. Bart STAELS) - Laboratoire 37 Fatty Liver Disease complication of Type 2 Diabetes J&K, Pôle Recherche Faculté de Médecine, Boulevard du Pr Jules Leclercq - Lille - sophie.lestavel@univ-lille.fr - +33 3 20 97 42 13 The nuclear receptor Rev-Erbα: a new player in intestinal dietary lipid Olivier BRIAND – INSERM U1011 – EGID - Laboratoire JK, Faculté de 37 metabolism? médecine, boulevard du Pr Jules Leclercq Lille - Phone : +33 3 20 97 42 11 – olivier.briand@univ-lille.fr Effects of maternal obesity on glucose homeostasis and susceptibility Christophe BRETON, UMR 1283-8199 INSERM/CNRS. Faculté de 38 to type 2 diabetes in offspring Médecine - Pôle recherche, 2ème étage (ouest), 1 place de Verdun, Lille. Tel: 03 20 62 68 28. Mail : Christophe.breton@univ-lille.fr Role of cell cycle and inflammation regulators in the dedifferentiation Jean-Sébastien ANNICOTTE – INSERM U1283/CNRS UMR 8199 EGID – 38 of pancreatic β cells during type 2 diabetes and aging. Faculté de Médecine - Pôle Recherche, 2ème étage Ouest- place de Verdun - Lille – 03 20 97 42 54 – jean-sebastien.annicotte@inserm.fr Epigenomic reprogramming of pancreatic β cells during type 2 Jean-Sébastien ANNICOTTE – INSERM U1283/CNRS UMR 8199 EGID – 39 diabetes. Faculté de Médecine - Pôle Recherche, 2ème étage Ouest- place de Verdun - Lille – 03 20 97 42 54 – jean-sebastien.annicotte@inserm.fr Implementation of in ovo electroporation technique for the Florence PETIT - EA7364 – RADEME, Université de Lille - Clinique de 39 characterization of regulatory sequences involved in limb génétique, Hôpital Jeanne de Flandre, CHU Lille, LILLE. Tél: development 0320 444 911 - Fax : 0 320 444 901 florence.petit@chru-lille.fr EMT mechanism and stem cell state in pancreatic cancer and their Kaja BALCER - Kaja.balcer@gmail.com - 06.79.16.47.39 - Laboratoire 40 implication in chemo resistance to FOLFIRINOX. accueil : Canther UMR9020 CNRS - U1277 Inserm Differential single-cell sequencing analysis of drug resistant Meyling CHEOK - meyling.cheok@inserm.fr - "CANTHER" - UMR 9020 40 subpopulation in acute myeloid leukemia CNRS - UMR-S1277 Inserm - Team "Factors of Leukemic cell Persistence" – IRCL - place de Verdun, LILLE - +33 (0)3 20 16 92 13 The Role of Pancreatic Stone Protein / Regenerating Protein (PSP/reg) Caroline BONNER, Institut Pasteur de Lille / Inserm U1190 Translation 41 in islet cell regeneration and diabetogenesis (M2 Precision Health). Research of Diabetes: phone: +33 (0) 32 06 23 413 ; email : caroline.bonner@univ-lille.fr
Cellular Integrative and Translational Neuroscience
Titre: Role of talin mechanotransduction in synaptic plasticity Sujet: Molecular Mechanisms of Hypothalamic Wiring Mentor: Sebastien G. BOURET - sebastien.bouret@inserm.fr Tuteur: Devrim KILINC - devrim.kilinc@pasteur-lille.fr The growing prevalence of obesity and associated type II diabetes is a Talin is an integral component of the protein complex that couples the major health concern, particularly among children. Recent evidence has cytoskeleton to the synaptic machinery, members of which have shown that obesity might be a consequence of alterations in the recently been implicated with Alzheimer’s disease. Each talin molecule developmental processes of neuronal systems involved in energy contains 13 mechanosensitive switch domains each of which can balance regulation, including the hypothalamus. The complex patterns assume an open/closed conformation depending on the changes in of neuronal wiring in the hypothalamus depend on a series of contractility due to acting force, leading to the differential activation of developmental events that establish a framework on which functional multiple signaling pathways. The role(s) of talin conformational changes circuits can be built. In particular, growing axons must then choose a and mechanotransduction in synaptic signaling and plasticity remains path to follow and must decide the direction to go on this path to unknown. This project aims to characterize talin conformational states innervate the proper nucleus or to avoid other nuclei. The rate and and mechanical tension across talin in vitro using fluorescent probes direction of axon growth are defined by diffusible axon guidance cues. and biosensors. Different talin conformations will be visualized and We recently published that development of hypothalamic circuits forces on talin will be measured in primary neurons cultured in requires semaphorins, which act as chemoattractive axon guidance microfluidic devices permit exclusively access synaptic regions and molecules1. Preliminary data from the lab also indicate that Slit, which expose them to Alzheimer’s disease-related synaptotoxic molecules. is most widely known as a repulsive axon guidance cue, is highly Chemical induction of synaptic plasticity will be used to explore the role expressed in the ventromedial nucleus during critical periods of of talin mechanotransduction in synaptic plasticity. In summary, this hypothalamic development. The overall hypothesis of this Master project will couple mechanobiology with neurobiology to describe project is that Slit signaling in the ventromedial nucleus repulses whether (i) changes in the shape of talin molecules occur during surrounding axons and that disruption of Slit signaling in the synaptic signaling and (ii) if these shape changes are involved in synaptic ventromedial nucleus disrupts hypothalamic development causing plasticity during physiological and disease-mimicking conditions lifelong metabolic perturbations (including obesity and type 2 diabetes). Loss of function mouse genetic (Cre/LoxP, adenoviruses), neuroanatomical (axon tracing), and physiological (metabolic cages) approaches will be used to test this hypothesis. 1van der Klaauw A#, Croizier S#, Mendes de Oliveira E, Banton M, Stadler L, Kong Y, Hendricks A, Tandon P, Keogh J, Park S*, Papadia S, Henning E, Bounds R, Bochukova E, Mistry V, O’Rahilly S, Simerly RB, INTERVAL, UK10K consortium, Minchin JEN, Barroso I, Jones Y, Bouret SG*, Farooqi IS*. *co-senior/corresponding authors. Semaphorin 3 signaling directs the development of hypothalamic melanocortin circuits involved in mammalian energy homeostasis. Cell, 176(4):729-742, 2019 9
Title: Qualitative aspects of memory processing in Alzheimer's disease and Title: Modelling in vitro brain networks involved in early stages of related disorders Alzheimer’s disease Supervisor: Maxime BERTOUX - maxime.bertoux@inserm.fr Supervisor: Sophie HALLIEZ, sophie.halliez@inserm.fr Behavioural variant frontotemporal degeneration (bvFTD) and Alzheimer’s disease (AD) are the most common cognitive degenerative diseases around 65 years old. For two decades, memory assessment was employed to distinguish both diseases Tauopathies are neurodegenerative diseases characterized by the clinically. The traditional clinical heuristic assumed that amnesia was a abnormal aggregation of the tau protein. Tau is a microtubule- characteristic of AD but not bvFTD. Recent studies however highlighted that severe associated protein that exist in the brain under multiple forms. In some amnesia could be observed in 50% of patients with bvFTD. Given the sporadic tauopathies, notably Alzheimer’s disease (AD), the distribution predominance of frontal atrophy in bvFTD, the classical approach would interpret of aggregates occurs in a stereotypical pattern among connected brain memory deficits in bvFTD as originating from a failure of strategic mnemonic regions that correlates with disease severity. Together with other processes linked to executive functioning. By contrast, memory deficits in AD would be interpreted by such models as impairments of memory storage and experimental evidences, this has led to propose that a cell-to-cell consolidation processes, in relation to hippocampal degeneration. Numerous and transfer of pathological tau species underlies the progression of these relevant evidences published from the past years however suggest that this view diseases. However, the existence of neuronal connections between two is outdated. Nevertheless, the qualitative explorations of memory deficits in bvFTD regions is not a sufficient condition to allow tau pathology propagation and AD that would allow to update this theory are still rare, as past studies were between them. This indicates regional/cellular specificity in the cell-to- only focused on quantitative performance. cell transfer of tau and/or in disease development. The present project aims to perform a qualitative study of memory performance The project aims to model in vitro the transfer of different tau species in bvFTD and AD. A short bibliographic phase will be first conducted to identify the different indicators of strategic mnemonic organization in words-list based tests. among neural networks. This will be performed through organotypic Then, the student will qualitatively analyse the individual performance of bvFTD brain slice cultures and/or primary neural cultures in microfluidic and AD patients (with and without neuropathological confirmation of diagnoses) devices and/or MicroElectrode Arrays. The system will allow both at the Free and Cued Selective Reminding Test. The project is retrospective: data network functional characterization and evaluation of cell-to-cell tau are already acquired and most of the neuropsychological records have been transfer via imagery technics. extracted from the clinical database of the Lille Memory Clinic. The student will record and measure the primacy and recency effects, index of subjective clustering, concreteness effects. S.he will also perform a count of errors and intrusions committed during the recall phases of the test, which will be classified in different types. The findings of the project should allow to update the traditional theory opposing frontal vs hippocampal functioning during the clinical memory assessment. It should also provide the first qualitative exploration of memory impairments in bvFTD in comparison to AD and has, therefore, the potential to identify key neuropsychological indicators to enhance the clinical diagnosis or help designing future assessment tools. 10
Title: Therapeutic potential of neuroprotection of anti-ferroptotic Title: Benefits of precise visual tasks and laser pointing tasks to improve drugs in Parkinson's disease. postural control in patients with Charcot-marie Tooth Main director: Arnaud DELVAL; co-director: Cédrick BONNET; Tutots : David DEVOS, Jean-Christophe DEVEDJIAN cedrick.bonnet@univ-lille.fr ; https://pro.univ-lille.fr/cedrick-bonnet/ david.devos@chru-lille.fr Patients with Charcot-Marie Tooth (CMT) are unstable upright as a consequence of their peripheral neuropathy. Postural instability is problematic Neurodegenerative diseases are an upcoming tsunami already affecting for everyday activities because it is directly linked to higher risk of falls and millions of people. After 40 years of failure, there is an urgent need of a related injuries. The project’s main objective will be to test the stabilizing game changing strategy for neuroprotective treatment. Degeneration power of performing two sorts of visual task on patients with CMT and healthy occurs in central nervous system regions associated with memory controls. In young adults, the realization of precise visual tasks and pointing (Alzheimer's disease), automaticity (Parkinson's disease, PD) and motor laser tasks is known to be beneficial to improve postural stability. Patients with function (amyotrophic lateral sclerosis), all of which require a high CMT et healthy controls will perform three studies. They will be standing on a oxygen demand for harnessing neuronal energy. force platform and will wear three markers (Polhemus motion system) located In PD, a progressive degeneration of the substantia nigra pars compacta at the head, upper back, lower back levels and an eye tracker (glasses). We will is associated with the appearance of iron accumulation. At a molecular measure kinematic eye and body movements, task performance as well as level, α-synuclein regulates dopamine and iron transport with PD- attentional resources to perform the tasks. The visual tasks will consist of i) maintaining a laser light as best as possible within a central target located in associated mutations in this protein causing functional disruption to front of the participants on a wall (study n°1); ii) localizing targets on pictures these processes. The molecular pathways that cascade down from such as best as possible (study n°2). Patients with CMT should improve their dyshomeostasis still remain to be fully elucidated but strong inroads postural stability more than healthy controls thanks to these visual tasks. In have been made in recent years. We demonstrated that these study n°3, we will study the stabilizing effects of the combination of these two alterations can trigger susceptibility to an iron-dependent cell-death tasks (secondary objective n°1). We will expect that pointing a laser within a pathway with unique lipoperoxidation signatures called ferroptosis. target and localizing targets within images simultaneously should better This project proposes to go further into key modulators of this cell- stabilize patients with CMT and controls than the realization of both tasks death pathway that could be new therapeutic targets against separately. In our secondary objective n°2, we will study 1) if healthy controls ferroptosis using human dopaminergic cell culture and unique murin get better visuo-motor performances than patients with CMT in the three models (GPX4 and ACSL4 KO) with genetic and pharmacologic studies and 2) if performances of patients are closer to the controls’ ones in study n°3 than in studies n°1 and n°2, thus showing the benefits of adding modulation associated with human dosages coming from large cohorts these tasks. Our project should allow us to discuss new therapeutic of patients and clinical trials in progress (European clinical trial Fairpark- perspectives for patients with CMT with respect to visual tasks with/without II) and upcoming (6 new drugs in development). pointing. The doctorate fellow will interact with two neurologists at the regional hospital of Lille (CHRU), one professor of rehabilitation (CHRU) and one American colleague. The experimental setup is ready for an optimal use. Thank you very much to contact Cédrick Bonnet if you would like to discuss this opportunity by zoom meeting. 11
Title: Study of the transgenerational transmission of maternal stress in Title: Maternal stress programs the sex mediated-increased sensitivity to rat: molecular and behavioral approaches cocaine reward in the offspring Supervisor: Sara MORLEY FLETCHER - sara.morley-fletcher@univ-lille.fr Supervisor: Stefania MACCARI - stefania.maccari@univ-lille.fr Perinatal stress in the rat (PRS) programs long-lasting neurobiological and Stressful events occurring during the perinatal period alter the behavioral alterations as increased sensitiveness to psychostimulants. Indeed, programming of the neurodevelopmental trajectory of the offspring in PRS males, we have gathered evidence for greater self-administration of (Maccari et al. 2014). We have shown that exposure to perinatal stress amphetamine and increased sensitiveness to locomotor activation induced by (PRS) in rats induces in the descendants’ long-term behavioral changes and nicotine. In PRS females, we have observed delayed metabolism following molecular alterations at the level of the hypothalamus pituitary adrenal MDMA “Ecstasy” administration. When assessed for place preference in (HPA) axis and circadian rhythms, in association with reduced neurogenesis response to natural stimulants, PRS enhances hedonic sensitivity in males and and glutamatergic neurotransmission in the hippocampus (Marrocco et al. reduces it in females, so PRS males behave like unstressed females, displaying 2012). Males appear to be more vulnerable than females and present a a demasculinized profile for behavioral response and activity of the general profile of demasculinization (being similar to unstressed females) glutamatergic synapse. The enhanced sensitivity to psychostimulants in PRS (Verhaeghe et al. Geroscience, in revision). The alterations induced by PRS rats is associated with changes in sex-dimorphic changes in risk-taking / are persistent along life span up to aging, and are predicted by the reduced exploratory and motivational behaviors. Furthermore, PRS induced maternal behavior as a consequence of gestational stress (Gatta et al. impairment in the glutamate machinery and metabotropic glutamate 2018). Altogether, this indicates the existence of epigenetic signatures receptors system together with an imbalance in the levels of gonadal and mediated by the mother in the programming induced by PRS. By mating stress/anti-stress hormones, a lifelong disruption in the activity of the HPA axis, first-generation (F1) PRS female rats with naïve males and exploring the hippocampal neurogenesis, as well as reduced oxytocinergic tone in the phenotype of F1 and F2 offspring, we have reported that 1) the effects of glutamatergic synapse. The differential impact due to sex on the long-term gestational stress on maternal behavior are transmitted from mother to neurodevelopment programming induced by early life stress is generally an under-explored question. We found that PRS adult rats of both sexes daughter, with a reduction in maternal behavior both in the female developed increased locomotor response to escalating doses of cocaine and a stressed during gestation (F0) but also in their lactating mother offspring greater cocaine-preference in a conditioned place preference (CPP) paradigm (F1) and 2) the effects of PRS in the offspring are transmitted from one with respect to sex-matched unstressed rats. generation (F1) to the second generation (F2), and to greater extent in Aim of this Master's project is to further examine in unstressed and PRS rats of males at the level of HPA axis, BDNF expression and exploratory behavior. both sexes, the effect of a history of chronic cocaine administration on risk- Aim of this Master's project is to further examine in two generations of taking behavior in the light/dark box test and its modulation by the hormonal both sexes of the PRS rat model, the transgenerational effect of maternal status. Furthermore, the project aims to investigate the PRS effects on the stress at the molecular level on the glucocorticoids/oxytocin balance, glucocorticoids/oxytocin balance, glutamatergic neurotransmission, sialylation glutamatergic neurotransmission, sialylation and DNA methyl-transferases and DNA methyl-transferases in offspring of both sexes and assess the role of in offspring of both sexes. Furthermore, this project proposes to study the maternal environment on this programming. The brain region will be the role of maternal environment in this programming. The brain region will be ventral and dorsal hippocampus, dorsal and ventral striatum, prefrontal cortex the hippocampus, a key region in the regulation of emotional processes and amygdala. Training in animal handling, behavioral characterization, qPCR and the stress response. Training in animal handling, behavioral and immunoblotting will be provided. characterization, qPCR and immunoblotting will be provided. 12
Title: Influence of mammary tumor extracellular vesicles on the microglial response in the development of brain metastases. Tutor: Christophe LEFEBVRE -christophe.lefebvre@univ-lille.fr The majority of intracranial tumors develop as a result of brain metastases (visceral dissemination of cancer cells). In this context, it is established that microglia (resident macrophages of the nervous parenchyma) are influenced by primary tumor factors to contribute to the preparation of metastatic niches. Although any peripheral cancer is likely to develop these metastases, the various subtypes of breast cancer account for about 20% of cases. The availability of mixed spheroid models specifically associated with these subtypes of breast cancer allows the in vitro reconstitution of a tumor microenvironment. This microenvironment, composed of cancer cells and immune cells, will be studied for its ability to produce pro-metastatic signals in the form of extracellular vesicles (EVs) even before the cells - in a context that would be in vivo - are able to migrate to other sites. The EVs produced will be isolated, characterized and used as peripheral tumor factors to activate microglia. Their effects on the inflammatory and pro-tumor profiles of microglia will be evaluated as well as on the microglial ability to recruit primary tumor cells by chemotaxis. The objective of this project will therefore be to discover and identify early molecular signals that may constitute new therapeutic pathways to prevent metastatic development. 13
Diabetes and Cardiovascular diseases 14
Title: Circadian regulation of the glycolytic pathway Title: Transcriptional control of hepatic cell phenotypic plasticity Mentor: Philippe LEFEBVRE - philippe-claude.lefebvre@inserm.fr Tutor: JÉRÔME EECKHOUTE - jerome.eeckhoute@inserm.fr Depending on the cellular state which can be very schematically defined https://u1011.pasteur-lille.fr/lunite/theme-4-analyse- as either quiescent (differentiated) or proliferating, glucose usage is transcriptionnelle-integree-des-maladies-hepatiques/ routed either toward a highly efficient slow oxidative phosphorylation, or toward fast, inefficient anaerobic glycolysis respectively. Metabolic The liver exerts instrumental metabolic functions which need to be pathways are submitted to numerous regulations to achieve adaptative constently adjusted to the nutritional and energy status of the body. We responses that match cellular energy requirement and fuel availability. have recently identified that the hepatic transcriptome is controlled by Among these regulations, the circadian rhythm is a major player and a functional interplay between the chromatin structure, the epigenome through components of the molecular clock (CMC), cellular responses and several transcriptional regulatory complexes. In this context, we are are adjusted to the day-night cycle. How the cross-talk between seeking to identify how transcriptional regulators interact with the circadian rhythm and glycolysis takes place is unknown. We have chromatin to ensure specificity and appropriate levels of liver gene discovered molecular interactions between CMCs and glycolytic expression. We are also interested in the perturbation of these enzymes (GE) that potentially control glucose routing toward aerobic or mechanisms in the context of liver dysfunction. We propose a Master 2 anaerobic glycolysis, hence facilitating, or not, cellular proliferation. internship on this topic for a student interested in the elucidation of the Project and technical aspects : The project aim at investigating molecular mechanisms of transcriptional regulation. molecular aspects of the CMC/GE crosstalk. Molecular and cellular biology techniques will be used to characterize cellular metabolic responses after manipulation of expression levels of CMCs and GEs through RNA interference or CrispR/Cas9 gene invalidation. Cellular differentiation and proliferation will be measured. Targeted or unbiased investigations of the transcriptome and/or the proteome will be used to assess the functional consequences of this cross-talk. Objectives : Upon completion of his/her training in an environment fostering scientific interactions, the candidate is expected to master basic cellular and molecular biology techniques and essential analysis tools, to be able to apprehend the general purpose of his/her research project, and to acquire written and oral presentation skills. 15
Title: Characterization of cardiac remodeling during the development Title: Impact of time of day on perioperative immuno-inflammatory of NAFLD (Non Alcoholic Fatty Liver Disease): focus on the role of response and myocardial remodeling after cardiac surgery myocardial immune cells. Mentors : David MONTAIGNE, david.montaigne@chru-lille.fr / Laura Mentors : Laura BUTRUILLE, laura.butruille@pasteur-lille.fr / David BUTRUILLE, laura.butruille@pasteur-lille.fr MONTAIGNE, david.montaigne@chru-lille.fr Aortic valve stenosis is the most common cardiac valvular pathology. NAFLD (Non Alcoholic Fatty Liver Diseases) are hepatic manifestations This valvulopathy is responsible for a chronic obstacle to the ejection of of the metabolic syndrome associated with obesity and type 2 diabetes. the left ventricle (LV). Faced with this high afterload, the LV adapts by The term NAFLD refers to the progressive succession of the NAFL (Non increasing its muscle mass. This initially adaptive remodeling Alcoholic Fatty Liver) stage characterized by the presence of hepatic contributes to the development of intra-myocardial fibrosis and an steatosis, followed by the NASH (Non Alcoholic Steato-Hepatitis) stage alteration in the relaxation and compliance of the LV. Myocardial characterized by the presence of hepatic steatosis and inflammation. remodeling thus becomes maladaptive and leads to heart failure. In the long term, NASH can lead to hepatic fibrosis, ultimately leading Aortic valve replacement (AVR) is the only therapeutic option. to cirrhosis or cancer. These chronic hepatic pathologies have no Pre-clinical studies establish a link between circadian rhythm, treatment to date, and numerous epidemiological studies report an inflammation and cardiac remodeling. We have recently demonstrated increased risk of developing cardiovascular pathologies such as that aortic valve replacement (AVR) is associated with fewer atherosclerosis, heart failure or arrhythmia in these patients. However, complications when performed in the afternoon vs. morning. We the mechanisms linking NAFLD to cardiac pathologies are imperfectly hypothesize that the biological clock modulates intraoperative understood. Our initial results suggest a deregulation of the innate immune cell recruitment and thus the healing process and myocardial immunity induced by NAFLDs, favoring the development of intracardiac reverse remodeling after AVR. We wish to complement our clinical inflammatory foci and fibrosis in the atria and ventricles. The project observations with a pre-clinical study in a mouse model. We will consists in characterizing these mechanisms in a mouse pre-clinical perform a transcriptome and epigenome on circulating leukocytes model. The description of hepatic and cardiac phenotypes will be based after surgery in the morning vs. afternoon to determine the impact of on macroscopic observations, functional cardiac stimulation tests, circadian rhythm on the systemic inflammatory response. We will histological analyses, gene and protein expression analyses and analyze intra-myocardial inflammatory cell populations using a complete immunophenotyping. These data will reinforce the clinical complete immunophenotyping. Finally, we will define the impact of studies carried out on myocardial biopsies obtained during cardiac REV-ERBɑ nuclear receptor and clock gene signaling on leukocyte surgery and the post-operative follow-up of patients from a Lille cohort epigenetic signatures and cardiac remodeling in this animal model. generated at the Heart-Lung Institute (POMI-AF: NCT03376165). 16
Title: Pathophysiological role of amino acids involved in the one carbon Title: FASTRIP- Targeting strategy for the inhibition of FAT10/PPARα interaction metabolosm in NAFLD: analysis of the molecular mechanisms of the to treat NASH variations observed in a cohort of patients Tutor: Réjane PAUMELLE-LESTRELIN. rejane.lestrelin@univ-lille.fr Tutor: Guillaume GRZYCH - guillaume.grzych@chru-lille.fr Non-alcoholic fatty liver disease (NAFLD) is rapidly becoming the most common NAFLD (Non Alcoholic Fatty Liver Disease), a major public health issue, is the liver disease affecting 80% of the obese population. NAFLD is initiated by the hepatic complication of the metabolic syndrome and is highly associated with accumulation of fat in the liver (steatosis) which evolves to non-alcoholic steato- diabetes and obesity. NAFLD is a progressive pathology characterized by liver hepatitis (NASH). NASH is a risk factor for disabling and deadly liver diseases, such damage due to an accumulation of triglycerides in the liver or isolated steatosis as cirrhosis and hepatocellular carcinoma (HCC), as well as cardiovascular disease. Currently, there is no drug treatment to limit the severity of NASH. In this context, (NAFL Non-Alcoholic Fatty Liver). In case of associated inflammation, NAFL it is important to well characterize the molecular mechanisms responsible for the evolves into steatohepatitis (NASH Non-Alcoholic Steato Hepatitis). Possible development and progression of this pathology in order to provide preventive complications of NAFLD are fibrosis, cirrhosis and hepatocellular carcinoma. and/or therapeutic solutions. The results of the UMR1011 laboratory revealed an The mechanisms inducing NASH from NAFL are still poorly understood. involvement of FAT10/UBD, in NASH progression. FAT10 is a member of the Through a cohort study, we have demonstrated in NASH patients a specific eukaryotic ubiquitin-like protein family not or poorly expressed in normal tissues, metabolic plasma profile involving changes in the amino acids involved in one which expression is increased in inflammatory context. FAT10 contains two UBL carbon metabolism (1C metabolism). This metabolism regulates methylation, domains allowing covalent interaction (FATylation) through ligases (USE1 and which can lead to epigenetic changes. In order to understand the molecular UBA6), or non-covalent interaction, leading its substrates to proteasomal or mechanisms underlying the plasma variations observed in NASH patients, we lysosomal degradation. Transcriptomic analysis showed a high increase of FAT10 wish to study these modulations in a mouse model in which NASH is induced expression in the liver of NASH patients, which correlated positively with steatosis, by a specific diet. The literature reports that activation of the nuclear receptor fibrosis, ballooning scores, and also NASH severity. Interestingly, FAT10 PPARɑ by fenofibrate in a mouse model and in humans leads to a increase of overexpression was associated with a decrease in the expression of the one intermediates metabolite of one carbon metabolism, homocysteine. Since peroxisome proliferator activated receptor-α (PPARα), a nuclear receptor the expression of PPARɑ is itself decreased in NASH, we hypothesize that controlling lipid metabolism and inflammation, as well as a down-regulation of the PPARɑ may be one of the regulators of one carbon metabolism in NASH. The PPARα-signaling pathway. Our results suggest that FAT10 may modulate NASH project aims to analyze plasma and hepatic amino acid variations as well as progression by interacting with PPARα and promoting its deactivation highlighting gene expression variations in a diet-induced mouse model of NASH with FAT10/ PPARα interaction as a new potential target to treat NASH. In this context, control of the expression and/or activity of PPARɑ. The mouse models used the objective of this project is: (1) to well characterize the type of physical will show diet-induced NASH with either genetic inactivation of PPARɑ (total interaction between FAT10 and PPARα; (2) to develop a cellular assay for analyzing Ko or specific Ko in hepatocytes) or pharmacological activation of PPARɑ (by the impact of FAT10/ PPARα interaction on PPARα activity; (3) to transfer the assay on the U1177 screening platform for miniaturization and automation to increase fibrates). Targeted metabolomics analyses by mass spectrometry will be the throughput; (4) to perform the screening of 30 000 compounds of the U1177 performed on plasma and liver samples from these models. Depending on the library to identify molecules inhibiting FAT10/PPARα interaction. metabolome results, gene expression analyses in the liver by Q-PCR or The Master 2 project will be involved in the part 1) and 2) of this project. We expect transcriptomic analysis will identify the genes responsible for the metabolic to identify new molecules disrupting FAT10/PPARα interaction that could enter a variations observed. drug discovery program to ultimately lead to an optimized candidate for a proof of This work will be carried out in collaboration with Dr Joël Haas and Pr Anne concept in murine model of NASH developed in the UMR1011 laboratory. The Tailleux (UMR1011 team 1). results should highlight additional mechanisms of the NASH development and lead to the identification of new therapeutic tools for this disease. 17
Title: Characterization of dendritic cell (DC) and T cell (T) interactions Subject: Characterisation of the metabolic effects of TGR5 activation in in non-alcoholic steatohepatitis (NASH) the gut: study in a murin model using a pharmacological tool Tutor : Anne TAILLEUX - anne.tailleux@univ-lille.fr Supervisor: David DOMBROWICZ – david.dombrowicz@pasteur-lille.fr Background - The intestine is an organ contributing to metabolic and inflammatory homeostasis via 1/ its nutrient absorption function, 2/ its Background. NASH or "fatty liver disease" is a pathology whose metabolically active commensal flora, 3/ its barrier function, by controlling incidence has increased dramatically worldwide and for which there is permeability, 4/ its enteroendocrine function, by synthesising and secreting currently no pharmacological treatment. We have shown (Haas et al. signalling molecules, and 5/ its homeostatic function, through the immune Nat. Metab. 2019), in humans and in an animal model, that this cells it contains. TGR5 is a G protein-coupled membrane bile acid receptor metabolic pathology is associated with profound changes in the expressed by different cell types involved in the regulation of metabolic immune system affecting in particular subpopulations of DCs (cDC1 and homeostasis, in particular the incretin glucagon-like-peptide-1 (GLP-1)- cDC2) and cytotoxic CD8 LTs. These alterations are potentially causal in producing enteroendocrine cells, known for its beneficial effects on metabolic the pathology but the functional mechanisms involved, including homeostasis.A pharmacological tool was developed, consisting of a interactions between DC and LT, remain unknown and these pharmacophore conferring agonist activity on the murine TGR5 receptor and a populations have not been precisely characterized. kinetophore that reduces its intestinal absorption and targets the actions of the molecule in the distal part of the intestine when administered orally. Aim. The aim of the Master 2 is to analyze the phenotypic and functional Hypothesis - Activation of TGR5 in the gut could lead to improved metabolic characterization of CD8 (and CD4) T cells populations. homeostasis, reduced food intake and improved glucose tolerance. Methods. In a mouse model of NASH induced by diet, the hepatic CD8 Objective - In M2, our objective will be to analyse the metabolic effects and and CD4 T lymphocyte populations will be characterized by various their molecular mechanisms of selective activation of the TGR5 receptor in the techniques: flow cytometry, RNA-seq on single cells (with a particular gut by a selective agonist, BDM72881. analysis of the metabolic pathways and of the antigenic receptor of the Methods - In male C57BL6 mice, the effects of acute administration of the T lymphocytes -TCR-), measurements of intracellular metabolism compound BDM72881 will be evaluated by measuring food intake and energy (Seahorse). Depending on the results obtained, interactions with DCs expenditure (metabolic cages), neuronal activation (immunohistochemistry), could be evaluated in functional assays. functional test to assess metabolic homeostasis (OGTT), as well as the Collaboration. This work will be performed in collaboration with Dr Joël determination of peptides co-secreted with GLP-1 (ELISA multiplex). Haas (UMR1011 Team 1). This master 2 project could lead to a thesis project which will evaluate more globally the role of TGR5 in the intestine on endocrine function. Keywords. NASH, T lymphocytes, DC, metabolism, scRNA-seq, Key words - TGR5 receptor, enteroendocrine function, incretins, bioinformatics, functional tests gastrointestinal peptides, metabolic homeostasis, pharmacological approach, biochemical analyses, histological analyses, gene expression measurement. 18
Title: Role of intestinal epithelial nuclear receptor FXR in the Non Title: Role of the mitochondrial protein import machinery in Alcoholic Fatty Liver Disease complication of Type 2 Diabetes angiogenesis in health and disease Supervisor: Sophie LESTAVEL - sophie.lestavel@univ-lille.fr Tutor: Anna Rita CANTELMO - anna-rita.cantelmo@univ-lille.fr The importance of the intestine and its crosstalk with the liver in the development of Type 2 diabetes (T2D) and Non-Alcoholic Fatty Liver Mitochondria exert central functions in bioenergetics, metabolism, and Diseases (NAFLD) has received increasing attention. Notably, the apoptosis. The correct function of these organelles requires the import dysregulation of intestinal endocrine and immune functions play a of > 1000 nucleus-encoded proteins as the mitochondrial genome central role in metabolic diseases and disruption of intestinal provides only 13 proteins. A key component of the mitochondrial permeability worsens T2D and NAFLD. FXR is a nuclear receptor protein import machinery is the evolutionarily conserved expressed in metabolic tissues such as intestine, liver, adipose tissue Mia40/CHCHD4 oxidoreductase that catalyzes the oxidative folding of and pancreas. FXR regulates energy metabolism via the modulation of targeted proteins after they cross the outer mitochondrial membrane. bile acid synthesis, and lipid and glucose metabolism. Our preliminary This mechanism is finely tuned and it is affected in disease. results show that FXR deficiency restricted to intestinal epithelial cells Using a multidisciplinary approach, combining molecular and cellular impacts on gut immune system, even if mice are submitted to a normal biology, and in vivo mouse models, this project aims at i) studying the chow diet. We have submitted, for 24 weeks, C57Bl/6 mice deficient for role and functional relevance of Mia40/CHCHD4 in endothelial cells, and FXR only in the epithelial cells of their intestine (intFXR KO mice) and ii) characterizing the signaling pathways that impact on the their control littermates to a control or a NAFLD-inducing diet. Mia40/CHCHD4-dependent import pathway in angiogenesis in disease. The M2 internship period will be devoted to the processing of the The working hypothesis is that aberrant activity of this import pathway samples we collected during the diet and at sacrifice. intFXR KO mice drives pathological angiogenesis. and their control littermates will be characterized on chow and NAFLD- The results generated with this project promise to provide inducing diet regarding progression of the hepatic pathology (body unprecedented insights that will be useful for the development of novel weight monitoring, plasma ASAT/ALAT by ELISA, qPCR and histology of therapeutic strategies for a variety of human diseases characterized by the liver) in relation to intestinal health (gut histology and dysfunctional vasculature, such as cardiovascular disorders and cancer. immunofluorescence) and gut permeability (serum IgA by ELISA). The study of the intestinal immune system and the immune cell recruitment will be performed in small intestine and colon (biocomputing and statistical analysis of immunophenotyping data generated at the sacrifice, qPCR, and immunofluorescence). This program should strengthen the preclinical proof-of-concept of FXR as a potential pharmacological target for the treatment of diabetes and its NAFLD complication. 19
Title: The nuclear receptor Rev-Erbα: a new player in intestinal dietary Title: Brown adipose tissue from embryo to adult: implications in lipid metabolism? metabolic diseases Supervisor: Olivier BRIAND – olivier.briand@univ-lille.fr Tuteur : Alicia MAYEUF-LOUCHART - alicia.mayeuf-louchart@inserm.fr Obesity and diabetes are multifactorial chronic diseases whose etiology Brown adipose tissue represents a new therapeutic target for the is an imbalance between energy intake and expenditure. Significant treatment of metabolic diseases. When activated by different stimuli abnormalities of intestinal functions, including overproduction of such as exposure to cold, brown adipose tissue metabolizes about 20% triglyceride-rich lipoproteins, accompany these metabolic disorders and of the daily energy intake. Some of the glucose taken up by brown contribute to the development of atherosclerosis and fatty liver disease adipocytes is stored as glycogen. However, little is known about the role (NAFLD). The nuclear receptor Rev-Erbα integrates the biological clock of glycogen and its fate in brown adipocytes. We recently published a with metabolism in major organs. Based on our current work, we paper showing that glycogen dynamics (formation and degradation) is hypothesize that Rev-Erbα in the gut is a key molecular player in the essential for the formation of lipid droplets during brown adipocytes orchestration of dietary lipid metabolism, as well as in the control of differentiation. lipoprotein production. The objective of this project is to study glycogen metabolism in brown This M2 project is focused on studying, in ex vivo organoid (or mini-gut) and beige adipocytes, in order to determine whether its metabolism models from human and murine origin, the mechanisms involved in the may represent a potential target for improving brown adipose tissue control by Rev-Erbα of the intestinal postprandial lipidemic response. activity in the context of metabolic diseases. The inhibition in enteroids of the expression of candidate target genes, This study will be based on experiments in the mouse model, during coupled with the use of inhibitors of biological processes (lipophagy, development and in adults under different pathophysiological vesicular trafficking...) will allow to elucidate the molecular conditions. During the M2R, the student will carry out experiments in mechanisms. The link with the clinic will be achieved by using histology (tissue sections, staining, immunoshistochemistry, pharmacological modulators of Rev-Erbα microscopy), cell biology (cell culture, immunohistofluorescence, The approaches used are based on cell and molecular biology confocal microscopy), molecular biology (RNA extraction, RTqPCR) and techniques (gene and protein expression analysis, indirect metabolism (biochemical assays). This project aims to initiate a thesis immunofluorescence, gene invalidation and overexpression...). This project. project is based on an important work of cell culture and image analysis. 20
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