Evaluation report

This report is the sole result of evaluation by the expert committee, the composition of which is specified below.

The assessments contained herein are the expression of an independent and collegial reviewing by the committee.

Unit name:

Laboratory In June 2015, the EA481 assembled hospital-university professors and lecturers (psychiatrists, neurologists, radiologists, anatomists and geneticists …) and full-time researchers. On January 1 st , 2017, members from the EA3922 'Estrogen, gene expression and pathologies of the central nervous system' will join the unit to bring preclinical models on feeding behaviour.

The LICN is located at the faculty of Sciences and techniques, at the University of Besançon. The LICN is one of the units of the federative research structure (Structure Fédérative de Recherche -SFR) SFR FED 4234 INSERM -Cellular and Tissular engineering and biology.

Management team

Mr Emmanuel HAFFEN is the director of the unit since the mid-term evaluation in 2014. Mr Jean-Louis MILLOT was the previous director of the unit.

HCERES nomenclature

SVE1_LS5 Neurosciences

Scientific domains

The LICN conducts research in two thematic areas: 1. Decision making -Reward and 2. Perception -Hedonia. The LICN is focused on the development and evaluation of new diagnostic and therapeutic methods and on the understanding of pathophysiological mechanisms in various pathologies including, mood disorders and neurodegenerative diseases, cerebrovascular pathologies, genetic disorders with cognitive repercussion, conduct attachment disorders. Theme 1: Decision making-Reward. Decision-making is altered in several pathologies such as psychiatric diseases (mood disorders, eating disorders, addictions, etc.) and neurological diseases (neurodegenerative diseases, stroke, multiple sclerosis). This axis concerns the study of the pathophysiological mechanisms of decision-making and some of its components using in vivo studies, pre-clinical and clinical studies with subjects or patients (depressed patients, movement analysis in subject). This theme is using different tools (Electrophysiology Electroencephalography ). An exploration of the cortico-subcortical network anomalies (limbic system, prefrontal cortex), to better understand the pathophysiology of the disease, is proposed and validate the use of non-invasive techniques of transcranial stimulation as therapeutic tools.

Theme 2: Hedonic-Perception. This thematic axis uses a multidisciplinary and translational approach from animal models to healthy controls subjects and patients with neuropsychiatric illnesses. The committee emphasizes that the unit's originality lies in the choices of emotional stimuli, such as odours, or the modelling / manipulation of generating precise sources of emotions. The LICN relies here on its behavioural, electrophysiological and immunohistochemical expertise.

Global assessment of the unit

The LICN gathers most, if not all, of the neuroscientists working in the hospital and the university environment in Besançon. As mentioned before, the LICN in its current form is built around 2 already promising research themes. The first theme consists of an original angle on 'decision making reward', which concerns the translational evaluation of neurostimulation techniques (rTMS and tDCS). The second theme (Hedonic -Perception) consists of another translational and proven fruitful model of research on emotional responses to olfactory and gustatory stimuli. The interactions between the two research themes reveal already that for the past five years not only the number, but also the scientific quality, of the publications have significantly increased. Funding seems solid and research collaborations involve other research teams at the local, national and international level. The LICN clearly makes efforts to promote national and international scientific collaboration.

Strengths and opportunities in the context

One of the strengths of LICN is the access to research platforms, which have been structured over the five past years and cover all of the methodologies requested to achieve the scientific program: Genomics and histopathology, Brain imaging, Electrophysiology, Non-invasive brain stimulation, Movement analysis and eye tracking and Animal facility. The association with specialists in neuro-and psychopathology for axis 1 and for axis 2 looks optimal to lead and coordinate the research activity of each axis according to their specific objectives. The numbers of engineers and support increased as requested.

One of the strongest opportunities of the LICN is the possibility to work around with translational models of neuro/psychopathology within the different strong areas of expertise. In this line, the combination with NIBS (Non-Invasive Brain Stimulation) techniques is not only a strength but also a major opportunity to understand brain function and to develop treatment algorithms for neuropsychiatric diseases. Furthermore, the favourable positioning of the LICN in translational research -in particular with the industrial world (COVALIA, DIXI-Microtechnique, etc.) -should promote interactive doctoral and postdoctoral training with engineers, science and technology, human and social sciences.

Weaknesses and threats in the context

In terms of human resources, on one hand, a researcher is retiring and another full-time researcher is envisaged to join the team; on the other hand, the unit is going to host several new associate professor members. Both changes will be a challenge for adaptation and integration. A more accurate description of who will do what would be welcome. Although the large number of new researchers seems to be distributed between the two research axes, how exactly this integration will affect the development of the existing research themes is not optimally defined yet.

Recommendations

Although the creation of the two research axes is a good and clever choice, the committee feels that future projects may benefit from an optimal collaboration among team members. This will be of special importance when the new research members will join the LICN. To optimally prepare for this new organisation, the axis supervisors may do well to clearly define the place of these new members within their teams according to their specific scientific projects. This organization is not clearly identifiable yet, but is of major importance.

Currently, the relevant scientific output of the LICN is difficult to assess because a large part of the publication list does not fit to the two research axes, but rather reflects the scientific production of individual team members in their own field of expertise. The EA481 may do well for its visibility by clearly distinguishing the two themes of research.

  location of the unit The research team, Laboratory of Integrative and Clinical Neurosciences (LICN) (EA481 or 'Équipe d'Accueil' 481) exists since 1996. It was originally composed of university professors and lecturers in the domains of biology and physiology, interested in neuroscience research focused on olfactory in animals and humans interacting with psychiatric and/or neurological problems. This was in the field of medical and health research at the University of Franche-Comté. Since 2008, the EA481 fruitfully integrated researchers and research professors from two university faculties: Faculty of Science and Techniques and Faculty of Medical and Pharmaceutical Sciences. Following the AERES evaluation in 2011, a midterm evaluation visit was hold in 2014 by a panel of scientists invited by the university. This led to a change in the unit's direction, with Mr Emmanuel HAFFEN superseding the former director, Mr Jean-Louis MILLOT. When the new director took on the unit in 2014, the lines of research were reformulated around two themes: 1. Decision making -Reward, and 2. Perception -Hedonia.

N3:N7

  Permanent researchers from Institutions and similar positions 5 5 Other permanent staff (technicians and administrative personnel) 3 10 N4: Other professors (Emeritus Professor, on-contract Professor, etc.) N5: Other researchers from Institutions (Emeritus Research Director, Postdoctoral students, visitors, etc.) N6: Other contractual staff (technicians and administrative personnel) 8 scientists having spent at least 12 months in the unit 1 2  Overall assessment of the unit Introduction According to the recommendations of the AERES in March 2011 the scientific objectives of the LICN have been restructured under two major headings: 1) Decision making and reward, 2) Hedonic -Perception. This scientific reorientation has been brought about in 2014 by a midterm evaluation of the 2010-2015 contracts by a scientific panel invited by the University of Besançon. This reorganization has been a major step for the unit.

  [EEG], Functional Magnetic Resonance Imaging [FMRI] and Positron Emission Tomography Scan [PETScan], olfactory measurement, movement analysis, visual tracking, and evaluation of inflammation mechanisms) and the effect and mechanisms of action of Non-Invasive transcranial Stimulation (NIBS) techniques (repeated Transcranial Magnetic Stimulation [rTMS], transcranial Direct-Current Stimulation [tDCS]

  of Integrative and Clinical Neuroscience

	Unit acronym:	LINC
	Label requested:	EA
	Current number:	481
	Name of Director (2015-2016):	Mr Emmanuel HAFFEN
	Name of Project Leader (2017-2021):	Mr Emmanuel HAFFEN
	Expert committee members
	Chair:	Mr Chris BAEKEN, Department of Psychiatry and Medical Psychology, Ghent, Belgium
	Experts:	Ms Martine CADOR, Université de Bordeaux
		Mr François MAUGUIERE, Université Claude Bernard Lyon (representative of CNU)
	Scientific delegate representing the HCERES:
		Mr Jacques NOËL
	Representative of supervising institutions and bodies:
		Mr Jacques BAHI, Université de Franche-Comté
	Head of Doctoral School:

Mr Thierry RIGAUD, Doctoral school n° 554, Environnements, Santé


Evaluation report

This report is the sole result of evaluation by the expert committee, the composition of which is specified below.

The assessments contained herein are the expression of an independent and collegial reviewing by the committee.

Unit name:

Génétique The research unit started in 1996 with an Inserm Research Contract (CRI) awarded to Mr Claude FÉREC for developing human molecular genetics. The research was initially devoted to the study of the CFTR gene and mutations causing cystic fibrosis, a disease particularly common in Brittany. The late 90s' were a fertile time for molecular geneticists, with the discovery of genes implicated in numerous diseases. Over the years, the unit also initiated new research projects, with a particular interest in chronic pancreatitis, polycystosis and haemochromatosis. Five years later, in 2001, a joint unit, associating Inserm, the local university (UBO: "Université de Bretagne Occidentale") and the French Blood Agency (EFS: "Établissement Français du Sang"), was created.

The Inserm UMR 1078 is currently organized around five main themes: (1) "functional genetics and epidemiology", (2) "gene transfer and gene therapy", (3) "RNA splicing, lipid metabolism and apoptosis control", (4) "yeast models of human pathologies" and ( 5) "channelopathies and calcium signalling". In addition, the unit hosts two technical platforms, one is dedicated to protein production and purification (PURIPROB) and the other is for testing non-viral delivery systems (SynNanoVect).

At the last evaluation, it was suggested by the visiting committee that, given the diversity of themes and the limited overlap between them, the research unit should evolve towards several separated teams. The different themes have therefore continued to be developed as independent research projects with the idea that three different teams could emerge. However, to meet the challenge of personalized medicine and remain competitive, bigger research structures with complementary expertises in different fields are now encouraged. Based on this analysis and also on the good collaboration spirit shared by all the theme leaders of the unit, the different groups of the unit have, thus, decided to stay together within a single entity, with three main themes that will still be developed as independent projects but with the shared objective of a better understanding of the molecular basis of phenotypes. They have also invited a group of researchers conducting a research program on the pulmonary microbiota of cystic fibrosis patients to join the unit, in order to benefit from their expertise in this field and develop novel integrative research projects, in particular pertaining to gene-environment interactions.

Further, in the future contract, three main themes will be presented with the merging of themes (2) and ( 4) into a single theme and theme (5) "channelopathies and calcium signalling" that will no longer be developed. The unit will include (1) Molecular genetics and genetic epidemiology that will include most of the members of UMR 1078 involved in the previous theme 1 and the members of the LUBEM involved in the study of the pulmonary microbiota; 2) Somatic gene expression and RNA splicing that will include the members of the previous Theme 3 and a few members of Theme 1 involved in the study of the genetic and cytogenetic abnormalities in myelodysplastic and myeloproliferative syndromes; (3) Biotechnological developments and chemobiological approaches, that will merge the previous Theme 2 on gene transfer and Theme 4 on yeast-based chemobiological approaches that will constitute its two main axes.

The dispersion of the working places, which are distributed on the three floors of the Faculty of Medicine and Health Sciences of Brest and also at Brest hospital (CHRU) and EFS (Établissement Français du Sang) premises, represents one of the current weaknesses of the UMR 1078. The construction of a new building "Institut Bréstois de Recherche en Biologie en Santé" (IBRBS) that just started in 2015 will put an end to this geographical dispersion at the beginning of the future contract in 2017.

Management team

The proposed director of the unit for the next contract is Ms Emmanuelle GÉNIN with Mr Marc BLONDEL as deputydirector. Ms Emmanuelle GÉNIN will take over from Mr Claude FÉREC the current director.

HCERES nomenclature

Scientific domains

The unit has develop a biomedical research with a particular focus on genetics and personalized medicine, starting from cohorts and biological samples of patients and epidemiological studies to the identification of new causative genes and their mutations, the elucidation of the functional consequences of these mutations, including somatic mutations, as they occur in cancer, and finally the exploitation of this knowledge toward the clinics through translational studies. Further, their main scientific objectives are to understand the genetic bases of human disorders (in particular rare diseases) and to exploit this knowledge to discover new and more personalised candidate treatments. Objectives achievement will be ensured by (1) identifying genes and genetic variants within these genes that are associated with disease susceptibility, disease severity and disease progression, (2) unravelling the molecular mechanisms involved, (3) developing efficient models to screen candidate therapeutics (drugs, genes, etc.).

Unit workforce

Unit workforce

Number The unit has started following the genetic mapping of the CFTR gene some 20 years ago. Since then, it has broadened its focus both from monogenic, via oligogenic, to complex and multifactorial diseases including haemochromatosis, chronic pancreatitis, congenital dislocation of the hip and others, and from mere genetic mapping to understanding the etiology of diseases and translating this knowledge into medical treatment. In particular since the last evaluation report (2011), genuine integrative genetic approaches to decipher Mendelian and complex disorders, gene regulation by genetic modifiers and environmental factors, mechanisms of alternative splicing and post-transcriptional regulation as well as translational approaches via drug identification in model organisms have been developed. For the future contract phase (2017-2021), the unit plans to strengthen this "from-bench-to-bedside" integrative research model, spanning from the identification of disease-causing (genetic) factors via understanding their physiological mechanisms to delivering promising drug candidates for future medical treatment. This is to be achieved by a single-entity, three-themes approach that additionally includes rare-variant mapping approaches, microbiota research, systems biological modelling and efficient screening models for therapeutics in the future.

Global assessment of the unit

The research program of the unit is driven by health-oriented research, involving genetic rare diseases, cancer biology and gene therapy. The quality of science is very good to excellent, with a considerable number of publications during the evaluation period, two technological platforms in place and excellent internal as well as external science communication. The unit has gathered an excellent national reputation but needs to strengthen its international visibility. The opening of Ms Emmanuelle GÉNIN as the new head of the unit provides a great opportunity, building on past achievements, to re-orient this excellent, dynamic and well progressing unit, both to broaden the data basis and the used analytical methods as well as to deepen the integrative research approach. The unit has presented a clear, comprehensive and solid strategic vision for the future contract (2017)(2018)(2019)(2020)(2021).

Strengths and opportunities in the context

The unit combines very good, complementary and well-recognized expertise in molecular genetics, statistical genetics and functional genomics. It has a clear strategic vision for the future evolution of the unit. Furthermore, the unit has access to well phenotyped cohorts of patients and healthy controls, access to very good genomic platforms and good links to local clinical research. Research topics are timely and ideally placed at the junction between basic and applied research. The unit is inserted in good national and international collaborative networks. It is actively involved in the training of PhD students, in the teaching of medical students, master students in various programs as well as students in paramedical courses. The unit is very well organized and this coherence should allow efficient pursuit of the unit's program. The organization promotes efficient scientific exchanges within the unit and outside.

Weaknesses and threats in the context

The unit comprises relatively small-sized groups involved in the various themes. Given the large number of distinct projects that are to be pursued, a risk of dispersion exists. Furthermore, although many collaborations exist, both the international visibility and the international network are not yet strong enough.

Recommendations

Given the small size of the groups, the unit leader has to be careful to keep them focused and to think of projects in agreement with the size of the thematic group. A focus should be put on the integration of Theme 2 in the unit. In this regard, hiring new post-docs (international post-docs if possible) and graduate students will be critical to the future success. To this end, a strategy to obtain ANR and EC grants is important. An effort should be made to extend participation in international networks and organization of international meetings to strengthen the international visibility of the unit.

  , Génomique fonctionnelle et Biotechnologies

	1  Introduction
	History and geographical location of the unit
	Head of Doctoral School:
		Mr Christian BROSSEAU, Doctoral School n° 373 "Santé, Information -
		Communications, Mathématiques, Matière -SICMA"
	Unit acronym:	GGB
	Label requested:	UMR INSERM -University of Brest
	Current number:	1078
	Name of Director (2015-2016):	Mr Claude FÉREC
	Name of Project Leader (2017-2021):	Ms Emmanuelle GÉNIN
	Expert committee members
	Chair:	Mr Michael NOTHNAGEL, University of Cologne, Germany
	Experts:	Ms Monique BOLOTIN-FUKUHARA, Université Paris-Sud
		Mr Ralph EPAUD, Université Paris-Est Créteil (representative of CSS Inserm)
		Mr Jamal TAZI, Université de Montpellier
		Ms Elisabeth TOURNIER-LASSERVE, Université Paris 7 (representative of the CNU)
	Scientific delegate representing the HCERES:
		Ms Sophie EZINE
	Representatives of supervising institutions and bodies:

Mr Christian BERTHOU, Faculté de Médecine, Brest Mr Rémi BRAJEUL, Centre Hospitalier Recherche Universitaire, Brest Ms Marianne DESMEDT, Inserm Mr Pascal GENTE, Université Bretagne Occidentale Ms Marie-Josèphe LEROY-ZAMIA, Inserm Mr Jean-Christophe PAGÈS, Établissement Français du Sang


Since its foundation in 1959 the main thrust of LPC has been on particle and hadron physics with participation in experiments in various laboratories including CERN, Fermilab and JEFFERSON Lab.

In the last decade the scope of the research at LPC has been enlarged including multidisciplinary activities at the border between physics and other sciences such as biology, health and earth science; these cover roughly 30% of the activity of the laboratory.

In the context of the new policy for the merging of the two universities in Clermont in the new Université Clermont Auvergne, three research units will be joining LPC on January 1 st 2017:

-Laboratoire Arc Électrique et Plasmas Thermiques (LAEPT) whose main scope is the study of the properties of thermal and non-thermal plasmas and the interaction of these plasmas with the environment;

-Mitochondrial Genome Repair (RGM) whose main scope is the study of mitochondrial changes during aging and mitochondrial DNA repair mechanisms;

-Characterization and Biologic security of nanostructured surfaces (C-Biosenss) with the goal to assess the relationship between clinical applications and material sciences.

Management team

The director, the technical manager and administrative manager form the laboratory management team. Deputy directors, in charge of important matters may be appointed for a limited time. They work with large autonomy and have frequent contacts with the director. The technical manager has the responsibility of monitoring the technical actions. The administrative manager directs the administration.

HCERES nomenclature

Domaines scientifiques :

-P : ST2 -S : SVE2 Domaines applicatifs :

-P : Santé humaine et animale -S : Environnement -S : Nanosciences, nanotechnologies, matériaux et procédés -S : Technologies de l'information et de la communication

Scientific domains

LPC is presently reorganizing into six research teams: 6

The team 'Particles and the Universe' includes activities in the fields of experimental particle physics (D0@Tevatron in Fermilab/Chicago until 2013, ATLAS@LHC at CERN, LHCb@LHC at CERN and preparation for future colliders) as well as astroparticle activities (ANTARES) and observational cosmology (LSST). Research is connected to fundamental physics questions: Standard Models and their extensions, dark matter and dark energy. The groups are involved in physics analysis and in detector construction.

The team 'Quarks and Nuclei' studies the properties of the Nucleon and those of the quark-gluon plasma. They have been involved in experiments at JEFFERSON Lab (Newport News, VA, USA) until 2011 and are now participating in experiments at MAMI in Mainz/Germany and in the ALICE experiment at LHC at CERN. They are contributing to physics analysis and to detector construction. The team 'Health and Environment' includes all activities where the technical competences of the laboratory are exploited for research at the interface with other disciplines. 'Health' includes topics like development and characterisation of biomaterials, dosimetry and online dose control in particle therapy, multi-scale dosimetry and evaluation of radiation-induced damage, radiation therapy physics and e-health & biomedical applications of grids and clouds. 'Environment' includes natural radioactivity and volcanoes, radiation and evolution of living organisms and the use of high-energy muons in the cosmic rays to probe large and dense structures like volcanoes (muography).

The team 'Technological Innovation and Transfer' has been formed only recently to promote research in instrumentation and informatics where the laboratory could develop innovative instruments or systems to be exploited in fields different from pure research.

The team 'Plasma Physics' studies the properties of low-temperature plasmas and the interaction of these plasmas with the environment with emphasis on electric arcs and thermal plasmas. This research domain covers a large number of applications. LPC researchers have consolidated the contribution to observational cosmology with the participation in the Large Synoptic Survey Telescope currently under construction in Chile.

Unit workforce

LPC researchers are highly connected to the local multidisciplinary research contributing for example to earth science with tomography of the local volcanoes. They have important involvement in health related research in national collaborations that will be further enlarged in scope with the acquisition of two research units on mitochondrial genome repair and on characterization and biologic security of nanostructured surfaces. LPC scope will be also enlarged to plasma physics with the merging of the 'Laboratoire Arc Électrique et Plasmas Thermiques'.

The experimental teams rely on highly performing services on electronics, informatics, microelectronics and mechanics. The organization of the laboratory and the scientific leadership offer a stimulating environment for researchers and technical staff resulting in very good scientific production.

Global assessment of the unit

LPC is well established and plays a role recognized at local, national and international levels.

The involvement in three large LHC collaborations with important responsibilities ensures a long-term high quality scientific return at the forefront of elementary and hadronic particle physics.

The recent involvement in Large Synoptic Survey Telescope (LSST) enlarges the scope of the laboratory to high quality observational cosmology.

The consolidation of research activity in high-quality multi-disciplinary domains (biology, medical and earth science) profiting from the instrumentation, techniques and methods developed for fundamental research, creates strong links with the local and national scientific environment.

LPC has strong links with University and contributes to teaching and professional training at different levels.

Strengths and opportunities in the context

The experience developed during several years in LPC in fundamental physics research at the energy frontier resulted in the design, construction and operation of complex detectors, the processing and analysis of data and in their theoretical interpretations. LPC is involved in international projects of the highest level like ALICE, ATLAS, LHCb and LSST.

The detectors they contributed to build and operate produced data of excellent quality that allowed important discoveries including the Higgs Boson and the measurement of the very elusive branching fraction for the decay of the B s meson in muon pairs. The new run at LHC offers concrete opportunities for new discoveries.

The cosmology activity with LSST, which started recently with good momentum, will grant LPC privileged access to one of the largest deep surveys over an enormous area of sky with high discovery potential.

The LPC teams rely on four performing technical services (electronics, informatics, microelectronics and mechanics) that offer the full range of skills needed to carry out ambitious experimental projects.

The technical expertise developed for fundamental research has allowed a wealth of spin off in multidisciplinary domains related to health and environment, which have grown to become one of the research unit's specificity. These domains have strong links with the society both at the local and national level. The field of applications is a source of innovation and offers LPC a strong route for innovation and technology transfer and involvement with societal challenges. These activities will profit in the future from synergies with the new research units that are joining the LPC in the next contract.

Medical physics and radiobiology applications are well integrated within the regional and national collaborative networks. There are strong links between the environment studies at LPC and locally strong groups in volcanology and geology.

Weaknesses and threats in the context

The planned merger of the University of Auvergne and Blaise Pascal University in the future University Clermont Auvergne has triggered a policy to define coherent priority research axes among the new university and the local research institutions. Fundamental research is not among the priority axes.

The involvement of LPC in fundamental research results in a good visibility of the laboratory at international level; however the participation of LPC members to the central management of the large experimental collaborations was rather limited.

The contribution of the LPC to the operation of the LHC detectors that they have designed and constructed and to their upgrades requires a continuous commitment of human resources that is more difficult to sustain when the number of permanent researchers and post docs is decreasing.

The possibilities to fund the PhD contracts are decreasing.

Most of the research groups have a large fraction of (assistant) professors with large teaching duties, which lowers their impact in research.

With a few notable exceptions, most of the research groups are formed by a small number of researchers. This fragmentation of the research lines makes them fragile on many aspects.

The LPC technical expertise has strengths that allow planning research and development of instruments and methods that have potentiality to be useful for the society. However in some cases this planning does not include a thorough study of the needs and usefulness of the potential technological transfer.

The recurrent financial support is steadily decreasing with time.

Recommendations

The 'raison d'être' of LPC is fundamental research. Fundamental research is also what makes LPC strong in technical expertise. It should be pursued during the next contract profiting from the participation of the LPC in large international experimental collaborations and from the discovery potential of these researches. The international visibility could be improved also exploiting the potential synergies between the theory group and experimental groups beyond what is already happening. Proactive participation in international conferences organization and editorial activities should be encouraged. 9

The field of applications is very important for LPC because it boosts its interaction with the local academic, social and economical environment. It gives access to regional and national contracts. It is coherent with the new policy of the site. It relies on the strong technical expertise developed for fundamental research and has developed since its own specific know-how. The resources devoted to this field should not be reduced, however the field should be consolidated on projects with strong and well-defined technological transfer goals building on the success of the presently active projects. This consolidation should profit from the merger with the new research units. International cooperation should be encouraged.

Fundamental research is not among the priority axes defined by the new university and the local research institutions. LPC should be proactive in trying to change these priorities on the basis that without a strong involvement in fundamental research and in the large international experimental collaborations the technological level of the laboratory would rapidly decrease with detrimental effects on its applied research and potentiality for technology transfer. In this context LPC could act in favour of and would benefit from an increased synergy among the high energy physics units of the newly merged region.

4

  Scientific delegate representing the HCERES: Mr Michel GARÇON Representatives of supervising institutions and bodies: Mr Alain ESCHALLIER, Université d'Auvergne Mr Pierre HENRARD, Université Blaise Pascal Mr Serge KOX, CNRS/IN2P3 Representatives of Doctoral Schools: Mr Jean-Marc LOBACCARO, ED n°65, École Doctorale des Sciences de la Vie, Santé, Agronomie et Environnement Mr Patrice MALFREYT, ED n°178, École Doctorale des Sciences Fondamentales (EDSF) 1  Introduction History and geographical location of the unit LPC Clermont is a UMR (Unité Mixte de Recherche) under the joint supervision of the University Blaise Pascal and CNRS. It is located on the university campus Les Cézeaux. LPC main activity is research in physics of the fundamental interactions and the laboratory is primarily attached to CNRS/IN2P3 (Institut National de Physique Nucléaire et de Physique des Particules). The diversity of the research of LPC justifies its secondary attachments to CNRS/INP (Institut de Physique) for theoretical physics, to CNRS/INSU (Institut National des Sciences de l'Univers) for cosmology and to CNRS/INSB (Institut des Sciences Biologiques) for biological sciences.

  The team 'Theoretical Physics' works in close connection with 'Particle and Universe' and 'Quarks and Nuclei'. Its research topics include Lattice QCD and non-perturbative methods, Beyond Standard Model Physics, precision tests of the Standard Model and dark matter.

  LPC Clermont is one of the important laboratories of IN2P3. It has strong involvement in elementary and hadronic particle physics, both in theory and experiments. Its researchers contribute to large international collaborations like ATLAS, LHCb and ALICE at CERN doing research with the most powerful accelerator ever built. They contribute to data analysis with a large number of publications and to detector construction. The theory group has high international reputation.

	2 Overall assessment of the unit
	Introduction
	Unit workforce	Number on 30/06/2015 (LPC/LAEPT/RGM	Number on 01/01/2017
		/C-Biosenss)
	N1: Permanent professors and similar positions	46 (32/5/6/3)	47
	N2: Permanent researchers from Institutions and similar positions	20 (20/0/0/0)	20
	N3: Other permanent staff (technicians and administrative personnel)	53 (47/3/2/1)	53
	N4: Other professors (Emeritus Professor, on-contract Professor, etc.)	5 (4/0/1/0)
	N5: Other researchers from Institutions (Emeritus Research Director, Postdoctoral students, visitors, etc.)	5 (4/1/0/0)
	N6: Other contractual staff (technicians and administrative personnel)	3 (3/0/0/0)
	N7: PhD students	31 (26/3/2/0)
	TOTAL N1 to N7	157 (130/12/11/4)
	Qualified research supervisors (HDR) or similar positions	45 (33/5/3/4)

Postdoctoral scientists having spent at least 12 months in the unit 20 (20/0/0/0) Number of Research Supervisor Qualifications (HDR) obtained during the period 9 (8/1/0/1)


president Michel Cosnard

Evaluation report

This report is the sole result of evaluation by the expert committee, the composition of which is specified below.

The assessments contained herein are the expression of an independent and collegial reviewing by the committee.

Unit name:

Neuropathies of the enteric nervous system and digestive pathologies: implication of enteric glial cells The unit has expanded in recent years. The number of employees, staff as well as researchers, has increased, as has the number of subprojects. The translational approach is made possible not only by the close geographic connection with the Hospital, but also due to a strategic decision to involve both clinical and basic researchers in scientific and training programs as well as by the creation of technical platforms.

Management team

The unit is headed by its founder Mr Michel NEUNLIST.

Scientific domains

The unit conduct translational research in Neurogastroenterology aiming at a better understanding of underlying mechanisms of several diseases with particular focus on gastrointestinal entities. Also the connection between enteric end central nervous disease mechanisms is addressed. Biomarkers and therapeutic alternatives for human diseases like inflammatory bowel disease (IBD), colorectal cancer and other chronic diseases are sought. Underlying disease mechanisms are studied in various animal models constantly refined and developed.

Unit workforce

Unit workforce

Number The main focus of the unit is to characterise various aspects of the concept of the neuro-glio-epithelial unit (NGEU). This includes carrying out clinical as well as basic research on the role of the enteric nervous system, including enteric glia, and in chronic intestinal diseases, but also to characterise NGEU dysfunctions in Parkinson's disease. Intestinal inflammation and the intestinal epithelial barrier (IEB) are of central interest to the unit. Enteric glia is found to be of importance for IEB repair, and several mediators, in particular n-6 derived lipids, are presently studied. Further, neurostimulation as a therapeutic option to restore IEB homeostasis has been suggested and these aspects are currently investigated.

The involvement of NGEU, as well as microbiota, during obesity, tumorigenesis and development is addressed with the aim of improving therapeutic handling and finding biomarkers. In Parkinson's disease, co-morbidity in the NGEU forms the basis to further study the NGEU as a source of biomarkers to evaluate disease progression and severity.

Since previous evaluation (in 2011) the scope of diseases and neuropathies investigated by the unit has significantly been broaden. The number of subprojects has markedly increased. Several new aspects on the possible role of NGEU in intestinal as well as central diseases are described and explored.

Global assessment of the unit

The close connection of the unit with hospital and university fosters translational research. The unit has an internationally leading position in Neurogastroenterology. It is well funded, from internal as well as external sources, and active in recruiting both clinical and basic science researchers and PhD students. The research profile is unique, innovative and translational and has fostered scientific collaborations in national and international networks as well as with industry. The unit is well organised concerning technical platforms, expertise, equipment, facilities and infrastructure. Internal and external communication is well structured. The unit is actively involved in basic education, public outreach and in several national and international scientific networks. The unit increased its interaction with the public significantly during the last years (national TV, press media and radio). The unit is very successful in raising internal and external funds. The funding has increased by 33% during the five-year period, in particular concerning private and public funding.

Strengths and opportunities in the context

The unit holds 4 patents. The expansion of the unit has led to the development of new experimental models and new therapeutic concepts. The unit has participated in 4 clinical trials. Scientific output is high and internationally recognised. The NGEU/IBD project is highly interesting, focussing on neuroimmune interactions, and has good chances to develop prognostic tools or to identify biomarkers to favour therapeutic progress. The NGEU/colorectal cancer project is highly original and might conduct to the identification of new molecular mechanisms essential for homeostasis. The NGEU/Parkinson project has a high international visibility and attracts funding.

Weaknesses and threats in the context

The expansion of the unit challenges the basic organisation of the unit (e.g. integration and incorporation of new staff and students). Recruitment of new PhD students, in particular from abroad, is reported difficult. There is a high risk that the increasing number of subprojects will be difficult to handle and cause fragmentation of the organisation and loss of scientific focus. This is of particular concern in the NGEU/neurodevelopment and neurodegeneration project, in which the studies on 4 different ENS and CNS (central nervous system) neurological diseases are interesting, but require different expertise in paediatric and adult fields, which threatens to dilute task forces. Also the NGEU/IBS project is very ambitious but in need of a strong immunological input. The value of DSS (Dodecyl Sodium Sulphate) and TNB (Trinitro Benzene sulfonic acid) models for this latter study is debatable. The project on NGEU and carcinogenesis is internationally very competitive, but recruitment of scientists to reinforce basic science approaches would markedly increase feasibility.

Recommendations

The main concern for the unit is the number of subprojects: there is an impressive number of subprojects reported in the program, but the feasibility is questionable in the current setting. There is a risk for superficial studies, generating several publications but not in depth studies, and thus harder to publish in high impact journals. The unit should emphasis quality rather than quantity.

The recruitment of, or the collaboration with, an immunologist in the IBD project would increase the strength of the project. Further, in the IBS project, the animal models should be evaluated concerning their appropriateness and the inclusion of additional models should be considered.

In the colorectal cancer project the influence of ENS on different digestive cancer types, such as colorectal and gastric, should be clearly examined and compared. Influence of other components in the microenvironment, such as myofibroblasts and vasculature, should be considered in order to obtain a complete map.

The project "neurodevelopment and neurodegeneration" would benefit if focused mainly on neurodegenerative diseases in order to further strengthen its international position.

The nutritional and microbiome aspects are rather underrepresented and do not really fit in the context of all other approaches. It could either be a topic of its own or dropped. The pig model, in case of delivering an appropriate immune response, could be used in the IBS project.

Recruitment of foreign PhD students and researchers should be intensified.

  Mr Pascal de SANTA BARBARA, Université de Montpellier (representative Inserm CSS) Mr Karl-Herbert SCHÄFER, University of Applied Sciences Kaiserslautern Campus Zweibrücken, Germany Scientific delegate representing the HCERES: Mr Jacques NOËL Representatives of supervising institutions and bodies: Mr Fréderic BENHAMOU, Université de Nantes Ms Meriem MAROUF-YORGOV, Inserm Ms Anne-CLaire de REBOUL, CHU of Nantes Head of Doctoral School: Ms Corinne MIRAL, Doctoral school ED n°502 "Biologie Santé" 1  Introduction History and geographical location of the unit The UMR 913 unit was formed in 2008 as a mono-team unit dealing with the concept of studying intestinal neuro-glio-epithelial interactions in health and disease. It was renewed in 2012. The unit is part of the "Institut des Maladies de l'Appareil Digestif" (IMAD) of the University Hospital of Nantes and a founder member of the "Département Hospitalo-Universitaire" (DHU2020). It is strategically localised in close contact with the University Hospital of Nantes and Nantes University. Such an environment strongly promotes translational research, which has been a key work model within the unit. The unit also has ongoing collaborations with industry.

on 30/06/2015

		Number on
		01/01/2017
	N1: Permanent professors and similar positions	5	8
	N2: Permanent researchers from Institutions and similar positions	6	6
	N3: Other permanent staff (technicians and administrative personnel)	5	5
	N4: Other professors (Emeritus Professor, on-contract Professor, etc.)
	N5: Other researchers from Institutions (Emeritus Research Director, Postdoctoral students, visitors, etc.)	4
	N6: Other contractual staff (technicians and administrative personnel)	6
	N7: PhD students	14
	TOTAL N1 to N7	40
	Qualified research supervisors (HDR) or similar positions	7
	Unit record	From 01/01/2010 to
		30/06/2015
	2  Overall assessment of the unit
	Introduction

signed by their chairman." (Article 8, paragraph 5) 2 The evaluation reports "are signed by the chairman of the expert committee". (Article 11, paragraph 2)

PhD theses defended 11

Postdoctoral scientistshaving spent at least 12 months in the unit 4

Number of Research Supervisor Qualifications (HDR) obtained during the period 5


Report 1 Introduction

• Date and execution of the visit:

The site visit took place over one day on January 12th 2011. The committee assisted as a whole at all interviews and presentations. The chairman worked in close collaboration with all members of the committee to present the present final report.

The visit was well organized and allowed each committee member to have enough time to be able to listen to the presentations, to assess the research performed by the group, to meet with scientists, students and technical personell, as well as with representatives of the local research organizations (regional delegate of the INSERM, delegate of the Hospital, and representative of the University of Nantes). At the end of each presentation, sufficient time was taken to allow discussion between panel members and presenters. At the end of the visit, sufficient time was also taken for members of the committee to discuss and summarize the salient issues to retain for the present report.

• History and geographical localization of the research unit, and brief presentation of its field and scientific activities

This research unit was originally created in 2008, perpetuating the themes developed in the Neurogastroenterology Unit U539 (2004-2007). The unit is part of the Institute of Digestive Diseases (IMAD: Institut des Maladies de l'Appareil Digestif), which is an hospital-based institute. The unit is located within the CHU HD of Nantes.

The research is devoted to the study of the role of enteric nervous system, and in particular enteric glial cells, in health and diseases. The Unit being composed of both basic scientists and clinician scientists, the scientific approache uses integrated basic and translational research.

• Management team

The unit applying for renewal will include about 20 staff members initially (scientists, clinician scientists, clinicians, research assistants, technicians and trainees). The unit will be headed by M. M. Neunlist, no deputy director was identified. The director has formed a laboratory council which is composed of researchers, one representative of the technicians and one representative of the trainees. The director is in charge of the management and all aspects related to the organization of the unit. No specific rules have been described for the financial and administrative management of each project.

The laboratory council meets regularly and decides collegially on organizational issues of the center, including prioritization of research projects.

As for scientitic interchange, laboratory meetings are organized on a weekly basis, where research-in-progress reports are presented by scientists and trainees, each presenting 2 to 3 times a year. No formal seminar series are organized within the unit, but access to seminars organized by the gastroenterology institute (IMAD) is available. 2 Overall appreciation on the research unit

• Summary

Overall, the unit is very productive considering the number of full-time researchers that compose this unit. The unit occupies a unique and original position in the scientific landscape related to Gastroenterolgy, focusing on the neuro-glial-epithelial unit. Clearly the research performed in this unit is of international standard, and the researchers have established the necessary collaborative links nationally and internationally to perform original research. Overall, this unit represents an excellent model of collaboration and complementarity between basic scientists and clinicians.

• Strengths and opportunities

• The publication record in terms of number and quality of publications is very good. It is important to note that both the number and impact of publications have increased steadily of the past years.

• The unit, by its very nature, holds very close links with clinical research, providing unique conditions to run successful translational research programs.

• The vibrant clinical-research environment has a major impact and constitutes an important factor in attracting and sustaining clinician involvement in basic research.

• National and international collaborations are in place to support the research program.

• Sufficient space has been identified and allocated to the unit, that would also allow the unit to grow significantly.

• Weaknesses and threats

•

The number of full-time basic scientists is relatively low in this unit, with only three full-time researchers, as of today. One of them is the director who necessarily devotes some time to the Unit management, another one should retire 2-years after 2012, and one full-time young investigator has been recently recruited.

Increasing the number of full-time basic scientists should be considered as a major priotity, considering the ambitious nature of the research projects described for this renewal, and the number of "hands and brains" necessary to supervise those projects.

• Related to the previous remark, no technical staff with permanent positions have been allocated to that unit. This aspect is fundamental to sustain continuity of expertise within the laboratories. The recruitment of fulltime permanent technical staff to the unit will be essential to their future scientific success.

• Being a relatively small research unit so far, no formal procedures and rules for general management of funds, research priorities, or career development are in place. It was felt by the committee during the visit, that all staff members were satisfied with the present organization and management. With the anticipated increase in the number of persons composing this unit, a more formal organization and management could be put in place.

• Recommendations to the director

• Pursue discussions with the institutions: INSERM, the Hospital and the university, in order to obtain dedicated technical positions. In particular, the University of Nantes, who's representative indicated to the committee the possibility of providing permanent contracts to technical staff who have been employed for more than 6years (one of the staff members is in that situation).

• Production results The quality and number of scientific communications are being regarded as excellent, especially, considering the number of full-time PIs. Each year, the unit has published a number of research articles in journals of impact factors superior to 9 (Gastroenterology, Gut, J. Clin. Invest., etc.).

A1

The unit has brought important new knowledge on the functional importance of enteric glial cells in human digestive diseases. In particular, they have demonstrated the role of enteric glial cells in intestinal permeability (publications in Gut and Gastroenterology), in cell to matrix adhesion and intestinal cell proliferation. Overall, the work performed within the Unit has lead to the new concept that enteric glial cells are major protective actors in gut pathologies.

The unit has established stable and fruitful collaborations locally, nationally and internationally.

Appreciation on the impact, the attractiveness of the research unit and of the quality of its links with international, national and local partners.

The visibility and scientific impact of members of the unit is extremely high to very good for the PI.

It should be emphasized that the unit has attracted a young and productive tenure-track scientist in the past year. Further recruitment of basic scientists should be fostered.

While on the surface it would appear that the unit has had limited success in attracting foreign trainees, this can be attributed, at least in part, to the French system of recruitment and the location of Nantes, remote from the major axes and from Paris.

The ability of the unit to raise funds has been very good, and has been impressively increasing steadily over the last years. Individuals should be encouraged to apply for European funds and to compete for higher levels of funding. Successful links with industry have been established (with Danone).

The unit has established good local and national scientific networks that should be nurtured in the future. Good relationships with the educational structures and public awareness activities were also noted, and should be maintained in the future.

• Appreciation on the management and life of the research unit

The director has good leadership skills, and from the site visit, the committee felt that the director was highly regarded by all staff members. It was particularly impressive to note the friendly and very collegial atmosphere among all staff members. The panel was especially impressed by the very strong collaborative spirit that obviously existed between basic science and clinical researchers. Scientific exchange is adequate through weekly lab meetings and seminar series in the clinical department (IMAD).

• Appreciation on the scientific strategy and the projects

The research unit has unique strengths to study the biology of glial cells in the gut. A number of projects in different areas were presented. They were all supported by solid preliminary data and their relevance to biomedical research was strong. Overall, good proof of concept towards feasibility was provided. The overall impression of the committee was that the scientific strategy should try to consolidate basic science aspects and to resist the temptation to embark prematurely on related clinical projects until the scientific basis and relevant techniques have been firmly established and validated. The committee acknowledges the presence in the scientific project of cutting edge research.

In conclusion, the committee felt that the Unit 913 is a very good research unit, with scientific productivity of international relevance. The originality of the research proposed is extremely high. The unit is recognized worldwide for its work in the domain of neuro-glial-epithelial cell interactions. Although the theme of IBD is relatively recent for the team, some publications and important preliminary data have been generated. In addition, partnerships and collaborations have been put in place to efficiently address the questions raised in the project. The project is based both on clinical studies and a basic science project.

• Conclusion Summary

The project is extremely original particularly from the perspective of studies on enteric glial cells. It is supported by interesting preliminary results although those results are mostly based on IBS. Several questions are addressed in the project and different directions are proposed both from a clinical and basic science perspective.

Strengths and opportunities

• The studies on glial cell biology are unique and the research unité is recognized worldwide for its studies in the domain

• The technology to study glial cell biology is well established.

• Good interactions between basic science and clinical science are feasible and should permit the performance of good translational research

• Well in line with the missions of the INSERM

Weaknesses and threats

• The clinical project seems a bit premature at this point. Validation of the techniques proposed to measure permeability in vivo in patients employing an endoscopic approach should be performed.

• More preliminary data generated from archival biopsies from IBD patients would be appropriate before starting clinical studies.

• The plans for basic, translational and clinical investigation are commendable but may be overly ambitious given the modest size of the group.

Recommendations

The project would benefit from a greater focus on glial cell biology since this is the most original part of the project. Basic science studies focusing on cellular and molecular aspects (signaling molecules) of enteric glial cell physiology should be encouraged. This team has been productive in the area of studies of the enteric nervous system in Parkinson's disease patients, publishing in very good journals (Gut 2008, NG&M 2009, PlosOne 2010, etc.). This scientific production has enabled that team to have an impact in the field, raising their visibility internationally. The group has established the necessary collaborations to be able to consolidate their multidisciplinary approaches (human biopsies, primate tissues, autopsy tissues, mouse models, etc.). The group is also very successful at raising funds. The project to investigate enteric nervous system lesions is very relevant, logical and has achievable objectives.

• Conclusion : Summary

The proposal sets out a series of experiments to address a very interesting area of investigation, with a high relevance. The project is well balanced between "safe" aspects (autopsy tissues), and more "risky" hypothesis (mechanisms of regulation, alpha-synuclein).

Strengths and opportunities

• Combination of a number of different approaches and tissues to answer important questions.

• Good visibility of the group

• Good translational research

• Good technology transfer potential with the potential to develop new diagnostic biomarkers

Weaknesses and threats

Colonic biopsies contain ganglia restricted to the sub-mucosal layer of the colon and may not be entirely sufficient to completely delineate all of the changes in the enteric nervous system associated with Parkinson's disease over time. Myenteric ganglia are more likely to be the primary neurons affected by Parkinson's disease pathology; the researchers seem aware of this limitation and have strategies to address it.

Recommandations

Careful examination of the enteric nervous system from Parkinson's disease patient autopsy tissues should be performed as a priority to further validate the appropriateness and limitations of colonic submucosal ganglia tissues.

Different regions of the gut could be examined and compared (foregut, mid-gut, colon) for potential variations in severity of the changes of the enteric nervous system.

The effects of deep central neurostimulation could be studied on the neuro-glial-epithelial unit response in the context of Parkinson's disease. Similarly, the effects of intestinal eptihelial barrier reinforcement could be investigated.

Statistiques de notes

•

  : Number of permanent researchers with teaching duties (recorded in N1) who are active in research 9 A2: Number of permanent researchers without teaching duties (recorded in N2) who are active in research 10 A3: Ratio of members who are active in research among staff members [(A1 + A2)/(N1 + N2)] 1 A4: Number of HDR granted during the past 4 years (Form 2.10 of the application file) 2 A5: Number of PhD granted during the past 4 years (Form 2.9 of the application file) Appreciation on the results This research unit is centered around the study of the neuro-glial-epithelial unit. The research performed is highly original. The organization of the unit provides a very successful translational research platform, where clinician scientists and basic science researchers interact most extensively and efficiently.

Project 1 :

 1 Neuro-glial-epithelial unit: Patho-pysiological mechanisms and therapeutic targeting during IBD. Project leaders: A. Boureille, Malvyne Roli-Derkinderen

Project 2 :

 2 Neuro-glial-epithelial unit in Parkinson's disease, Project leader: P. Derkinderen

globales par domaines scientifiques

  (État au 06/05/2011)

Sciences du Vivant et Environnement

	Note globale	SVE1_LS1_LS2	SVE1_LS3	SVE1_LS4	SVE1_LS5	SVE1_LS6	SVE1_LS7	SVE2 _LS3 *	SVE2_LS8 *	SVE2_LS9 *	Total
	A+	7	3	1	4	7	6		2		30
	A	27	1	13	20	21	26	2	12	23	145
	B	6	1	6	2	8	23	3	3	6	58
	C	1					4				5
	Non noté	1									1
	Total	42	5	20	26	36	59	5	17	29	239
	A+	16,7%	60,0%	5,0%	15,4%	19,4%	10,2%		11,8%		12,6%
	A	64,3%	20,0%	65,0%	76,9%	58,3%	44,1%	40,0%	70,6%	79,3%	60,7%
	B	14,3%	20,0%	30,0%	7,7%	22,2%	39,0%	60,0%	17,6%	20,7%	24,3%
	C	2,4%					6,8%				2,1%
	Non noté	2,4%									0,4%
	Total	100,0%	100,0%	100,0%	100,0%	100,0%	100,0%	100,0%	100,0%	100,0%	100,0%
	*

les résultats SVE2 ne sont pas définitifs au 06/05/2011. Intitulés des domaines scientifiques Sciences du Vivant et Environnement • SVE1 Biologie, santé SVE1_LS1 Biologie moléculaire, Biologie structurale, Biochimie SVE1_LS2 Génétique, Génomique, Bioinformatique, Biologie des systèmes SVE1_LS3 Biologie cellulaire, Biologie du développement animal SVE1_LS4 Physiologie, Physiopathologie, Endocrinologie SVE1_LS5 Neurosciences SVE1_LS6 Immunologie, Infectiologie SVE1_LS7 Recherche clinique, Santé publique • SVE2 Ecologie, environnement SVE2_LS8 Evolution, Ecologie, Biologie de l'environnement SVE2_LS9 Sciences et technologies du vivant, Biotechnologie SVE2_LS3 Biologie cellulaire, Biologie du développement végétal

Project 3: Nutritional targeting of the neuro-glial-epithelial unit, Project leader: M. Neunlist

The general aim of this project is to determine the extent to which the luminal environment, in particular the nutrient content, impacts on enteric neuron biology and thereby on digestive tract function. Relatively few publications related to nutritional influences on the enteric nervous system have been generated by the team so far since this is a new direction. However, in general, the number and quality of publications by the team in the domain of enteric nervous system biology is excellent. Considering the project presented and the means that have been allocated to this project, it is likely that a good scientific production will be associated to this project.

• Conclusion : Summary

This project brings together an internationally recognized team with complementary expertise to investigate important questions about dietary influences on gastro-intestinal functions. Gastro-intestinal disorders have enormous societal impact and a better understanding of the influence of diet, that could definitively be achieved through the present project, could lead to new therapeutic options.

Strengths and opportunities

• Good complementary expertise on the project with in vitro, in vivo models and clinical partners.

• The approach uses state-of-the-art techniques to investigate enteric-glial-epithelial interactions.

• Strong translational element bringing together clinician and basic scientists.

• Collaboration with industry is in place and fully allows the researchers to publish their findings. Contracts of collaboration have already been put in place through INSERM-transfer, and the comittment of the industrial partner was felt to be strong.

• Weaknesses and threats

• The project should consolidate the basic science aspects before considering studies in patients with diabetes and obesity.

• The project is ambitious and would necessite clear leadership, particularly in making strategic decisions regarding scientific direction.

• Recommendations

Considering the ambitious nature of the project as a whole, some themes should be prioritized. For instance, more emphasis should be put on the part of the project focusing on the maturation of the enteric nervous system and the characterization of the neuro-glial-epithelial unit. The clinical project on obesity and enteric nervous system function should be deferred until the former has been completed and experience gained from it utilized to maximal benefit.


 Introduction History and geographical location of the unit

The unit "Thérapeutiques Cliniques et Expérimentales des Infections" is issued from the EA 3826 headed by Mr Gilles POTEL since 1987. The AERES evaluation held in 2011 noticed an important dispersion in projects addressed by the team. This main weakness led the group to split the initial team into two separate research entities: the unit "thérapeutiques cliniques et experimentales des infections" headed by Mr Karim ASEHNOUNE and the unit "Microbiotas, Hosts and Antibiotic Resistance (MiHAR) headed by Mr Eric BATARD and Mr Didier PELETTIER. The current unit associates a very large clinical network to a more basic research team, giving a great opportunity to evaluate clinically relevant questions. The thematic of the new unit will be based on translational research and the role of host immune response to bacterial infections.

The laboratory is located in the medicine faculty building in Nantes. The laboratory is expected to move into the new "Institut de Recherche en Santé" (IRS-2) (expected date: June 2016), close to the new university hospital "Ile de Nantes".

Management team

For the next period, the unit will be headed by Mr Karim ASEHNOUNE, replacing Mr Gilles POTEL the former head of the unit.

HCERES nomenclature

SVE1-LS6

Scientific domains

The scientific field covers all the aspects of the host-pathogen relationships from the consequences of bacterial infections on cells of the immune system to the role of antibiotics and virulence factors on immunity in both animal models and immune cells from patients.

5

Unit workforce

Unit workforce

Introduction

The unit evaluated in 2011 had shown a high dispersion of the projects; this main weakness led the group to split the initial team into two research entities. It was recommended to focus all the projects on a limited number of themes.

In the past five years, the EA focused on pathophysiology of extracellular bacteria. More specifically, experimental models were generated in order to improve the knowledge of pharmaco-kinetic/dynamic parameters of antibacterial drugs. The research also included epidemiology of bacterial infections and resistance of bacteria to antibiotics. The present scientific field, more focused, will cover the study of acquired immunosuppression after an acute stress, leading to nosocomial infection in humans, more specifically the role of dendritic cells and NK cells in infection. The current unit associates a very large clinical network to a more basic research team giving a great opportunity to evaluate clinically relevant questions.

Global assessment of the unit

This unit is mainly focused on 4 general themes; (i) study of acquired immunosuppression after an acute stress during a nosocomial pneumonia: the group developed a clinical network for treatment testing, and built a biocollection. Mouse models were also generated (haemorrhage and pneumonia). The group used clinical samples as well as mouse models to evaluate the response to severe trauma and brain injuries; (ii) role of dendritic and NK cells after Methicillin-Sensitive Staphylococcus Aureus (MSSA) or P. aeruginosa pneumonia; this was performed in immunocompetent mice models; (iii) role of virulence factors in the immune response upon bacterial infections: the group generated a model of E coli osteo-articular infection along with cell co-culture approaches. The group also performed a collaborative work using P. aeruginosa in a pneumonia hypoxic model; (iv) modulation of the host immune response by antibacterial agents: a pre-clinical approach was used in this last part of the research showing the activity of new molecules in animal models. In these models, the host immune response is also evaluated.

Globally the unit uses a large number of models, a large number of pathogens and it is quite difficult to identify a united program, even though part of the initial unit has left.

The EA 3826 represents a laboratory in which the University of Nantes and local supporting companies (pharmaceutical and biotech) have heavily invested, both in scientific personnel and via other supports, indicating that, from their standpoint, the unit represents a sound investment for the future. The scientific production is of overall good quality and the level of publications is good, although not equally distributed among the team members. The laboratory attracts a large number of master and PhD students but no post-doctoral scientists. The unit has obtained a significant level of financial support, via contracts with the private sector (pharmaceutical, biotech) and national granting agencies. In contrast, European and international funding remain rather modest. Despite the strong scientific activity in the unit, the overall orientations and goals of the projects do not appear particularly integrated among team members, although an increase in intra-team collaborations has occurred over the period. A wider use of state-of-the-art rodent models of infection developed by the team in the studies carried out will allow reaching higher impact science for the entire unit.

Strengths and opportunities in the context

The first strength of the unit is a large clinical network: the team can either prospectively or retrospectively (using the biocollection) set up studies to answer clinically relevant questions studying human response to sepsis or potential therapeutic interventions. From these data, the unit can construct pathophysiological hypotheses that can be evaluated in cells and animal models. Along these lines, the unit associates basic researchers to hospital-based doctors, which is definitely an asset for translational research. Thus, the group can easily start very large clinical trials.

The second strength of the unit is to possess a large number of animal models and several cell culture models. They, therefore, can easily test the hypotheses coming from the bedside. Together with the number of models, the unit has the opportunity to evaluate a large number of antibiotics and, more interestingly, to focus on antibiotic associations on "difficult-to-treat" pathogens like multi-drug resistant or pan-resistant bugs.

The third strength of the unit is the large number of excellent specialty papers published in various domains and the important established collaborations.

The unit appears to be undergoing a strong positive evolution, getting important research results, with increasing scientific productivity and international attractiveness. The research is of high interest and highly relevant, in the context of hospital-acquired pneumonia and pneumonia of the host acutely immunosuppressed, in order to improve organ failure in intensive care units. A strong rational appears between human pathologies and the research project developed. Following recommendations of the previous AERES committee, the unit focused its research axis on theses aspects. The strength of the unit relies on the internationally recognized expertise of its members in the host-pathogen interaction domain including the generation of animal models adapted to the their project. The research scope is quite supported by institutional agencies, such as "région Pays de la Loire", and by big pharmas and the laboratory is deeply connected to university and medical school.

Weaknesses and threats in the context

If the clinical network is a great strength and an important opportunity, the committee felt that it is very difficult to identify a clear line of research, due to the number of infection animal models with, finally, an evaluation of several antibiotics in the different models.

The committee feels that the topics are chosen based on the opportunities of collaborations rather than built up in a research program rationale.

Analyzing the projects of the unit as well show a high dispersion, with even new models (e.g. spinal cord injury or phagotherapy).

Given the type of the university and/or university hospital positions of the team members, many of them have to dedicate a significant amount of their time to education, teaching and training.

The technical support is quite limited given, the specific objectives and the relative large number of faculty and research staff. A significant increase of its international competitiveness hinges on strengthening such technical support. Despite the solid competence of the unit members, funding for the development of specific instrumentation will be difficult to obtain, given the positioning of this group at the moment. The international visibility of the unit, despite the high quality and competence of the researchers must be enhanced in order to attract excellent students and post-docs form abroad.

Recommendations

The clinical network should be the platform of the project, with a narrowing of the topics mostly based on the choices that have to be made with the basic research models. It seems impossible to address in one unit so many areas of research with so many different pathogens and models. The common determinant is the host immune response that can be declined from the clinical data to the cellular and animal models. However, the committee suggests choosing one pathogen and one clinical target.

The laboratory might concentrate resources, both financial and human, on the two promising projects and work to better position the unit in the national and international landscape.

The committee encourages the unit to reach a more aggressive publishing policy, based on prioritizing research goals to the most significant translational purposes.

N7

  Other researchers from Institutions (Emeritus Research Director, Postdoctoral students, visitors, etc.) N6: Other contractual staff (technicians and administrative personnel) 2

Postdoctoral scientists having spent at least 12 months in the unit Number of Research Supervisor Qualifications (HDR) obtained during the period