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INFINITE offers a unique research environment around inflammation. INFINITE welcomes scientists, clinicians doctors, pharmacists, students, manufacturers and innovators in a very open structure, which fosters creativity, promotes innovation and includes all types of skills.
You will find below our PhD program, internship and job offers.

Master 2 subject proposed by Cécile Vignal

Effets d’une exposition périnatale aux nanoparticules sur la santé intestinale chez la souris

Tuteur : Cécile Vignal – This email address is being protected from spambots. You need JavaScript enabled to view it.

 

description du projet : Les maladies inflammatoires chroniques de l’intestin (MICI) sont des pathologies multifactorielles qui se caractérisent par une inflammation d’une partie de la paroi du tube digestif. L’origine de ces pathologies est mal connue. On suppose aujourd’hui qu’elles résultent d’une anomalie de la réponse immunitaire de l’intestin survenant chez des individus génétiquement prédisposés. De nombreux gènes de susceptibilité pour ces maladies ont été identifiés mais ils ne permettent d’expliquer qu’une fraction mineure de leur développement. En revanche, de plus en plus d’arguments soulignent l’importance des facteurs environnementaux dans leur survenue. Notre équipe s’intéresse à la notion d’origine développementale de ces maladies et en particulier la période critique que constitue la vie embryonnaire. Notre projet consiste en l’étude des effets d’une exposition de la souris gestante aux nanoparticules sur la santé intestinale du petit de sa naissance à l’âge adulte. Les effets seront évalués sur des marqueurs histologiques, moléculaires et fonctionnels.
Ce projet permettra de mieux comprendre l’impact d’une exposition périnatale aux facteurs environnementaux sur la survenue à l’âge adulte d’une maladie chronique ainsi que la fenêtre d’opportunité qu’offre cette période pour la prévention.

Master 2 subject proposed by Mathilde Body-Malapel


Etude des altérations de la défense contre les infections pulmonaires suite à l’exposition aux particules de l’air

Tuteur : Mathilde Body-Malapel (Infinite-U1286)– This email address is being protected from spambots. You need JavaScript enabled to view it. et Muriel Pichavant (CIIL) - This email address is being protected from spambots. You need JavaScript enabled to view it. 

 

description du projet : L’exposition à la pollution atmosphérique a été montrée comme augmentant les risques d’infections respiratoires mais les mécanismes ne sont pas connus. Le but de ce projet est d’étudier les effets de l’inhalation de particules de l’air sur la défense de l’hôte contre 2 types d’infections respiratoires : les infections par Streptococcus pneumoniae et par Haemophilus influenzae non typable.
Des souris seront exposées en chambre d’inhalation à des particules de l’air à des taux similaires à ceux rencontrés en cas de pic de pollution atmosphérique. Les phases d’exposition aux particules atmosphériques se feront soit en amont, soit pendant la phase de développement des infections. L’impact de l’inhalation des particules de l’air sur la défense contre les infections respiratoires sera déterminé sur les taux de survie, les taux bactériens pulmonaires, le recrutement de cellules immunitaires et l’expression de cytokines au niveau pulmonaire. Des cibles mécanistiques seront identifiées par cytométrie en flux et microarray, et ces pistes seront étudiées à l’aide de souris spécifiquement invalidées pour la cible ou de molécules modulatrices de cette cible.
Ce projet devrait permettre de mieux comprendre comment la pollution atmosphérique altère la réponse immunitaire contre les infections pulmonaires et de proposer d’éventuelles pistes thérapeutiques.

Master 2 subject proposed by Mathilde Body-Malapel

Importance de la réaction de sevrage dans la programmation pathologique de la susceptibilité aux additifs alimentaires.

Tuteur : Mathilde Body-Malapel (Infinite-U1286)– This email address is being protected from spambots. You need JavaScript enabled to view it.

 

description du projet :La réaction de sevrage a lieu entre le 14ième et le 28ième jour de vie chez la souris en réponse à la diversification de l’alimentation. Il se produit alors un boost inflammatoire au niveau de l’iléon, et l’absence de cette réaction provoque à l’âge adulte une susceptibilité aux modèles expérimentaux d’inflammation intestinale. D’autre part, certains additifs alimentaires sont soupçonnés de favoriser le développement des maladies inflammatoires chroniques de l’intestin (maladie de Crohn et rectocolite hémorragique), car leur ingestion provoque une inflammation intestinale de bas grade.
Notre hypothèse est que les sujets rendus susceptibles à l’inflammation intestinale par un défaut de réaction de sevrage vont présenter une hypersensibilité aux additifs alimentaires.
L’effet de l’intoxication de l’alimentation par des additifs alimentaires sera comparé à l’âge adulte entre des souris ayant développé une réaction de sevrage normale et des souris chez lesquelles la réaction de sevrage aura été inhibée. Les effets de l’intoxication alimentaire seront évalués sur des paramètres cliniques, histologiques, et moléculaires d’inflammation colique et iléale.
Ce projet permettra d’apporter un lien entre la programmation pathologique périnatale et les facteurs de risque environnementaux et donc de mieux comprendre les conditions dans lesquelles les additifs alimentaires entrainent le développement de symptômes digestifs.

Mobility offer - Assistant Engineer

Le LIRIC is looking for an Inserm Assistant Engineer in mobility

Profile of the vacancy

Thesis project proposed by David LAUNAY

INTERACTION BETWEEN B-CELLS AND SKIN IN SYSTEMIC SCLEROSIS

Thesis Director: David LAUNAY

 

Keywords : systemic sclerosis, B lymphocytes, fibrosis, organoids, omics

Profile and skills required: Dynamic and motivated candidate Autonomy Expertise in cell culture, RT-PCR, FACS, histology, western-blot Knowledge in Immunology

Project description:

Fibrosis is a major health problem in modern societies. Recognized as a common consequence of a wide spectrum of chronic diseases, fibrosis is associated with a high morbimortality mainly because of organ failure and is responsible for almost 45% of deaths in the developed world (1). Among chronic diseases, immune-mediated inflammatory diseases (IMIDs) are a frequent common cause of fibrosis and have been useful to decipher mechanisms of aberrant fibrogenesis. Especially, the role of inflammation and immune system in fibrosis have greatly benefited from the study of IMIDs. IMIDs include both organ-specific diseases like digestive (e.g. inflammatory bowel disease (IBD), and lung inflammatory diseases (e.g. lung fibrosis) and systemic inflammatory diseases like connective tissue diseases, which are characterized or can be complicated by fibrosis, with a major impact on morbimortality. To date, the lack of effective therapies to prevent or reverse fibrosis is a major issue, especially in IMIDs. Among connective tissue diseases, systemic sclerosis (SSc) has the highest mortality from all inflammatory rheumatologic disorders and a heavy morbidity (2). SSc is characterized by progressive skin and organ fibrosis. Its pathophysiology is characterized by an aberrant activation of the immune cells and uncontrolled fibrogenesis. SSc is both a dismal disease and a therefore a very interesting and prototypical representing model to decipher the role of the immune system in fibrogenesis in IMIDS and beyond.

State-of-the-art

SSc is the most severe connective tissue disease. It is characterized by skin and organ fibrosis (mainly interstitial lung disease, which the host team we showed to concern 40-50% of patients together with severe vascular complications such as pulmonary arterial hypertension (PAH in 5-10%), renal crisis (2%), and digital gangrene (5%) (Figure 1)

SSc pathogenesis is characterized by three pillars: (1) early vascular abnormality leading to endothelial injury and subsequent hypoxia; (2) disturbed immune response such as altered T and B lymphocyte functions and production of proinflammatory and profibrotic cytokines (such as IL-6 or TGFß) that promote secondarily (3) mesenchymal cell disturbances with transition to myofibroblast that produce in excess extra-cellular matrix components and lead to fibrosis (Figure 2).

Interestingly, this pathophysiology is common for all the fibrotic complications of SSc including skin and organ fibrosis.

Within the immune system, B cells play a central role in SSc pathophysiology, as recently reviewed by the host team (Figure 3). Indeed, beyond the simple production of autoantibodies useful for the diagnosis of the disease, B cells homeostasis and functions are disturbed during SSc, mainly through a dysregulation of B cell receptor (BCR) signaling and an overproduction of B cell survival signals (Forestier et al.). These alterations of B cell homeostasis induce several dysfunctions, some of them possibly involved in the inflammatory and fibrotic events observed during SSc: pathogenic autoantibody production, secretion of pro-inflammatory and pro-fibrotic cytokines (like IL-6), alteration in IL-10 producing regulatory B cells and direct cooperation with other cells involved in SSc pathophysiology (fibroblasts, T cells…). Moreover, anti CD20 therapy and other B cell targeted therapy in SSc pathophysiology (fibroblasts, T cells…). Moreover, anti CD20 therapy and other B cell targeted therapy show promising results could become attractive options in this disease (Thiebaut M et al.). Finally, B cells are found in most fibrotic tissue in SSc including the skin and the lung (3) as well as in other fibrotic IMIDs (4) and are markedly reduced after B-cell targeted therapy in SSc (Lafyatis et al.). We also recently showed that B cells infiltrates the skin in an experimental model of SSc (5).

In order to better understand how B-cells could have a direct role in the aberrant fibrogenesis observed in SSc, some authors assessed the interactions between B-cells and fibroblasts, trying to make a link between the B cell infiltration observed in the skin and the aberrant fibrogenesis. Indeed, the most important extracellular matrix-producing cells are the fibroblasts and their dysregulation explain fibrosis. In human SSc, Francois et al. showed that normal B-cells co-cultured with human SSc dermal fibroblasts were potent inducers of collagen and TIMPS (Tissue Inhibitor of metalloproteinase) production by fibroblasts, profibrotic cytokines and TIMPS (Tissue Inhibitor of metalloproteinase) involving cell-cell contacts and TGF-ß (15). Dumoitier et al., did not explore cell-cell contacts but rather supernatants of activated or resting B-cells culture and showed that fibroblast proliferation and collagen production were also significantly increased in the presence of B cell supernatant from SSc patients as compared to healthy controls, (29). This direct role of B cells on fibroblast has also been studied in other conditions. For example, Störch et al., have studied the interaction between B-cells from healthy donors with fibroblasts from patients with osteoarthritis. They did not observe any overexpression of profibrotic markers but rather an overexpression of proinflammatory markers (IL-6, IL-8 and metalloproteinase 3 (MMP-3)).

In animal models, the supervisor’s team has shown from cultures between splenic B-cells from a mouse model of SSc and 3T3 syngeneic fibroblasts, that: (i) interactions between fibroblasts and B cells enhance the B cells survival ; (ii) non-activated B cells promote a profibrotic profile on fibroblasts, with the expression of fibrosis genes by fibroblasts; (iii) • activated B cells have no direct profibrotic effect • on fibroblasts, but rather induce a • proinflammatory profile, with a marked synthesis • of IL-6 by fibroblasts (unpublished-preliminary results).

Yet, many aspects have not been addressed so far in human SSc on the interaction between B cells and the skin : no study has focused on the cellular interactions between B cells from patients with SSc and fibroblasts; no study has assessed whether or not, the activation status of B cells could modify the cellular interactions with fibroblasts in patients with SSc; and no study has assessed the impact on B cells of the cell-cell interactions with fibroblasts the skin. The model used have been two-dimensional (2D) culture system of fibroblasts, which are not reflecting what is ongoing in vivo, while attractive skin models including fibroblast in a more physiologic environment are quickly developing (6). Furthermore, the cell-cell interactions have been assessed with simple conventional approach (RT-qPCR), while modern approaches including single cell RNA-Seq have not been used. The latter has yet allowed a dramatic increase in the understanding of fibrosis pathophysiology (7).

Our project thus aims to go beyond the current state-of-the art by directly assessing the interactions between SSc B cells and skin in innovative models and approaches, which has never been done before. Beyond deciphering the direct role of infiltrating B-cells in organ fibrosis in SSc, it will provide very important data on the role of B-cells in fibrosis in general, on B-cells modifications in fibrogenesis and pave the way of innovative treatment in SSc and in fibrotic IMIDs.

The overall objective of this project is to investigate the direct interactions effects between B cells and skin in SSc to answer 2 scientific questions: 1. what are the effects of B cells (activated or not) on human skin models in SSc? 2. what are the modifications induced in B cells by their contact with human skin models in SSc?

The specific objectives will be

  • O1. to define optimal conditions of co-culture and analysis of the impact of B cells in the healthy skin model (task 1)
  • O2. to implement a 3D full thickness skin organoid model obtained from SSc patients (task 2)
  • O3. to assess the impact of B cells in the SSc 3D full thickness skin organoids to assess whether SSc B cells can modify the fibrotic profile (task 3)
  • O4. To assess by in depth analysis the molecular impact of SSc B cells on fibroblasts and keratinocytes both in the healthy and SSc skin models (task 4)
  • O5. To assess by in depth analysis the molecular impact of healthy and SSc skin models on SSc B-cells (task 5)

Thesis proposed by Cécile Vignal

Impacts of a food contaminant on the microbiota and intestinal homeostasis in humans

thesis supervisor: Cécile VIGNAL / Ariane LEROYER

mail: This email address is being protected from spambots. You need JavaScript enabled to view it.

 

details about the project :
Deoxynivalenol (DON), a mycotoxin produced by Fusarium species, is a frequent contaminant of grains and cereal products worldwide. DON causes many toxic effects on growth, immune response, reproduction, development… At the intestinal level, DON has been demonstrated to affect key immune functions which could lead to the induction and/or persistence of intestinal diseases. Study of the potential link between DON exposure and human Inflammatory Bowel Diseases (IBD) is the global aim of this proposal. Indeed, the different actors participating to the pathophysiological process leading to IBD development are still not well understood. We hypothesize that an improper detoxification of DON, implicating the gut microflora and/or endogenous enzymes, would lead to an increased susceptibility to DON toxicity in IBD patients. The objectives of this proposal are to compare, in healthy and IBD suffering individuals: 1) the cartography of DON absorption, distribution, metabolism and excretion; 2) the detoxification of DON by the gut and the consequences of DON exposure in term of immune homeostasis; 3) the effects of DON on the gut microbiota composition and the reciprocal effect of the gut microbiota on DON metabolism studied in vitro. The study of consequences of oral subchronic exposure of DON in humanized gnotobiotic mice colonized with a healthy or an IBD patient microbiota is our fourth objective. Our proposal is interdisciplinary bringing together gastroenterologists and researchers on nutrition, risk assessment, pathophysiology and microbiology.

keywords: dietary contaminant, gut microbiota, immunity, gut homeostasis

required skills: strictness, team work, motivation