 Introduction History and geographical location of the unit

The Jean-Pierre Aubert Research Center (JPARC) was created on January 1 st 2007. It resulted from the fusion of the four Inserm units present at the time at the Lille University Medical School, and led to the pooling of Inserm personnel and resources dedicated to studying cancer and the neurosciences. Joined by the current team 3 for the current contractual period, JPARC is now proposing to welcome a new team of medicinal chemistry. The unit, scattered in different buildings situated at walking distance from each other, is located on the Lille 2 campus, at the foot of the University Hospital Research Center, of which it is a flagship.

Management team

Mr Pierre FORMSTECHER has managed the JPARC since its beginning and in particular during the current 5 year contract period (2010)(2011)(2012)(2013)(2014). He smoothly passes the torch to Mr Luc BUÉE, who acted as deputy unit director during the current contract. 2  Assessment of the unit

AERES nomenclature:

SVE1-LS5 Neurobiology

Unit workforce

Strengths and opportunities related to the context

The unit had an excellent scientific production over the past years. The international visibility of key researchers is also excellent. They performed an impressive emphasis upon intellectual property management: 19 filed patents or patent applications, 2 spin-off companies and 1 drug entering Phase I. They launched successful programsof translational research in their field of expertise. The integration of clinicians within the unit and close relationship with university hospital is also excellent.

Weaknesses and threats related to the context Publication profile could be improved by aiming at publishing in higher impact journals perhaps favoring larger andmore comprehensive studies instead of splitting data into several reports as it seems to occur in some cases. The national funding situationcould surely be improved, as well as the relative lack of international funding (the unit support comes mostly from French grants). At the international level, they are in a very competitive field for at least what concerns research on Alzheimer's and Parkinson's diseases.

Recommendations

Here are the recommendations that the committee would like to offer for the unit:

setting up a lab life at the unit level;

establishing mechanisms by which the different teams will learn to know each other: internal seminars, day of retreat for all team leaders at the center, etc;

promote social and after-work interactions between PhD students and post-docs from the different teams to further improve the communication within the unit; -increase the possibility for career progression for university employees.

 Detailed assessments

Assessment of scientific quality and outputs JPARC as a unit has produced a large number of contributions (>580 peer-reviewed papers) with >300 with JPARC members signing a first and/or last authors and >270 in collaboration. The major contributions appeared in top journals while most production comes out in leading specialty journals. The appraised period has seen an attempt to publish in high profile journals, an effort that must be pursued while the "salami" publishing strategy (slicing into several papers stories that could be told in one single very high profile publication) should be avoided. Both the former and proposed directors are fully aware of such a need.

Assessment of the unit's academic reputation and appeal

JPARC is obviously well connected with the academic world as supported by the large number of published collaborations (>270), the numbers of grants received in collaboration, and the extensive network supporting the research efforts. The committee wishes to see more international students (PhD, post-doc) as well as more visiting professors or scientists. This is in contrast with the strong involvement in excellence grants such as SIRIC OncoLille, the Labex DISTALZ and the LIA Neurobese (which strikingly does not lead to a lot of exchanges between California and Nord-Pas de calais).

Assessment of the unit's interaction with the social, economic and cultural environment JPARC is a leading unit in Europe with regard to the interaction with the economic world. Not only JPARC holds a number of funded collaborations with industry but it also features the striking particularities of (I) issuing a large number of patents ( 19), (II) favoring the spin-offing by JPARC researchers (2 spin-off companies) and (III) having one proprietary molecule (protected by one of their patent) entering Phase I clinical trial. This is clearly an asset of JPARC that must be continued.

Assessment of the unit's organisation and life

Attention of director's efforts should be directed towards the aim of creating a lab life, a sense of unity and belonging. Both the scattered organization in several (3 now, 5 tomorrow) buildings as well as the variety of research topics (neuroscience, oncology, medicinal chemistry) call for active policies favoring scientific exchanges and the cross-fertilization among research topics (the experts committee clearly sees the advantage of mixing oncology and neuroscience). Experience demonstrates that such communication among teams is achieved through students and post-docs. Regular internal seminars (scientific and technical) as well as social events should be organized for budding future visibility of JPARC/Campus through dissemination of scientists willing to send their own students in such environment.

Assessment of the unit's involvement in training through research

JPARC members are involved in teaching at university and in training through research at the expected level for a unit of that size on a campus like Lille. The meeting with the head of the main École Doctorale (446 Biologie Santé Lille, Nord, France) indicated that the unit is very active in the training of graduate and PhD students in the university. Moreover, the training effort of the unit is quite evident at the interface between fundamental and clinical research, since both scientific and medical students obtain excellent research training in the unit. The unit is obvisouly well-visible in the university for its training and formation capacity.

Assessment of the strategy and the five-year plan

Transition between the former and proposed director is exemplary with a continuity in envisionnning what the future of the unit should be.

The committee, however, felt that teams in general are very large (6 teams for >220 persons) and that the emergence of new independent teams should be supported. JPARC structure is currently at odds with international view of research organization in smaller teams led by a single team leader. While the committee ackowledges the history, it also encourages more junior researchers to take their responsibility and accept to face the challenge.

4  Team-by-team analysis The group has contributed to the understanding of tau protein phosphorylation and splicing with the discovery of the abnormal tau splicing and tau protein pattern in myotonic dystrophy, topics that continue to be investigated with success. Another original aspect of the research in the group is the study of the interaction between the environment and development of tau dysfunction and related diseases. This includes the epigenetic studies. The output is good, many papers have been published by the group, and some in excellent journals (J. Neurosci., Neurology, Diabetes). The Alzheimer's field is very competitive and sometimes publishing in good but not excellent journals is the way to publish first, this is a pity because the work that the group is doing could be published in top journals and this is what the group should aim for. This point is also recognised by the principal investigator in his report were he hopes that the arrival of new postdoc-fellows will allow to publish in top scientific journals.

Assessment of the unit's academic reputation and appeal

The group is at the forefront of international research on dementia in particular on research in tau protein pathology and Alzheimer's disease. Accordingly the principal investigator is often an invited speaker (including plenary lectures) at international conferences on neurodegenerative diseases and is awarded important prizes.

Assessment of the unit's interaction with the social, economic and cultural environment

The interaction of the team with the environment, either social, economic or cultural is excellent. The team has helped to develop facilities for clinical diagnoses for Alzheimer's disease and tauopathies in the neighbouring hospital, has several patents, a spin off company and a drug going to phase one. They are involved in the public engagement inscience, with interaction with students, patients and general lay people.

Assessment of the unit's involvement in training through research

A team member is in charge of the doctoral studies and members of the group have trained and are training several students at different levels. Therefore the group is greatly involved in training through research. Besides this the team has been involved in European training consortia.

Assessment of the strategy and the five-year plan

The plan for the next 5 years is clearly described, it is strong and based on results previously obtained from the group but also develops new findings in the field such as spreading of tau protein. The original epigenetic work will be further developed. The group has several transgenic models that will be used for identification of toxic mechanisms that could become a target for therapies. The link with team 6 will become stronger when they become member of the center and it is likely that new molecules will be developed and tested in the available model. The future of the team is solid.

Conclusion

This is a strong team at the forefront of international research on Alzheimer's disease and tauopathies in particular. The future plan supports that the international visibility and competitiveness of the group will continue in the future.

 Strengths and opportunities:

Large number of publication in specialty journals.

Historical focus maintained upon a booming field (anticipation).

Exciting high risk/high gain project on tau presence/translocation to nucleus.

Spin-off company with a compound entering phase I directly arising from team's work (basic & preclinical science).

International collaboration.

Large visibility as supported by the number of invitations, the Claude Pompidou Prize, etc.

 Weaknesses and threats:

The team project is situated in a highly competitive field.

 Recommendations:

Underselling the high-quality work of the team, acknowledged by the group leader, should be minimized in the future.

Supporting the budding off of junior teams.

Assessment of scientific quality and outputs

The team assembled by the group leader to study the 'Development and Plasticity of the Postnatal Brain' is a very strong one. The group leader and a researcher are internationally recognized investigatorsdoing beautiful work; a junior researcher is a rapidly rising star. They have been productive scientifically, as evidenced by their list of impressive publications. In particular, 4 Cell Metabolism, 1 PLoS Biology, 1 PLoS Genetics and 1 PNAS papers that have emerged from the teamcan be highlighted.

Assessment of the unit's academic reputation and appeal

A number of researchers in this team are bona fide world leaders in their respective subject areas, particularly in the specialties of tanycyte biology and hypothalamic development and plasticity. They are also well known and respected in the broader fields of fertility/reproduction and obesity respectively. Part of their strength is that they represent a very 'outward-looking' and cosmopolitan lab, with close interactions with the Saban Research Institute in Los Angeles California, USA. This is consequently reflected in the attractiveness of the lab to many researchers from outside France, which is always a healthy situation for any research institute.

Assessment of the unit's interaction with the social, economic and cultural environment

It is clear that fertility and obesity are critical topics that are ever present in the social, economic and cultural environment of today. The members of this team certainly play their part, actively interacting with the media and lay public, both in terms of disseminating their scientific findings, but also in engaging the lay public on broader scientific issues. Here, the teams links with the Saban and with EU consortia, ensures that this engagement is truly international.

Assessment of the unit's involvement in training through research

Members of this team have displayed a commitment to training of the next-generation of scientists. For example, the team members were key drivers in a FENS (Federation of European Neuroscience Societies) summer school and other European union wide training programmes. They have trained a number of masters, PhD students and post-docs.

Assessment of the strategy and the five-year plan

The strategy and five-year plan is well structured, with a nice mix of exciting projects ranging from low to high-risk prospects. The committee is somewhat surprised however, that the team did not focus a more on the topics in which they are undoubted worl-leaders. Specifically, tanycyte and hypothalamic development are only addressed in one of the objectives; and the actual biology of tanycytes, particularly their role as 'gate-keepers' in regulating the transport of peripheral signals and hormones into the hypothalamus, is not addressed at all.

Conclusion

This is a very strong team, within a very good unit, and their strategy is a good exemple of what is required to ensure international competitiveness.

 Strengths and opportunities:

World-leader team in the tanycyte and post-natal hypothalamic development fields.

Team is well known in the field of reproduction and obesity.

 Weaknesses and threats:

Puzzling lack of ANR (Agence National Recherche) funding.

 Recommendations:

Recruitment of an electrophysiologist. Take advantage of the team's expertise and study the tanycyte biology.

Further increase interactions within the unit. Assessment of scientific quality and outputs

The Team "early stages of Parkinson's disease" is a relatively young team created in 2010 with a main focus on the biology and symptomatology associated with early Parkinson's disease. During the last 4 years, the team has participated in the identification of a new gene involved in PD (EIF4G1) in collaboration with a laboratory in Canada, and participated to the genetic effort in Parkinson's disease (new mutations in known genes (SNCA) involved in Parkinson's disease). By using transcriptomic analyses, the team has identified the impairment of new molecular pathways in peripheral blood cells from Parkinson's disease patients. In addition, the team has implemented a new rotenone-base model of Parkinson's diseasein order to investigate the early phase of Parkinson's disease (unpublished yet). In parallel, the clinicians of the team have built well-characterized cohorts of Parkinson's disease patients, particularly at the early stage of the disease. Thanks to these efforts, the team has played an important role in international Consortia of genetics and clinical research in Parkinson's disease, although there are more limited scientific production as primary authors (e.g. Lancet Neurol publications).

Assessment of the unit's academic reputation and appeal

The team is well recognized at the national and international level in the genetics of Parkinson's disease with several international collaboration and invitations to international events. The reputation goes far beyond what could be expected from a team that size. The preclinical work, however, does not succeed in attracting the same attention or the same appeal. We recommend the team to look for international post-docs in both domains.

Assessment of the unit's interaction with the social, economic and cultural environment Involvement of the group leader in several national policy making councils, effort in publicizing science towards lay audience, patient organizations. Such involvement is clearly above what could be expected from a small team but the efforst are down to a single individual.

Assessment of the unit's involvement in training through research

The team is participating in the local Master and PhD programs, as well as the training of medical students for the clinicians. Since 2008, the team has hosted 6 Master 2 and 4 PhD students.

Assessment of the strategy and the five-year plan

The projectis in the continuity of previous objectives and findings. The project focuses on the investigation of the new molecular cascades that have been identified by transcriptomic analyses in peripheral blood cells. The project is relatively straightforward concerning the part aiming at deciphering the role of these pathways by using gene targeting approaches in animal models and cell models. The toxic model is probably interesting for exploring these pathways at a very early stage of the disease although the link between the peripheral markers and the pathological process in the brain remains to be clarified. Pharmacological approaches are also proposed, particularly with new potential neuroprotective compounds. Is the toxic model sufficiently reproducible for testing these compounds ?

The biomarker project is based on the cohorts that have been implemented by the clinicians and the expertise of the team in transcriptomic and RNAseq analyses. Is the RNA a suitable material for clinical use as a peripheral blood marker ? Is there any protein marker that could be used instead ?

Conclusion

In conclusion, a good team with a large collaboration network thanks to their cohort management and expertise in genomics. Attention to be paid onto (I) managerial transition and (II) relative weakness of the preclinical research output.

 Strengths and opportunities:

Arrival of new team members (scientist, post-doc) stregthning the working capacity.

Well defined cohorts allowing to focus on early stages of the disease.

The Ghrelin project is an asset for the team.

 Weaknesses and threats:

Team management at time of current PI retirement is unclear with a clear threat upon cohort management (or access to cohorts).

Is the toxic model aneasy reproducible and viable model for testing disease-modifying compounds ?

Funding of preclinical research.

Peripheral blood biomarker is highly competitive field: How to use RNA as clinical screen ?

 Recommendations:

Careful analysis of the selected spreading model vis-à-vis the current available manpower for testing diseasemodifying candidates. A better focus on transcriptomics and genomics may be recommended.  Detailed assessments

Assessment of scientific quality and outputs

The team as a whole have produced a high number of publications (163 since 2008) mostly in specialised journals like Blood, Leukemia, Haematologica and a couple of high impact factor papers in New England Journal of Medicine, Nature Medicine, etc, either as primary or as collaborations. Most of these publications come from their work on the genetic analysis and screening of mutations and the association of these mutations with clinical outcome. This team is indeed recognised nationally for their work on this aspect and is really well-linked with clinical consortium and well-involved in the follow-up of clinical trials. The work on the aspect of cell dormancy is producing considerably less.

Assessment of the unit's academic reputation and appeal

The team is well recognized at the national level for their genetic analysis and screening of mutations in leukemia. The team is a member of the European Leukemia Net and its reputation in dormancy is also recognised by his invitation to international meetings.

Assessment of the unit's interaction with the social, economic and cultural environment

The team has been helping the creation of a Biotech company, they have link with industrial company (SERVIER, ONcoVET), and have some visibility at the European level with an involvement in the European Leukemia Net.

Assessment of the unit's involvement in training through research

The team is participating in the local Master M2R Lille, as well as in the training of PhD students and masters. Since 2008, the team has hosted 18 Master 2 and 11 PhD students. The implication of the team in the overall graduate training is thus excellent, both in fundamental and clinical cursus. To note here the lack of post-doctoral fellows.

Assessment of the strategy and the five-year plan

The projectis in the continuity of previous objectives of the team especially on the aspect of genetic screening using both targeting mutations analysis and next generation sequencing technique. The recent to the team of a brilliant pharmacogenomic investigator nicely complements the study of genomic markers. The project will also bring the xenotransplantation model for the study of clonal evolution. The project on dormant cells will be extended with the use of new mouse models (both syngeneic, xenotransplantation model and possibly melanoma model). The insertion of 4 members of team 4 will bring a new expertise in tumor metabolism, cell death and drug targeting DNA notably which might be helpful to better define dormant cells.

Conclusion

The team is well-recognised for its works on genomic analysis, "minimal residual disease" evaluation after treatment and thus should continue to build-up upon its establsihed track-record. The addition of the xenotransplantation model both for the study of clonal evolution and pharmacogenomic is certainly going to strenghten this aspect of the work. The aspect of dormant cells is a really competitive field.

 Strengths and opportunities:

A clear opportunity will be to build-up upon established track-record especially genomic study and minimal residual disease evaluation. Another opportunity will be to take advantage of primary patients samples.

Development of new models for dormancy / residual malignant cells (like xenotransplantation, melanoma project).

Rising of pharmacogenomic with the hiring of an experienced researcher.

Genomic screening is an asset.

 Weaknesses and threats:

Very competitive field with highly specific (re)definition of dormancy concept needed.

Unclear what is the effect of immortalisation of dormant cells.

 Recommendations:

Taking advantage of the minimal residual disease and chemoresistance with the pharmacogenetic project, should help bring the themes of the team together and help reinforce collaborative studies between team members. It will be indeed helpful to delineate better the "dormancy concept" and see how this overlaps with minimal residual disease and chemoresistant cells. This will allow more interaction between team members. Take advantage of the integration of new researchers with expertise on solid tumors and metabolism. Take advantage of the establishment of the xenotransplant model to study "dormant cells" and look into the overlap with chemoresistance.

Considering cooperation with team 5 for stemness project.

Working onto inter-team scientific exchanges (especially with other oncology teams via SIRIC) should be encouraged.

Recruitement of more post-docs should also be encouraged. Qualified research supervisors (with an HDR) or similar positions 14 13

 Detailed assessments

Assessment of scientific quality and outputs

The team has a long experience in the field of mucins, since it is a continuation of a group working on the structure and biology of mucins for over 40 years. It started out by the Aubert group that identified MUC5AC and MUC5B and the human orthologue of MUC4 (previously described in rat by Carraway et al.). The group has then decided to focus on the transmembrane mucins MUC1 and MUC4 in relation to cancer development. These are two different mucins belonging to two different groups of transmembrane mucins. The MUC1 mucin has been extensively studied in relation to cancer for many years. The MUC1 interaction with galectins and galectin 3 has been studied by several groups. The MUC4 mucin is unique in higher organisms as it is only one of its type (NODO-AMOP-VWD) in comparison to MUC1 (SEA-type) that is part of a larger family. Little is known of the MUC4 mucin except that it might bind ErbB2. Actually, the role of the transmembrane mucins is still an open question and they are probably important for some of the altered properties of cancer cells and metastasis as they are important for cell interactions. Less is understood on how these molecules could be involved in tumor cell progression.

The team is very familiar with mucins, a difficult area to work with. There are few competent groups in the world in this area and, as the interest is increasing, there is an interesting opening for further development. The study of gene regulation and role of epigenetics is unique for the group and has given important knowledge. This team is the only known research group that is able to develop this area.The scientific production of the team is globally satisfactory. Its most recent focus on the study of the role of cell membrane-bound mucins in epithelial carcinogenesis was very productive. However, many of the papers of these last five years were produced in collaboration and are not related to the main and highly visible topics of the team (e.g. Ann Surg Oncol., Eur J Surg Oncol, Ann Surg).

Assessment of the unit's academic reputation and appeal

The group benefitsfrom international and national recognition in the field of mucin biology. It participates in several national networks. International recognition of its director is well demonstrated by her participation as invited speaker in specialized international meetings. Concerning attractivity, it should be noted that the number of postdocs who joined the group during the last five years was very limited and should be increased in the future. Globally, the team leader should recruit more skilled scientists and full time researchers to reinforce the group. The team has a great ability to raise funds. However, these allocations are essentially fromregional and national origin. No European grant was obtained during the last five years.

Assessment of the unit's interaction with the social, economic and cultural environment

The group was strongly involved in the diffusion of scientific information by press articles and conferences. It also developped strong translational research with clinician teams. Its director must be cautious, however, concerning the risk of thematic dispersion induced by too many and too diffuse and collaborative projects.

Assessment of the unit's involvement in training through research

The team is very well involved in training through research since several of its members have been involved in the conception and coordination of several modulesand teaching units of the master degree (level master 1 and master 2). It also participates inthe animation of the doctoral school ED 446.

Assessment of the strategy and the five-year plan

The number of models under study seems excessive and the ten research programs mentioned in the project of the team (not including translational research projects) may be difficult to manage at the same time. The large number of projects induces a serious risk of thematic dispersion. The group is recommended to focus more on fewer projects, particularly interesting is the MUC4 mucin and its normal function, for example NIDO-AMOP-VWD domains, and focus less on MUC1 as there is more competition and especially too many incorrect publications to work against (more difficult to publish that something is wrong than to publish something new).

Conclusion

This team makes globally a very good job and beneficiatesfrom an international recognition in the field of mucin biology. However, its director must avoid a dispersion of thematic projects and focus on the areas of excellence in which the team is recognized. The group includes too few skilled full-time scientists and the recruitment of new full-time researchers and post-docs should be highly encouraged. Publications of the team should be more focused on its field of excellence. European grant applications should be deposited.

 Strengths and opportunities:

Good productivity considering the number of researchers.

Great visibility in the mucin field.

Main project on mucins (especially MUC4) is unique, very interesting and original. The scientific quality of the members of the team is strongly established. Their scientific production in terms of articles during the previous period (2008-13) is important with 66 published articles, some in excellent journals of the field (e.g. ACS Chem Biol, J Med Chem). Their integration in JPARC could however lead to an increase of the impact factor of their papers.

Assessment of the unit's academic reputation and appeal

The academic reputation of the members of the team is good and especially attested by the number of international congresses to which they were invited during the previous period. Their international reputation remains however to be improved. Their ability to obtain grants is excellent.

Assessment of the unit's interaction with the social, economic and cultural environment

The industrial development strategy of the members of the team is excellent with 13 patents, the contribution to the marketing of a drug and the creation of a spin-off, at a level well beyong the national competition.

Assessment of the unit's involvement in training through research

The activity of the members of the team in training through research is very good and correlated to their number.

Assessment of the strategy and the five-year plan

The strategy of the future team will succeed if it becomes a true resarch team and not only a "service delivery platform". Consequently it will have to limit the number of its projects and to give the priority to those which will concern validated targets concordantly studied with the other teams of JPARC. This medicinal team will have also to be a "prime mover" in this field.

Conclusion

The integration of a medicinal chemistry unit in a biology reaserch center is an exciting challenge with some risks but the results previously obtained by the members of the future team speak for the succes of the objective of the latter especially in its novel scientific environment. A chance should be given to this project.

 Strengths and opportunities:

Patent publications and deliveries.

Successful past collaborations with JPARC teams.

Industrial partnerhsip.

Technological transfer strategy, among the rare example of succesfull transfer of academic medicinal chemistry to market/clinic. Large number of post-docs.

Opportunity for improving publication profile within thre JPARC environment.

Strong local and institutional support.

 Weaknesses and threats:

Different locations from the rest of the teams (5 min walk but still away…).

Lack of scientific focus (too many projects).

Succeed in integration of biology and biology researchers in the projects.

 Recommendations:

Integration of biologists into the medicinal chemistry team.

Co-supervision of PhD students or post-docs on specific projects with the other teams ? Management of distance by regular scientific meetings, journal clubs, etc..

N3:

  Development and plasticity of the postnatal brainName of team leader: Mr Vincent PRÉVOT Workforce Permanent EPST or EPIC researchers and similar positions 3 3 Other permanent staff (without research duties) 2 2 N4: Other professors (PREM, ECC, etc.) N5: Other EPST or EPIC researchers (DREM, Postdoctoral students, visitors, etc.students having spent at least 12 months in the unit 5 Number of Research Supervisor Qualifications (HDR) taken 2 Qualified research supervisors (with an HDR) or similar positions 8 7

  Other professors (PREM, ECC, etc.) N5: Other EPST or EPIC researchers (DREM, Postdoctoral students, visitors, etc.

  Other professors (PREM, ECC, etc.) 1 N5: Other EPST or EPIC researchers (DREM, Postdoctoral students, visitors, etc.spent at least 12 months in the unit 1 Number of Research Supervisor Qualifications (HDR) taken Qualified research supervisors (with an HDR) or similar positions 5 8

  Other professors (PREM, ECC, etc.) N5: Other EPST or EPIC researchers (DREM, Postdoctoral students, visitors, etc.spent at least 12 months in the unit 1 Number of Research Supervisor Qualifications (HDR) taken 4

2 N4: 6 

 26 Permanent EPST or EPIC researchers and similar positions N3: Other permanent staff (without research duties) 2 Other professors (PREM, ECC, etc.) N5: Other EPST or EPIC researchers (DREM, Postdoctoral students, visitors, etc.) spent at least 12 months in the unit Number of Research Supervisor Qualifications (HDR) taken Qualified research supervisors (with an HDR) or similar positions 6 Detailed assessments Assessment of scientific quality and outputs

Team 1: Alzheimer's & tauopathies Name of team leader: Mr Luc BUÉE Workforce Team workforce Number as at 30/06/2013 Number as at 01/01/2015 N1: Permanent professors

	and similar positions	9	9
	N2: Permanent EPST or EPIC researchers and similar positions	5	4
	N3: Other permanent staff (without research duties)	4	4
	N4: Other professors (PREM, ECC, etc.)	1
	N5: Other EPST or EPIC researchers (DREM, Postdoctoral students, visitors, etc.)	1	5
	N6: Other contractual staff (without research duties)	7	2
	TOTAL

N1 to N6 27 24 Team workforce Number as at 30/06/2013 Number as at 01/01/2015

	Doctoral students	10
	Theses defended	10
	Postdoctoral students having spent at least 12 months in the unit	1
	Number of Research Supervisor Qualifications (HDR) taken	1
	Qualified research supervisors (with an HDR) or similar positions	11	13
	 Detailed assessments
	Assessment of scientific quality and outputs

 Supervising bodies general comments

Specific points to be mentioned:

The meeting with the funding/supporting institutions was particularly impressively attended by institution representatives from INSERM (national and local representatives), Université de Lille 2 (Research vice-president + deans of medecine and pharmacy), Centre Hospitalier Régional Universitoire (Research vice-president of the directoire), Université de Lille 1, Université d'Artois, Institut de Recherche sur le Cancer de Lille and the Nord-Pas-de-Calais region. Those representatives expressed their support and the importance of the unit for the local and national strategy. The experts committee was unanimous in stating this had not been seen before in previous committees.


Management team

The unit is directed by Mr Bart STAELS. He is assisted by a Management Committee composed of team leaders and key persons. -planned access to new laboratory space in 2016;

AERES nomenclature

SVE1 LS4

Unit workforce

Unit workforce

-several teams (teams 1, 2 and 3) have been joined by clinical researchers and medical doctors allowing further development of well-defined translational projects;

-human resources are anticipated to increase further. The evolving organisation, integration of additional clinicians and planned projects are likely to allow further development of translational Bench to Bedside projects;

-unit is part of the Hospital University Department (DHU) entitled « Coeur et Vaisseaux : de la Prévention au Traitement, facteurs de risque, cibles métaboliques et pathologie cardiovasculaire »;

-strong, long-lasting and highly productive partnership with Genfit SA, a biopharmaceutical company which emerged from Inserm U545 and which is engaged in the discovery and development of medical compounds in the therapeutical area of cardiometabolic disease;

-wide collection of transgenic animals in the field with creation of a new animal facility dedicated to metabolic diseases;

-strong collaborations and excellent attractiveness of the unit at the national and international levels;

-unit teams are highly complementary and interact closely;

-significant contribution to the creation and expansion of the European Genomic Institute of Diabetes (EGID), awarded Excellence Laboratory (LabEx) through the national Investment for the Future program;

-excellent interactions of UMR1011 with the local environment (in particular with Federative Research Institutes 114 and 142);

-projects are fully integrated in the Scientific Strategy Policy of the University of Lille 2;

Weaknesses and threats related to the context -the geographical distribution on two distinct sites requires a strong and effective management;

-highly competitive fields of research with breakthrough technology and experimental design of increasing cost, thus requiring appropriate/elevated funding;

-relatively low number of full-time researchers;

-numerous, highly skilled team members on non-permanent positions;

-loss of full-time permanent INSERM positions (retirements) without replacement in spite of the overall expansion of the unit staff over the last years;

-IFR-driven technical platforms deserve reorganization and reinforcement;

Recommendations

-to maintain and reinforce the current management strategy which allows frequent interactions and complementary competencies on the two sites;

-to finalize expansion of human resources as anticipated;

-to maintain the excellent relationships with social, economical and cultural environment;

-to foster recruitment of young, full-time researchers through national competitive calls (Inserm, CNRS);

-to sustain the emergence of promising, young team leaders;

-to reinforce the permanent administrative staff (in particular through permanent Inserm and University positions);

3  Detailed assessments

Assessment of scientific quality and outputs UMR_S 1011 has an international reputation and leadership in studying the physiological function, regulation and pharmacological modulation of nuclear receptors in immune-inflammatory and cardiometabolic diseases. These are complex disorders with inter-organ cross-talk mechanisms that are investigated here in an integrative and comprehensive manner. UMR_S 1011 combines multidisciplinary approaches (including metabolic, immune, inflammatory and vascular insights) that rely on complementary methodological approaches and know-how (including biochemistry, histology, molecular epigenetics, development of genetically-engineered mouse models, metabolic immunophenotyping, cell and whole-body imaging, animal physiology, chemical screening,…). Most of them are accessible through common technical platforms which are in direct and tight link with research projects. Additional external platforms are accessible as core facilities of EGID LabEx, IFR114 and IFR142.

Scope of the research can be summarized as two complementary and well-defined axes: 1) investigation of cellular and molecular mechanisms controlling lipid and glucose metabolism, and 2) development of preventive and therapeutic strategies against dyslipidemia, type 2 diabetes, atherosclerosis and cardiovascular diseases.

UMR_S 1011 involves 4 distinct, but complementary and interacting teams:

-Team 1 'Nuclear receptors in the metabolic syndrome' is devoted to studies of the metabolic functions of nuclear receptors (PPARs, FXR, Rev-erba, RORa) using animal models and human translational research approaches and their interest as potential therapeutic targets in humans ; -Team 2 'Molecular control of monocyte/macrophage functions in cardiometabolic syndrome' focuses its activities on the role of macrophage subsets in the development of atherosclerosis and their control by PPARs and LXRs. The role of PPARs and LXRs in the molecular regulation of monocyte differentiation and macrophage functions in adipose tissue during obesity is also studied ; -Team 3 'Nuclear receptors, immuno-inflammation and cardiometabolic diseases' is devoted to studies of the mechanisms by which nuclear receptors control the function of immune cells and their impact on atherosclerosis ;

-Team 4 'Molecular analysis of gene regulation in cardiometabolic diseases' investigates how nuclear receptors control gene expression and affect immune-metabolic functions, aiming at unraveling novel regulatory pathways in order to validate nuclear receptors as pharmacological targets ;

Remarkably, each team develops its research program in close interaction with the others, thus facilitating multidisciplinary and translational approaches. It is highlighted by a number of joint publications (involving authors from two teams or more). In addition, dynamic and productive collaborations have been set up with external technical platforms and with clinical departments, in particular from the EGID LabEx and the University Hospital of Lille.

Past activity of the unit is outstanding. Among the number of advances and breakthroughs of the 2008-2013 period:

the role of PPARa in non-alcoholic steatohepatitis (NASH) and the development of a novel dual PPARa/d agonist ;

the role of the nuclear bile acid receptor FXR in the control of lipid and glucose metabolism by bile acids, in particular with consequences on adipocyte differentiation, pancreatic beta-cell function, and glucose homeostasis ;

the role of Rev-erba in mitochondrial biogenesis, function and autophagy, thus identifying Rev-erba as a possible pharmacological target in some myopathies ;

the modulation of macrophage phenotype (notably by nuclear receptors or by the tumor suppressor gene P16INK4a) and its consequences on inflammation, atherosclerosis and obesity development ;

the contribution of adipose tissue macrophages to the development of cancer in obese patients;

the contribution of PPARa dysregulation to atopic dermatitis ;

-the role of PPARa and -g as negative regulators of IgE-mediated systemic anaphylaxis;

-the contribution of PPARb/d to hepatic fibrosis;

-the implication of PPARa in the resistance to sepsis in mice;

-the control of glycolysis in the liver by FXR and its sensitivity to cellular energy levels;

-the description of novel roles for nuclear receptors in the control of liver and pancreatic b-cell physiology;

-the impact of epigenomic DNA modifications (DNA methylation or hydroxymethylation) on PPARg-driven adipocyte differentiation and induction of TLR4

Scientific production of the 2008-2013 period is outstanding, with 224 publications (including 42 reviews, 2 book chapters and 14 letters or editorials). Eight publications with Impact Factor above 20, 23 with IF ranging between 10 and 20, and 109 with IF between 4 and 10.

Team members show outstanding track record and citation index, including H index of 100 for one member with more than 33000 total citations without self-citations. In a recently published and independent analysis of most cited authors in Europe (Lab Times, 2013), one unit member was ranked 4 th for the citation number of articles published by european pharmacologists and pharmacists between 2005 and 2011 in 'pharmacology and pharmacy' journals (as listed by Thomson Reuters' Web of Science).

On average, there are 3000 citations per year for publications of all unit members over the 2008-2013 period, with many articles in high-rank, peer-reviewed journals.

Unit members have been invited more than 180 times to national and international conferences as invited speakers.

They have given more than 200 oral or poster presentations in national and international meetings.

Assessment of the unit's academic reputation and appeal

Over the 2008-2013 period, UMR_S 1011 made significant and major contributions 1) to the creation of the European Genomic Institute of Diabetes (EGID) which was awarded an ANR LabEx funding for 8 years, 2) to the creation of the Hospital University Department (DHU) entitled "Coeur et Vaisseaux : de la Prévention au Traitement, facteurs de risque, cibles métaboliques et pathologie cardiovasculaire", 3) to the regional CPER plan axis entitled "Diabetes and cardiovascular diseases", 4) to the attraction and recruitment of new fellows on permanent Inserm or university positions, 5) to a transatlantic network of excellence in cardiovascular disease and therapeutic targets (Leducq Foundation), and 6) to European programs. UMR_S 1011 has set up and developed numerous scientific collaborations worldwide (USA, The Netherlands, Denmark, Poland, Great Britain, Germany, Belgium, Austria, Switzerland, Portugal, France,…).

Unit members have received a number of national and international prizes and awards, among them Senior member of the Institut Universitaire de France, European Lipid Science Award 2010, "Jean-Paul BINET" prize 2011 from the Fondation pour la Recherche Médicale (FRM), the 2012 "Distinguished Leader in Insulin Resistance" award from the international Committee for Insulin Resistance (ICIR),... Several members of the research unit are recipients of the Prime d'Excellence Scientifique Inserm and/or Interface Grants.

The research unit has a strong attractiveness for high-standard visiting fellows from many countries and has numerous and productive collaborations worldwide.

During the 2008-2013 period, 22 postdoctoral fellows joined the research unit.

New permanent positions were created, and additional fellows (including 13 clinicians with MCU-PH, PH or PUPH positions) will join teams 1 and 2 of the unit on January 2015. In 2013, unit UMR_S 1011 organized the COST meeting entitled "HDL, from biological understanding to clinical exploitation" and gathering participants from 15 European countries. During the 2008-2013 period, the unit has coordinated the scientific animation of the axis "Diabetes and cardiovascular complications" of the région Nord Pas de Calais. This axis comprises five labelled units, and covers a large number of laboratories of the Lille 2 University.

During this period, 73 conferences (42 French speakers, 26 speakers from other European countries, 5 non-European speakers) have been organized.

Assessment of the unit's interaction with the social, economic and cultural environment

The Genfit biotechnology company was co-founded by the unit director who is currently president of the Genfit Scientific Council. The tight partnership of Genfit and UMR_S1001 led to the registration of several patents. Remarkably, recent and ongoing interactions of UMR_S1011 and Genfit led to the development of the GFT505 PPARagonist which is currently in Phase IIb clinical development for the treatment of non-alcoholic steatohepatitis, a major public health concern. UMR_S1011 has also set up a strong collaboration with UMR761 for drug discovery with planed patent registrations.

Several members of UMR_S1011 take a significant part in research administration and evaluation at a local, national and international level (including head of the ethics committee for animal experimentation of the Nord-Pas de Calais Region, AERES delegate and members of AERES evaluation committees, elected members of Inserm and university Scientific Councils, members of learned societies, members of medical training/education councils,…) UMR_S1011 is integrated in the "Nutrition-Santé-Longévité" competitiveness cluster of the Nord-Pas de Calais region.

With respect to cultural interaction with the environment, the unit participates actively in the "Pasteur kid Campus" and INSERM "Destination Labo" initiatives, which allow children from primary and secondary schools to get in touch with research. The unit also contributes annually to the "Fête de la Science" event, as well as to the "Salon de l'étudiant et de l'étudiant santé", the "Salon des grandes études et de la recherche" and the "Salon des Masters".

Members of UMR_S1011 deliver general public conferences (e.g. "Pasteur 5 à 7 meetings") which target a nonspecialist adult audience.

Communication to the general public is also made through the internet web site of the research unit (http://www.u1011.lille.inserm.fr), a video with general information on unit activities, conference presentations to local industrial partners at the "Pépite Lille Metropôle Innovation" meeting, and several interviews published in local or national newspapers (i.e. Le Monde, 9 mars 2013).

Assessment of the unit's organisation and life

The organisational flow chart of UMR_S1011, as provided, is functional and well-defined, with 4 research teams and 1 administrative and logistical team.

Briefly, the statutory unit Council (unit director, financial officer, persons in charge of the Pasteur Institute and CHRU sites, team leaders, elected members) meets twice a year, with a General Assembly once a year.

The Scientific Council of UMR_S1011 is common to the EGID Scientific Council as part of the PIA LabEx program.

A Management Committee of the unit (composed of the unit director, team leaders and key persons) meets on a weekly basis. It is the operative part for the daily management of the unit. It interacts with external institutions and makes strategic choices. Scientific coordination is made through project follow-up meetings (on a weekly basis, including students/postdocs and team leader), thematic group meetings (every 2-3 weeks, including project members and team leader), and a steering committee (every 6 weeks, including project members and unit director).

Finally, research teams are supported by a logistical and administrative staffs, which ensures interactions with institutions (Inserm, Université de Lille2 and Institut Pasteur de Lille). This staff contributes also to grant applications and management (interactions with Région Nord-Pas de Calais, Europe, ANR,…), financial management, laboratory safety, scientific animation, communication, etc… Besides providing technical know-how and support to the other teams of the unit, each team is also interacting and collaborating with teams outside the unit, in particular by giving access to their platforms. Even though priority is given to the unit's research projects, the platforms are open to other teams (mostly, but not exclusively in Lille) yielding several productive collaborations through specific technological competences (including for instance laser micro-dissection, histology, and immunophenotyping). When appropriate, technicians and engineers appear as coauthors on scientific publications.

Internal scientific animation of the unit is remarkable with seminars by invited national and international collaborators, organization of internal "unit meetings", "journal club", one annual EGID "Think tank" (one full day of presentation of Egid projects), and oral or poster presentation of research data during seminars.

Impressively, unit UMR_S1011 has made a highly significant contribution to creation and upgrading of a number of technical platforms. Organization of and access to technical platforms, whether they are internal, common/shared, or external is exemplary. A brief overview of technical platforms is provided below:

-Internal platforms:

Biochemistry platform: it allows measurement of classical range of biochemical parameters (glucose, lipids, transaminases ...) and is required for proper mouse phenotyping. It allows fruitful academic and industrial collaborations.

Histology platform: it has been recently completed with a laser capture microdissection station. This device allows the isolation and study of the properties, distribution and functions of cells from the arterial wall and metabolic tissues that are obtained from human clinical studies or genetically-modified murine models.

Epigenetic platform: a microarray station is used to analyze mRNA and miRNA expression profiles in cellular models, primary cells and tissues of various origins. An evolutive bioinformatic pipeline has been implemented and is routinely used to process and analyse new generation sequencing data.

-Common/shared platforms:

Access is given within the EGID framework, and within the framework of the ANR Labex and the Region Nord Pas de Calais.

Metabolic immunophenotyping: The metabolic immunophenotyping platform is expected to open during the first semester of 2014. It will allow to explore further the complex link between changes in immune cell populations/functions and metabolic alterations.

Animal facility and metabolic platform: a new animal facility is currently built up on the hospital campus. It comes in addition to the animal facilities at Pasteur Institute and will include new paradigms dedicated to metabolic phenotyping.

Whole body imaging: UMR_S 1011 has access to Computed Tomography for whole-body scanning of mice. This equipment has been set up in the High technology IMPRT-IFR114 Animal Facilities on the hospital campus and is made accessible to other researchers.

Exploration of cardiovascular function: invasive and non-invasive measurements of cardiovascular functions (blood pressure, heart rate…) in genetically-modified and dietary manipulated animal models are currently upgraded. These measurements are relevant to all experimental animal protocols used in the unit.

-External platforms:

Members of UMR_S 1011 have access to the cell and animal imaging, microarray and proteomic analysis platforms of the "Institut de Médecine Prédictive et Thérapeutique" IMPRT/IFR114 and the Pasteur Institute/IFR142. UMR_S 1011 also benefits from numerous academic, industrial and clinical collaborations with several (inter)national groups and through industrial and European consortiums. Transversal collaborations within the Prime axis (supported by the région Nord Pas de Calais) allow drug development using a screening platform to identify new chemical entities which regulate genes of interest in metabolic and cardiovascular diseases.

Assessment of the unit's involvement in training through research

A number of members of UMR_S1011 are teachers at the faculties of pharmacy and medicine of University Lille 2 (14 full and associate professors). Unit members are actively involved in the Master "Biologie-Santé" of the University of Lille 2 for both academic and laboratory training. The unit hosts many trainees (Master 1 and 2, BTS technical degree, PhD students). Several members of the academic research staff (other than teachers) of the unit also teach in the Master school or continuous educational programs (i.e. animal experimentation training).

PhD Students (not exceeding 1.5 PhD students per thesis supervisor) follow a compulsory doctoral training organized by the doctoral school. Students are asked to present in English and on a regular basis their results during the unit's meetings. The scientific communication and interactions between students are facilitated through a weekly journal club in English which gathers all the PhD as well as Master students and post-doctoral fellows. They are encouraged to actively present their results in national (NSFA, Symposium ALFEDIAM, …) and international meetings (EVGN, ELC Tützing, EMBO conferences, Cell Signalling meetings, Summer School on Nuclear Receptors, AHA,...). At the end of the PhD training period, each student has taken part in at least one meeting. PhD students benefit from a compulsory annual follow-up meeting with external advisors. The unit hosted Erasmus students from Italy, Poland and Turkey. Overall, unit members significantly contribute to organisation and management of the doctoral school (Conseil de l'École Doctorale, Comités de suivi de thèses, jury de concours pour l'attribution des allocations doctorales).

Once a year, and starting from 2014, an internal mini-congress will be organised within EGID, with all the features of an international congress (including call for abstracts managed by an external selection committee). Posters and oral sessions will give students the opportunity to improve their presentation skills. The teaching project of the unit is actually tightly linked to the EGID student training project, as part of the local Master Program Biology-Health. From 2010, novel courses have been introduced at the M1 and, more intensively, the M2 levels, with "thematic days" dedicated to themes directly connected to scientific research of the unit. On this basis, a course/speciality entitled "Diabetes, obesity and cardiometabolic complications" has emerged within the Master Program. It has been formalised in 2013 and will be effective from 2014. This master will allow attracting students in the field of cardiometabolic diseases and might evolve towards an Erasmus Mundus Master.

The first EGID summer school has taken place in September 2013. It was open to PhD students, post-doctoral students and engineers from European laboratories. This Summer school will be renewed every 2 years.

Since 2008, 13 students from the unit defended their PhD thesis, and among them 8 are currently post-doctoral fellows in France or abroad. One PhD student now holds a researcher position in France (at University), and another one is working in a Biotechnology company.

Since 2008, 5 competencies for research direction (HDR) have been defended by young researchers or teachers from UMR_S 1011 and 3 are scheduled in the near future. Today, 13 researchers of the unit hold HDR.

Assessment of the strategy and the five-year plan

Research plans, very well defined, are in direct link with the 2008-2013 fruitful past activities.

For the next 5-year period, UMR_S 1011 will pursue the investigation of the molecular and biological mechanisms involved in dyslipidemia and type 2 diabetes and their cardiovascular complications. Special interest will be given to specific nuclear receptors with the aim to identify new targets or treatment strategies to correct the defective pathways.

Undoubtly, UMR_S 1011 possess the know-how, and has access to all required molecular tools and technological equipment (cellular and molecular biology, biochemistry, histology, animal experimentation, animal models, immunophenotyping, EGID animal facility).

Beyond the administrative organization in 4 teams, the global strategy of the unit is remarkable and consists of a transdisciplinary, translational approach focusing on 3 transversal topics associating nuclear receptors and cardiometabolic diseases: 1) Fatty acids and PPARs, 2) Bile acids and FXR, and 3) Circadian rhythms and RORα-Reverbα.

UMR_S 1011 is one of the three founder units of EGID. This new institute (supported by Inserm, CNRS, CHRU Lille, University Lille 2, Institut Pasteur de Lille, Lille Communauté Urbaine, région Nord-Pas de Calais as institutional and/or financial partners) is expected to expand by 2020. UMR_S 1011 will remain a major contributor to the development of the EGID Labex project.

Several grants will continue beyond 2015 (EuRhythDia, Chronotherapeutic lifestyle intervention for diabetes and obesity to reset the circadian rhythm and improve cardio metabolic risk in the European working population). The Leducq Network is running until the end of 2015, and the RESOLVE project until 2017. Several funding applications are continuously submitted by members of the unit.

Of course, UMR_S 1011 will pursue numerous collaborations with local, national or international laboratories.

In order to reinforce research on cardiovascular diseases in Lille, and to increase interaction with CHU de Lille, the Unit is actively involved in the creation of a DHU (Département Hospitalo-Universitaire -"Coeur et Vaisseaux : de la Prévention au Traitement, facteurs de risque, cibles métaboliques et pathologie cardiovasculaire"). The DHU project is in the development phase, but has already gained principle of agreement of the key participants and of Université Lille 2 and the CHRU Lille. During the 2008-2013 period, the various team members have contributed to 143 publications (57 with 1 team member as first and/or (co-)last author) including 113 original publications. The list of publications of this group is impressive and of very high impact (Nature Medicine, Hepatology, Gastroenterology, J Clin Invest) demonstrating the ability of the team to produce high-ranking research with several highly referenced papers in the field. They published numerous articles in journals with an impact factor > 9. The team has a very strong international reputation for its research. In summary, this team has reached a very high level of scientific quality and expertise in the field. The publication output is outstanding and the impact of the group is major in all the domains covered.

Assessment of the unit's academic reputation and appeal -recruitments: A young researcher with teaching duties joined team 1 in 2010. In addition to 5 post-doctoral fellows (of whom 4 have left Team 1 since 2010), 4 post-doctoral fellows were further recruited; -edition: Team leader is/was an editorial board member of several journals and contributed to/co-edited the International Union of Basic and Clinical Pharmacology (IUPHAR) Compendium of Nuclear Receptors; -expertise: team members perform scientific expertise for (inter)national institutions and funding agencies; international journals and scientific committees; -invitations: Team leader (137 invited lectures) and members of Team 1 are regularly invited to national and international meetings; -coordination and public funding: Team 1 is/was coordinator of different projects (FRM-P16 (2007(FRM-P16 ( -2010)), FCA-PPARs (2006-2009) Assessment of the unit's interaction with the social, economic and cultural environment Team 1 has/had several contracts with pharmaceutical, biotechnology (Genfit) and nutrition industries. Several patents have been registered. Of note, continuing collaborations exist between Team 1 and Genfit yielding one compound currently in Phase IIb clinical development. Team 1 participates in several private-public consortia (IT-Diab, AMIDIAB, OSEO-Olnorme, FUI-BETADIAB). The biochemistry platform participates in fruitful academic and industrial collaborations thanks to its mouse phenotyping expertise. The team leader is co-coordinator of the European Genomics Institute of Diabetes (Labex) and Diabetes from Metabolic syndrome to Cardiovascular complications of the 7th CPER.

Assessment of the unit's organisation and life

The team is composed of a substantial number of researchers, engineers and students. On January 2015, the team will be composed of 1 researcher, 4 MCU, 4 PU and 1 MCU-PH, 6 engineers and 2 assistant-engineers. Three researchers with teaching duties and 1 academic clinician will join the team because of complementary expertise and previous collaborations. Team organization is founded on different subgroups with specific projects.

Assessment of the unit's involvement in training through research

Team 1 is affiliated to the PhD program ED446 Biologie-Santé, Lille, and the Master Biologie-Santé (M1 Lille 2, M2 Lille 1-Lille 2). Most of the team members have high teaching duties. Three members of Team 1 have a HDR in 2013. In 2015, Team 1 will have 5 members with HDR. During 2008-2013, Team 1 has formed 6 Master 2 and 6 PhD theses were defended. Presently, 1 Master 2 and 3 PhD training programs are on-going. No information is currently available on the follow-up of doctoral students in link with doctoral schools and the care taken with the integration of doctors into the job market.

Assessment of the strategy and the five-year plan

The overall objective of the team is to decipher the molecular and cellular impact of nuclear receptor, such as PPARs, FXR and Rev-erb/ROR, in the metabolic homeostasis. Three main projects will be developed during the next five years: i) NASH, Metabolic Syndrome and PPARs, ii) Bile Acids, FXR and the Metabolic Syndrome, and iii) Circadian Rhythm, Metabolic Syndrome and Rev-erb/ROR. These projects rely on the internationally recognized expertise of the different team members and may lead to major breakthrough in the field. All the projects are based on the development of sophisticated experimental models of genetically modified mice. Of great interest, at least two projects (project i and project ii) have strong translational aspects including the use of human samples and identification of synthetic compounds that may have therapeutic applications. In this line, the team has already screened and identified synthetic compounds acting on TGR5 (patents registered; project 2). Overall, the project of team 1 is an excellent, high standard, serious and well-conceived research project based on excellent preliminary results and a long-standing experience in the field. It is a translational project that runs from basic science to clinical investigation. This project may lead to the identification of potential gene networks and biomarkers associated with metabolic diseases.

Conclusion

 Strengths and opportunities:

Already long history of excellent track record (many publications of very high quality)

International reputation

Appropriate current funding level

High quality of the proposed project

 Weaknesses and threats:

No weakness intrinsic to the scientific capability and organization of the team.

 Recommendations:

The team leader is encouraged in his long-term policy to support the development of young staff members as independent researcher.

The team should aim at attracting at least 1 permanent position from Inserm.

Team 2 :

Molecular control of monocyte / macrophage functions in cardiometabolic syndrome Name of team leader: MS Giulia CHINETTI The research activity of the team is well focused on the study of monocyte/macrophage populations in atherosclerosis and obesity with a specific emphasis on the role of the molecular pathways involving the nuclear receptors PPARγ and LXRs. The main results highlight the role of PPARγ and LXR pathways in the heterogeneity of the macrophage populations within human atherosclerotic plaque (in terms of cell surface markers associated with metabolic and phagocytotic functions). The comparative study between human adipose tissue and tumour associated macrophages reveals unexpected similarities. The approaches have been mainly performed on human samples (native cells obtained after immunoselection, laser-captured materials or in vitro differentiated cells) re-inforcing the pathophysiological relevance of the observations. An additional original research axis has been developed and concerns the role of the cyclin-CDK inhibitor CDKN2A p16 INK4a (p16), a key regulator involved in age-related diseases and in monocyte/macrophage polarization. The approaches performed on murine models (mouse p16 INK4a deficiency, mice transplanted with p16(-/-) bone marrow) and on ATM, MDM and human blood monocytes allowed to decipher the role of p16 in macrophage polarization and its consequence on atherosclerosis development, obesity, and glucose intolerance.

Workforce

Local and international collaborations have been set up on several axes (PBMC and ATM from obese subjects; TAM; CD68(+) (MR)(+) M2 macrophages in human atherosclerotic plaques).

The results obtained are original and published in the best journals of the field. Since 2008, the team has produced 51 original articles (12 with IF>9, 22 with IF>5) including 17 directly from the group (Blood 2011, Diabetologia 2011, Circ Res. 2011, 2013, J. Biol. Chem 2012, Arterioscler. Thromb. Vasc. Biol. 2012) and 35 in collaboration and 16 reviews. Twenty-eight publications are collaborations with team 1, 3 and/or 4. They are regularly presented at major national and international meetings in the field.

Assessment of the unit's academic reputation and appeal

The team has national and international regognized expertise in the field of nuclear receptors in inflammation in vascular and metabolic diseases as shown by 19 invitations in lab seminars and congress (national and international).

The team was involved in the coordination of national projects: FRM, 2011FRM, -2014;;Fondation de France, 2011-2014;ANR "AIMHA", 2010-2013;CPER "ChoMetAlt" 2008-2010. Members of the team have been recipients of an Inserm Interface Contract (2008Contract ( -2013)), "Prime d'excellence scientifique" (PES) from Inserm (2011Inserm ( -2014) ) and from the Université de Lille 2 (2012)(2013)(2014)(2015)(2016).

Members of the team are experts for the Ministère délégué à l'Enseignement Supérieur et à la Recherche « partenariat Hubert Curien » project, for « conseil régional de la région Nord Pas de Calais », and for AERES. The team has a high capacity to get financial support (since 2008 1 640 355 € ) at the local (University), regional and national (ANR, FRM), european (participant EU project TOBI (2008-2011) and international (participant in the Fondation Leducq Transatlantic network of Excellence -"High-density lipoprotein dysfunction in the development of cardiovascular disease and as a therapeutic target" (2010-2014)) levels.

The team is involved in "Fête de la science".

Assessment of the unit's organisation and life

In June 2013, the team is composed of 5 researchers, 3 PhD students, 4 post-doctoral fellows and 5 permanent and 2 non-permanent technicians. Starting from 2015, members of the EA2693 team of the University of Lille 2 will join Team 2.

Assessment of the unit's involvement in training through research

The team is affiliated to the doctoral school 446 (Biologie et santé)

The team has 3 HDR, and 4 PhD theses have been trained since 2010, 3 are in progress and one is scheduled late 2013.

The team is actively involved in the Labex EGID training project, as part of the Master Biologie-Santé of Lille (novel courses M1 and M2 level, with "thematic days"), coordinates an ERASMUS exchange program with the University of Padova (Italy), Faculty of Pharmacy.

Three post-docs were in the team and 4 are currently trained by the team; one post-doc has been recruited as MCU at the University of Lille 2. Visiting students (Italy, Austria) are mentioned.

Assessment of the strategy and the five-year plan

The proposed project is in the line with the past activities (characterization of macrophage subsets in human atherosclerotic lesions, impact of obesity on monocyte phenotype) with additional interesting and original axes including the contribution of macrophages and their subtypes to vascular calcification in atherosclerosis with the study of calcium phosphate homeostasis in macrophage sub-populations and the impact of PPARγ target genes in the trans-differentiation of macrophages to osteoblasts and/or osteoclast. Preliminary results as mentioned support the working hypotheses.

Another new research axis is proposed and concerns the early phase of the fibro-calcific process of aortic valves and more specifically the involvement of interstitial cells. This new axis is original, based on expertise of the clinicians joining the team and may open original and interesting research area.

The proposed approaches are broad, ranging from the « omics » (including transcriptomic (with mirRNAs), proteomic analyses of LCM-isolated macrophage, and mass spectrometry imaging (MSI) technology) to histological atherosclerotic plaque sections, in order to establish a signature of human macrophage subtypes.

The project is original and based on the technical know-how and expertise of the team. Some new approaches will be performed in collaboration and the feasibility is sustained by the ongoing collaborations with clinicians and benefits from a very good financial support.

Conclusion  Strengths and opportunities:

Recognized expertise in the field of nuclear receptors in inflammation and in vascular and metabolic diseases Broad approaches from mouse models to human biopsies with emphasis on native cells (laser-captured cells)

Established collaborations with clinicians and many interactions with the other teams Development of an original and interesting research axis on fibrocalcification process of aortic valves

 Weaknesses and threats:

The research projects may remain descriptive in its preliminary phase  Recommendations:

The committee recommends to maintain the research focus on the involvement of nuclear receptors in macrophages in vascular and metabolic pathologies and to continue to develop mechanistic and integrative approaches. The team "Nuclear receptors, immune-inflammation and cardiometabolic diseases" headed by David DOMBROWICZ has been created in 2010 when he moved from Inserm U547. During the current term, the team leader gradually adapted the project of immune-inflammatory studies in allergy (where the team has a proven track record of excellence) to the study of immune-inflammation in metabolic diseases. Many of the achievements of the 2008-2013 evaluation period still relate to the work initiated in Inserm U547, but the transition phase is well underway.

Since 2010, the team has been able to increase in size with 4 persons hired under permanent contracts including 1 researcher with teaching duties (MCU), 1 academic clinician and 2 technicians. The team has also recruited several new post-doctoral fellows. Since 2008, the team has published 67 research papers consisting of 49 original publications with about 1/3 (16) directly emanating from the team, and the others corresponding to collaborations (either with the other teams of the unit or with outside research groups). The publications are of good quality some of them with an impact factor close to 10 (2 JACI, Blood). Most of the other publications from the group are in journals relating to their specialty. Some of the collaborative work has been published in very high impact factor journals (2 Nat Med). Team members have also written 18 reviews witnessing the recognition in their field.

Assessment of the unit's academic reputation and appeal

The team is a well established, nationally and internationally recognized research group in the field of allergic immuno-inflammatory studies. Its reputation in the new field of research cannot be judged due to the fact that this change occurred very recently. Members of the team have coordination responsibilities both in National (ANR, PHRC) and international grants (EU Cost) and the team leader has important editorial tasks in different journals (Ass. Editor J. Immunol, Int. Arch All. Immunol), as well as in evaluation bodies (AERES). Over the years, the team has built a large number of both national and international collaborations that have led to common publications. The attractiveness of the team leader is also underlined by many (15) invitations to International meeting (Japanese Society of Allergology), as well as good success in obtaining funding. The team has obtained international contracts for collaborations with industry and several ongoing contracts. Some of them capitalize on the recent switch in thematics, partly based on the unique expertise of the team on the analysis of immune cell functions. The switch to the field of metabolic research, now largely underway after the transitional phase, undoubtedly represents a new opportunity on which the team can capitalize.

Assessment of the unit's interaction with the social, economic and cultural environment Although the team abandons somewhat its traditional field, the team leader has made a strategical decision to develop a new research axis. Examination of the role of immune cells in cardiometabolic disease now provides an opportunity for interdisciplinary research. The team's unique and outstanding expertise in the analysis of immuneinflammation is highly integrative, thus favouring collaborations with other team members. It has led to obtaining collaborative grants with industry (OSEO Micropath). The team offers strategic specific expertise for the setup of animal models as testified by the team leader position as the president of the Ethics Committee for Animal Experimentation Nord -Pas de Calais (CEEA75) since 2009. The team is highly engaged in the planning of the new animal facility that will be housed in a new building. The presence of an academic clinician favours translational research in the original field of dermato-allergy, which is now connected to the vasculo-metabolic field. The team, based on its unique expertise within the EGID labex represents also an essential driving force for the establishment of the new metabolic immuno-phenotyping platform. Finally, the team can be viewed as a highly integrative driving force both at the unit, but also at the Nord-Pas de Calais regional level.

Assessment of the unit's organisation and life

During the first term within the unit, the team has incorporated well into the unit activities. The project is highly integrative and collaborations with other team members are favoured in a highly efficient manner as testified by the many common publications with other teams of the unit. Members of team 3 have taken on important responsibilities, notably the establishment of an immunophenotyping platform useful for all unit members. The team leader is highly engaged in getting the animal platform going. Indeed, the visiting committee could appreciate that other permanent staff members recognize the valuable expertise of the team leader in the management of animal studies. By restructuring the group, the team leader allowed the emergence of a new synergy in a novel interdisciplinary research area. The team has been able to grow and set up a coherent organisation strategy THAT capitalizes both on the experimental animal interface but also on the opportunity to engage clinically related translational research.

Assessment of the unit's involvement in training through research Team 3 is affiliated to the PhD program ED446 Biologie-Santé, Lille. The team leader is currently co-supervising a PhD student studying the involvement of innate lymphoid cells in obesity-induced asthma. As team leader in Inserm U547, during the 2008-2009 period, he (co)supervised 3 PhD thesis, which were successfully defended: Role of PPAR in atopic dermatitis, Role of IgE and IgG receptors in atopic dermatitis, Eosinophils and innate immunity: expression and role of TCR in anti-tumoral defense. The team has also supervised 1 Erasmus Master (University Perugia, Italy, 2011) on the expression of FXR in T lymphocytes and has hosted another Erasmus fellow (Jagellonian University Krakow, Poland) for a 3 month summer visit to work on the regulation of MCP-1-Induced Protein/Regnase-1 by PPAR. The team has supervised 4 local master (M2R) students during the period (Expression of TCR by mouse eosinophils, 2008; Role of CX 3 CR1 in lymphocyte polarization in atopic dermatitis, 2009; Is TReP-132, a nuclear receptor co-factor, involved in smooth muscle cell proliferation ?, 2010; Psoriasis and metabolism: a pathohysiological link, 2012).

Assessment of the strategy and the five-year plan

The five-year plan clearly indicates that the transitional phase of the first term is terminated with all projects being now clearly oriented towards the general theme of the unit, and allowing efficient collaboration within the unit. One project will examine the pathophysiological link between psoriasis and metabolism based on a number of indications in the literature that there could be a connection. This connection will be investigated both in animal models of psoriasis and clinical studies building on a cohort of patients (Psoriasis/ Atopic Dermatitis) distinguished by their metabolic phenotype. Preliminary results indicating changes in glucidic metabolism and insulin signalling have already been obtained. The second project examines the relationship between bile acids, immune cell metabolism and energy homeostasis. It is based on experimental animal studies in which bile acid responsive elements such as the TGR5 cell surface receptor and the FXR nuclear receptor will be examined after specific knock-down in immune cell population using Cre technology based on primary expression analysis. Initial results have already been obtained, notably in B cells. The third project examines the immune regulatory mechanisms operative in adipose tissue inflammation and metabolic dysfunction, again based on specific knock-down of nuclear receptors in identified immune cell populations. This project is also associated with the regional excellence cluster EGID LabEx benefiting of a cohort of diabetic and non-diabetic morbidly obese patients undergoing bariatric surgery. It indicates the full integration of the team in the general scientific policy of the unit. The projects show that the team has an unique expertise in analysing immune cell phenotypes and function. It opens up a new promising research axis both at the level of the unit and within the North Pas-de Calais region. The projects are consistent, original and ambitious. They represent a balanced mix of studies in animal models and studies in patient cohorts based on the expertise of the team leader and the clinical associated service. All projects are funded. They are feasible as preliminary results have been obtained, but, given the still relatively small size of the team, it is possible that some reflection to cut-back on some aspects may be necessary unless additional personnel is recruited.

Conclusion

The team has a good publication record and during the first term has managed to shift from immunoinflammation in allergy models to immunoinflammation in vasculo-metabolic models. This additional effort, in continuation of the earliest projects of team, should be welcomed. It clearly represents an asset for the unit, providing a new dimension of research to the field of immuno-inflammatory investigation. The new project is ambitious involving a good mixture between animal studies and patient investigations and is based on the complementary expertise of team members. The team takes on important responsibilities both at the unit and regional level.

 Strengths and opportunities:

The team has high level of expertise in the analysis of immunoinflammation, now being applied to a new topic with considerably interdisciplinary potential. The team represents a driving force for development of a state-of-theart platform on metabolic immunophenotyping both for animal studies and investigations in humans. The interdisciplinary approach of the new project provides clearly an asset on which the team can capitalize. Experimental animal studies will be helped by the newly developed animal platform conceived under the supervision of the team leader. The clinical studies are based on cohorts available in the associated clinical services and integration in the labex EGID excellence cluster  Weaknesses and threats:

Three large scale projects are presented for a relatively small team. Although during the visit, the team leader clarified the individual responsibilities (involving experienced post-docs, but on a contractory basis), the threat remains that projects, which involve high level of animal breeding strategies cannot be completely secured due to the small size of the team.

 Recommendations:

Recruitment of a permanent researcher (EPST) should be envisaged. The team leader bears enormous administrative responsibilities some of which he should consider to abandon.

 Detailed assessments

Assessment of scientific quality and outputs Team 4 focuses on the molecular mechanisms involving members of the Nuclear Receptors superfamily, in the context of metabolism and inflammation in cardiometabolic diseases. As such, team 4 has the specificity in the unit of carrying the most updated molecular approaches, with a clear aim in understanding molecular mechanisms. With that respect, all projects that are developed within team 4 are carefully selected for their coherence with the projects performed in other teams.

The productivity of team 4, created in 2010, is presently taking a very dynamic shape. A total of 37 papers, of which 21 correspond to the ongoing projects started in 2010. Beside an important JCI paper in 2010, the production in 2011 and 2012 can be considerate as moderate in terms of impact. However, the team can present for 2013 an outstanding performance by publishing in a high impact generalist journal (JCI) and in the best of the specialty (Hepatology) as well as three other papers. There is no doubt that this reflects an excellent emerging scientific production.

Being in charge of a crucial platform for molecular approaches is also a demanding task that must be recognized as it serves the whole unit and beyond.

Assessment of the unit's academic reputation and appeal

The members of team 4 are well-known in the field of nuclear receptors, albeit the number of invitations remained modest (4 invitations). The high quality of the 2013 publications is likely to give a much better visibility of the team.

The team is involved in coordinating or contributing to one FP7 and three ANR projects. It also clearly contributes to the local and regional efforts in coordinating research platforms.

The team could recently attract one CNRS staff researcher, 2 post-doc fellows and 2 technicians. Team members are solicited as reviewers for funding agencies (French and European) and for international peer-reviewed journals.

Assessment of the unit's interaction with the social, economic and cultural environment Team 4 has an important role in teaching, particularly in the pharmacy school, and contributed to the establishment of a professional title (licence, DEUST) in "Health and environment".

In parallel, members of team 4 obtained and managed grants from the pharmaceutical industry, totaling 1.1.M€. They also participate to fund-raising committee in the context of EGID.

Sensitization of a broad public to science carriers is proposed through participation of the team to various forums.

Assessment of the unit's organisation and life

In 2013, the team is composed of 2 full-time researchers, two assistant professors, and 4 engineers, 3 postdoctoral fellows and 4 PhD students. Altogether, this composition is well equilibrated. Internal meetings as well as meeting across the full unit allow regular presentation and discussion of the various projects, ensuring that integration and appropriate collaboration take place.

Assessment of the unit's involvement in training through research

Team 4 is affiliated to the Doctoral School ED446. Over the last 5 years, they have been supervising 9 master students and 8 PhD students. Given the size of the team, this is a very good contribution to research training.

Assessment of the strategy and the five-year plan

As stated above, the goal of team 4 is on the one hand to maintain and further develop a high quality expertise in NR-related molecular mechanisms, particularly those requiring unbiased approaches, and on the other hand to pursue specific projects anchored in the recent and novel observations of the team.

Along with the latter line, one project will pursue the characterization of FXR post-translational modifications, more specifically its phosphorylation status, and its interactome. A second project, centred on the role of PPAR in NASH will benefit of a PPAR mutant, recently created by the team, that allows dissociation of the DNA binding-dependent activities from others.

Along the former line, one project will develop the tools to assess the epigenomic events regulating nuclear receptor function in adipocyte differentiation. This will be complemented by approaches allowing the study of long intergenic non-coding RNAs. Finally the bio-informatic support will be further reinforced to meet the requirements of the projects of the team and those of the whole unit.

Altogether, these projects are original and ambitious. The proposed techniques are well mastered and will be efficiently updated, in part through collaborations. There is an excellent integration of each project within the themes developed by the unit. The feasibility is very reasonable.

Conclusion

Team 4 was created de novo in 2010. In this short period of time, the committee considers that the team has achieved the expectations that were pointed at the time of the creation: bringing a high quality expertise in new methods for analysing molecular mechanisms, and integrating the general themes covered by the unit, both in terms of project designs but also in terms of making the team being really a part of the unit, regardless the geographical distribution.

Albeit the visibility of this team remains to be improved, the scientific records are showing very high dynamism.

 Strengths and opportunities:

-High levels of competence in new technologies -Ambitious and original projects allying epigenomics and genetics -Key role for the whole unit in helping projects from each team to further mechanistic approaches  Weaknesses and threats:

-International visibility needs to improve -Helping various projects in the unit may disperse the efforts of the team  Recommendations:

-The good integration of the projects with those of the entire unit must not have a dispersive effect for the team 4. Cohesion of the projects within team 4 must also be a priority.

-This may mean that, if the team does not grow, a tightening of the themes may be needed.

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The excellent bioinformatic expertise should be secured

  location of the unit UMR_S 1011 was created in January 2010, evolving out of unit 545. UMR_S 1011 is affiliated to IFR142 and IFR114. UMR_S 1011 is located on 2 distinct sites: Pasteur Institute of Lille and University Campus Lille 2 (in close proximity to the University Hospital)

  Strengths and opportunities related to the context -strong and recognized expertise of UMR_S 1011 with a first rank, leading position worldwide; -outstanding track record of unit director and team leaders; -well-defined research plans with excellent feasibility (in line with previous advances and ongoing workpackages of the unit); -the unit has access to the necessary platforms and possesses the capacity to develop new technologies. Additional facilities are planned to open by the end of 2015; -research themes and geographical distribution allow close interactions with strong clinical and surgical departments of the University Hospital and the University, and with strong basic research teams on the Pasteur Institute campus;

  The unit director is a member of numerous meeting program committees (Co-Chairman of the Basic Cardiovascular Sciences Conference 2008 (BCVS) -Keystone, CO, USA, July 28-31, 2008; Faculty and Program Committee member of the Annual World Congresses of the Insulin Resistance Syndrome (WCIR); Member of the EAS Program Committee and Advisor to the Executive Committee; Member of the International Advisory Board of the 10th European Symposium on Metabolism -Padua, Italy, October 7-9, 2010; Co-organizer of the 2012 Keystone Symposium on Genetic and Molecular Basis of Obesity and Body Weight Regulation -Santa Fe, New Mexico, USA, January 29 -February 3rd, 2012).

  spent at least 12 months in the unit* 8 Number of Research Supervisor Qualifications (HDR) taken Qualified research supervisors (with an HDR) or similar positions 4 5  Detailed assessments Assessment of scientific quality and outputs

  ,CPER-DIABETE (2007-2009),CPER-REGUCLOCK (2008-2010), CPER-PRIM, ANR-FXREN). Team leader is coordinator of the 'cardiometabolism' axis of the 2007-2013 CPER project and is co-founder of LABEX ANR EGID; -participation to other public funded projects: Team 1 is/was participant in numerous (inter)national funded projects (EU projects HEPADIP LSHM-CT-2005CT- -018734 (2005CT- -2010)), X-TRA-NET(-2008),TOBI (2008TOBI ( -2010)),STIGO (2007STIGO ( - 2011)), COST Actions BM0602(-2011) and BM0904 (2010-2014), EuRhythDia (2011-2016), DIAMAP (Road Map for Diabetes Research in Europe FP7 200701),FUI -BETADIAB (2009-2011), AMIDIAB (2006-2009),OSEO -OLNORME (2007-2009), Fondation LEDUCQ (2010-2015), EU FP7 RESOLVE, IT-Diab,…); -prizes: Team leader has received the European Lipid Science Award 2010, Munich; the "Jean-Paul BINET" prize 2011 from the Fondation pour la Recherche Médicale, Paris; and the 2012 "Distinguished Leader in Insulin Resistance" award from the International Committee for Insulin Resistance (ICIR), Los Angeles;

  Assessment of the unit's interaction with the social, economic and cultural environment Members of the team participate in collaborative contracts with Genfit SA and ImaBiotech (France), Bicoll (Germany): OLNORME Eurotrans-bio project: « Occurrence of novel Ligands for Nuclear Orphan Receptors in plant metabolites » (2007-2010), Servier (since 2002), Roche (2010-2011), Friesland Foods corporate research (since 2008). One Patent is mentioned (Provisional-US. Application N°: 60/999,119. Filing date: 16/10/2007).

N4:

  Other permanent staff (without research duties) 2 3 Other professors (PREM, ECC, etc.) N5: Other EPST or EPIC researchers (DREM, Postdoctoral students, visitors

Unit workforce Number as at 30/06/2013 Number as at 01/01/2015

	Doctoral students	10
	Theses defended	13
	Postdoctoral students having spent at least 12 months in the unit*	20
	Number of Research Supervisor Qualifications (HDR) taken	3
	Qualified research supervisors (with an HDR) or similar positions	13	17
	2
		Number as at	Number as at
		30/06/2013	01/01/2015
	N1: Permanent professors and similar positions	5 (2.2)	14 (6.4)
	N2: Permanent researchers from Institutions and similar positions	16 (11.2)	15 (10.4)
	N3: Other permanent staff (without research duties)	24 (2.5)	32 (26.2)
	N4: Other professors (Emeritus Professor, on-contract Professor, etc.)
	N5: Other researchers from Institutions (Emeritus Research Director, Postdoctoral students, visitors, etc.)	24 (22)	20 (18.5)
	N6: Other contractual staff (without research duties)	7 (7)	6 (6)
	TOTAL N1 to N6	76 (44.9)	87 (67.5)

 Overall assessment of the interdisciplinary unit

Team workforce Number as at 30/06/2013 Number as at 01/01/2015

	Doctoral students	3
	Theses defended	4
	Postdoctoral students having spent at least 12 months in the unit*	6
	Number of Research Supervisor Qualifications (HDR) taken	1
	Qualified research supervisors (with an HDR) or similar positions	3

 Detailed assessments

Assessment of scientific quality and outputs

Supervising bodies' general comments