M Pierre

M Eric Thervet

Thierry Defrance

M Joost

Van Meerwijk

M Thierry

M Yvon

M Nicolas Glaichenhaus

Ms Catherine Labbé-Jullié

The visit started on February 15, 2011 at 2:30 am and ended the same day at 6:00 pm. The scientific program included an overall presentation of the Unit by its Director during 30 minutes followed by three scientific presentations of the past activity and projects by three team members (30 minutes each). Meetings with PhD students, engineers technicians and administrative staff, researchers with permanent positions were also organized to discuss issues of group management.

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

The research unit is located at the Faculty of Medecine and Pharmacy, Limoges. From 2004 to 2007, this research unit was an « équipe d'acceuil ». It became an INSERM research unit in 2007. This research unit studied the pharmacology of immunosuppressive treatment used after organ transplantation, their conseqences with regards to efficacy and safety and other aspects of transplantation including anti-viral drugs. The scientific rationale relies on (1) the large variability in the outcomes of transplant patients and grafts in response to immunosuppressive drugs, (2) the absence of significant long-term survival improvement, (3) the poor selection criteria among the multiple immunosuppressive regimens, (4) the renal and cardiovacular toxicity of some of immunosuppressive drugs, and (5) the need for early biomarkers of efficacy and/or toxicity.

 Management team 2  Overall appreciation on the research unit

 Summary

During the past period, the group has developed original approaches in 2 fields (pharmacokinetic and pharmacogenomic). A latter topic (pharmacodynamic) has started more recently and most of the results are still preliminary. A main feature is a strict focus on their topics. Overall, the research unit has demonstrated an excellent ability to perform the analysis of data from several multicenter trials. In pharmacokinetic, they have developed valuable tools that have been transfered to the clinic for daily practice. Thank to these results and a good focus of their research in one field, they have an excellent national and international visibility within their field of research.

For the future, the projects presented show the ability to promote new aspects with an original pharmacodynamic approach. Because of the large number of projects that have been presented, they should focused on some specific aspects.

 Strengths and opportunities

The work of the unit greatly improved the knowledge of the therapeutic drug monitoring of immunosuppressive treament and has had a successfull translation to clinic.

This was possible because of the presence of a dynamic director who has succeded in building a well focused research unit during the past 5 years. The Unit presents a very good national and international visibility and is well known in the field. This was associated with a very good management and a very good spirit. The development of pharmacokinetic model has been possible by the presence in the unit of a talented mathematician who has played a critical role in building Bayesian models. The unit has also developed strong links with local clinicians both from Limoges but also nationaly through networks of clinicians involved in transplantation and with other nationalities. They have also developed strong links with pharmaceutical companies. They benefit from a strong support from the Hospital and the University materialized by 2 Praticien Hopitalier (PH) in the unit provided and by the move in a new building in the forthcoming years, therefore allowing the members of the unit to develop new collaborations.

This has allowed an excellent scientific output for the field and for the future the development of an original pharmacodynamic approach for the future.

 Weaknesses and threats

The research unit does not seem to have a strategy to recruit full time researchers, i.e. researchers without teaching or clinical duties.

Beside the originality of the pharmacodynamic project, it is not clear whether the research unit will have the ressources to achieve it in all its aspects because of the relatively low number of unit members involved. For instance, the heart transplant mouse model may be difficult to implement locally.

Despite the originality of the method, the relatively low number of patients planed to be enrolled in the disease progression modeling project (pharmaco-metrics axis) may impair the results obtained.

Threats also include the dependency on external collaborations with various renal transplant centers in France and in Europe because of the relatively small number of renal transplant performed locally.

 Recommendations

Despite its dynamism, the sub-team working on pharmacodynamics should focus on fewer projects.

Team members working in the pharmacogenetic axis should go further to elucidate molecular mechanisms.

Team members working in the pharmacometrics axis (disease progression modeling project) should develop a strategy to enroll more patients through the collaboration with existing cohorts of patients in other centers.

Team members working in the pharmadynamics and pharmacokinetic axis should include biological agents in their study.

 Production results

* 5 declared on form 2.9 + 2 PhD theses defended at end 2010 3  Specific comments

 Appreciation on the results

-The relevance and the originality of the research, the quality and the impact of the result

The research unit pursued three main objectives.

Pharmacometrics of immunosuppressive drugs:

Although therapeutic drug monitoring (TDM) of immunosuppressor drugs is mandatory or consensually recommended, current limitations include (1) the fact that classical exposure indices are not relevant in all clinical situations, (2) complex pharmacokinetic profiles with delayed absorption, flat of multiple concentration peaks, and (3) the highly variable and hardly predictable overall exposure. During the past 5 years, the members of the unit have developed valuable tools that have been transfered to the clinic to improve therapeutic drug monitoring including Bayesian estimators of AUC. They have proposed a specific internet site (ABIS) which allows the clinicians to individualize immunosuppressive treatments including mycophenolate mofetil, tacrolimus and cyclosporine, which are the 3 drugs the more often used after organ transplantation. More than 9000 requests have been recorded from many transplant international centers last year.

Pharmacogenetics of immunosuppressive drugs:

Members of this team have studied the genetic variability of immunosuppressive drugs with regard to the pharmacokinetics/pharmacodynamics measurements and the efficacy/toxicity ratio. They have also developed during a post-doc in the US an interesting approach to clinical side effects of mycophenolate mofetil. The work involves both in vitro and clinical studies. During the past 5 years, the members of the unit did not obtain clear evidence that genetic forecasting of dose might particurlarly useful for immunosuppressor drugs (apart from CYP3A5 genotype and tacrolimus/sirolimus dosage). However, these PG-PK studies did allow the identification of critical proteins involved in immunosuppressive concentrations. This has provided candidate genes and mechanistic hypothesis involved in adverse effects of immunosuppressive drugs.

Pharmacodynamics of immunosuppressive drugs:

Pharmacodynamics of immunosuppressor drugs : The work during the past 5 years has focused on (1) the early screening of urinary biomarkers, (2) pharmacodynamics studies to elucidate the links between immunosuppressor drugs nocuity and graft dysfunction, and (3) graft preconditioning (FRETEP). For the past 5 years, the unit members have published a total of 94 articles in peer-review journals, among which 56 were signed by a member of the unit as first or last author. Out of these 56 papers, 12 are ranked among the top 10%. This is an excellent achievment in this field.

The unit members have a good amount (55) of international and national invitation for academic conferences.

The unit has produced 5 PhD thesis (+ 2) by the end of 2010.

-The quality and the stability of partnerships

The unit has developed stable partnerships with regional (Toulouse and Bordeaux) and national (Groupe René Spiesser) networks allowing many scientific publications. They have also developed links with internation group.

 Appreciation on the impact, the attractiveness of the research unit and of the quality of its links with international, national and local partners -The number and the reputation of the awards obtained by staff members, including invitations to international conferences and symposia

The head of the unit is president-elect of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology IATDMCT, member of the editorial board of three international pharmacology journals, coordinator of drug committee of the French-speaking Society of Transplantation. Another lab member is vice-chair of the pharmacometrics committee of the IATDMCT and coordinator of the TDM committee of SFPT. Also several lab members were awarded national distinctions.

The unit members have a good amount (55) of international and national invitation for academic conferences.

The unit has organized the biannual meeting of IATDMCT in 2007.

-The ability to recruit high levels scientists, post-docs and students, and more particularly from abroad

Two foreign postdoctoral fellows and several foreign PhD students have joined the research unit during the past 5 years. A total of 14 PhD students have been trained in the lab during the past 5 years.

The implication of team members in research have allowed the attribution of a 6-month full research period for the co-director if the Unit and a hospital interface contract for 2010-2012 for another member of the unit.

-The ability to raise funds, to successfully apply for competitive funding, and to participate to scientific and industrial clusters

The unit has obtained several grants including 1 ANR as coordinator, 1 ANR as a participant, 1 grant from the Ligue Nationale Contre le Cancer (LNCC), 3 from the Limoge CHU and 2 with the company Roche Pharma.

The unit has also obtained 4 PHRC, and contracts with AFSSAPS, ABM, Ligue, VLM, CORC, Canceropole GSO, Roche, Novartis, Astellas, Wyeth, and BMS.

-The participation to international or national scientific networks, existence of stable collaborations with foreign partners

The members of the unit have developed international, national and local collaborations with several teams including with labs in Belgium, Germany, The Netherlands and Spain. Many of these collaborations have resulted in copublications.

The unit has been involved in many clinical trials promoted by a national network of 13 renal transplant centers which have resulted in co-publications.

-The concrete results of the research activity and socio-economic partnerships

The Bayesian pharmacokinetic tools that have been developed in the research unit have been made public for clinician through a Hospital based internet site (ABIS). This has allowed many clinicians nationally and internationally to improve the care of organ transplant recipients.

Furthermore, this web site has been able to generate economic benefit for the Hospital (cotation of each patient pharmacokinetic analysis).

 Appreciation on the management and life of the research unit

-The relevance of the research unit organization, quality of the management and of the communication policy

Seminars are organized weekly. PhD students and other lab members have also the opportunity to follow English courses every week and to attend at least one international meeting during their PhD. Most PhD students who have been trained in the lab have obtained permanent positions in the academic or the private sector. Most students who are currently in the lab are committed to pursue a career in research, either in the the academic or the private sector.

-The contribution of the research unit staff members to teaching and to the structuration of the research at the local level

The research unit belongs to the SFR superstructure and has submited a proposal to the ANR LabEx call (together with 3 other labs in Limoges).

All researchers of the unit have teaching duties and 5 out of 9 coordinate teaching programs. Unit members also actively participate to trainings organized by INSERM, other French universities, private companies, international associations.

 Appreciation on the scientific strategy and the project -The existence, relevance and feasability of a long term (4 years) scientific project

For the next 5 years, projects will continue to focus on (1) pharmacometrics, (2) pharmacogenetics and (3) pharmacodynamics.

Pharmacometrics of immunosuppressive drugs:

The team will attempt (1) to generate models for population Pharmacokinetics (PK)/Pharmacodynamics (PD) and disease progression, (3) to investigate clinical outcome scores and benefit-risk ratios, (4) to study Pharmaco-Epidemiology and Pharmaco-Economics, and (5) to study resistance to, and Pharmaco-Economics of anti-Cyto Megalo Virus (CMV) drugs in transplantation.

The generation of models for PK/PD is feasible because of the tools are already developped and the presence of a talented mathematician. The disease progression model with the definition of clinical outcome score my be render more difficult because of the large numbers of variables that have to be included in the model and because the cohort of patients is relatively small (n=666).

Pharmacogenetics of immunosuppressive drugs:

The team will (1) perform in vitro studies to appreciate the metabolism, the transport and the cellular pharmacogenetics of immuno-suppressor drugs, (2) study clinical Pharmacogenomics (PG) and (3) pharmacogeneticpharmacodynamic relationships. More specifically, the Polycis (POLYmorphisms of protein targets of Immuno-Suppressants and Implication in the drug response in transplantation) will aim at identifying the most relevant polymorphisms to study, to investigate their functional consequences and to investigate their influence on immunosuppressant efficacy or toxicity in transplantation. Another project entitled PTLD (Post-Transplant Lymphoproliferative Disease) will aim at identifying the genetic polymorphisms associated with PTLD in renal transplant recipients. A larger approach to mechanistic explanation of the role of the detected polymorphisms could be of interest.

Pharmacodynamics of immunosuppressive drugs:

The team will study (1) immuno-suppressor nocuity, and biomarkers of renal graft lesions. Regarding the immunosuppressive drugs nocuity, they will study the nephrotoxicity and intracellular pathways including in vitro and in vivo approaches. Regarding the biomarkers of renal dysfunction, they will use targeted screening protein and peptide biomarkers in the urine and a renal tissue mass spectrometry approach (collaborations with another team).

-The existence and relevance of a policy for the allocation of ressources

The unit has increased the size of the unit staff with 7 HDR in comparison with the unit staff at its creation.

-The originality and existence of cutting edge projects Among the projects, the disease progression modeling project and the pharmacodynamics bear a good potential and originality. The disease progression modeling project proposes an original approach with the building of nonparametric algorithms and a non-linear mixes effects models to predict the renal function deterioration. The pharmacodynamic project proposes an original approach to gain better understanding and early diagnosis of IS nocuity.

This is a sound project, logically designed and well presented. The subjects are focused even though the experimental approach is broad. The project could become of great medical relevance for the better use of the immunosuppressive drugs and understanding of their nocuities.



  Date and execution of the visit

A1:

  Number of permanent researchers with teaching duties (recorded in N1) who are active in research 7 A2: Number of permanent researchers without teaching duties (recorded in N2) who are active in research 0 A3: Ratio of members who are active in research among staff members [(A1 + A2)/(N1 + N2)] 88% A4: Number of HDR granted during the past 4 years (Form 2.10 of the application file) 1 A5: Number of PhD granted during the past 4 years (Form 2.9 of the application file) 7* -The quality and the number of the publications, scientific communications, thesis and other outputs

Sciences du Vivant et Environnement

				Statistiques de notes globales par domaines scientifiques
						(État au 06/05/2011)
		Note globale	SVE1_LS1_LS2	SVE1_LS3	SVE1_LS4	SVE1_LS5	SVE1_LS6	SVE1_LS7	SVE2 _LS3 *	SVE2_LS8 *	SVE2_LS9 *	Total
		A+	7	3	1	4	7	6		2		30
		A	27	1	13	20	21	26	2	12	23	145
		B	6	1	6	2	8	23	3	3	6	58
		C	1					4				5
		Non noté	1									1
		Total	42	5	20	26	36	59	5	17	29	239
		A+	16,7%	60,0%	5,0%	15,4%	19,4%	10,2%		11,8%		12,6%
		A	64,3%	20,0%	65,0%	76,9%	58,3%	44,1%	40,0%	70,6%	79,3%	60,7%
		B	14,3%	20,0%	30,0%	7,7%	22,2%	39,0%	60,0%	17,6%	20,7%	24,3%
		C	2,4%					6,8%				2,1%
		Non noté	2,4%									0,4%
		Total	100,0%	100,0%	100,0%	100,0%	100,0%	100,0%	100,0%	100,0%	100,0%	100,0%
	*
			Intitulé UR / équipe		C1	C2	C3	C4	Note globale
	PHARMACOLOGIE DES IMMUNOSUPPRESSEURS EN TRANSPLANTATION	A	A	A	B	A
	C1	Qualité scientifique et production
	C2	Rayonnement et attractivité, intégration dans l'environnement
	C3	Gouvernance et vie du laboratoire
	C4	Stratégie et projet scientifique

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


M Frédéric Becq

Mrs Cécile Gauthier-Rouviere

Mr Frédéric Dardel

Mrs Véronique Delmas

Mrs Catherine Dargemont

The visit was held in the building of the "Institut de Physiologie et de Biologie Cellulaires" (IPBC). The visit started on March 9th at 10am and was completed on March 10th at 6pm. The whole committee listened to the presentations by the Director and the 3 team leaders. Separate sub-groups of the visiting committee also discussed with the different personnel categories (researchers, technical personnel, PhD students and Post doc). A meeting with the director and then with University and CHU representatives were held. No representative from INSB CNRS was present. The committee had closed-door meetings for organization of the visit and discussions. This visit had been carefully prepared by the Director and all IPBC members.

 History and geographical localization of the research unit, and brief presentation of its field and scientific activities IPBC is a CNRS unit (UMR6187) of the Institute of the Biological Sciences (INSB). IPBC is in a single building with a working surface of 6699 m2 located on the campus of the faculty of Sciences of the University of Poitiers. IPBC is the largest laboratory in the field of biological sciences and health in the Region Poitou-Charentes-Limousin and it is highly connected with the University of Poitiers and the CHU La Milétrie. IPBC assembles about 110 people.

IPBC has a good expertise in the field of physiology and pharmacology of ionic channels, intercellular communication mediated by GAP junctions or by soluble factors of the vitamin K-dependent protein familly, calcium and Rho GTPases mediated signalling patways. IPBC is also actively engaged in the study of the cellular and molecular basis of pathologies such as cystis fibrosis, cardiac arrhythmias, muscular myopathies, leukemia, neuroblastomas and glioblastomas. The teams show a strong translational activity, which in the reviewed period led to a total of 10 patents.

 Management team

The current management team includes the Director and an administrative assistant who ensures effective organization and financial administration of the IPBC. The management team for 2012-2016 will include a Deputy Director. Each month a directive committee consisting in the director, deputy director, the three team leaders and project leaders discuss the scientific organization and strategy for the laboratory. A laboratory council also meets once a month. A health and safety committee has been held as well as a platform committee to coordinate the financial management and the functional organization of the six platforms created.

The committee recognizes the major contribution and efforts made by the current Director to reorganize the unit and better structure IPBC in view of the future contract (2012)(2013)(2014)(2015)(2016).

 Staff members (on the basis of the application file submitted to the AERES) 2  Overall appreciation on the research unit  Summary

The IPBC will be reorganized around three teams which creates a new dynamics for this institute and have strong potential for collaborative synergies. IPBC covers broad scientific topics that extend beyond basic research by developing several initiatives of translational research and research valorisation. Beyond this apparent heterogeneity lies, however, a community of concepts and technical approaches, including molecular mechanisms of human pathologies (cystic fibrosis, myopathies, cardiopathies and cancers) with a special interest for the role of ionic chanels and intercellular communications. The IPBC succeeds in attracting scientists from the local environment : 1) a relatively large number of clinicians joined the unit to support the approaches dedicated to cancer research 2) a group from Tours will reinforce the field of ionic chanels 3) the merge of scientists of the past IPBC with newcomers leads to propose interesting projects on lipid droplets.

Overall, the research carried out at the IPBC can be qualified as medium to good. The committee noticed a substantial heterogeneity in the performance and the quality of the research of the various groups. The committee was unanimous that given the projects and the expertise of most groups, the scientific production should increase further in quality during the next five years period in order to remain internationally competitive.

IPBC is the largest public research laboratory in the field of biological sciences and health in the region Poitou-Charentes and it ensures the responsabilities linked to this by playing an important role in promoting valorisation and science teaching. 27 IPBC members have teaching responsibilities at the different academic levels of education (Bachelor and Master).

The Institute has organized and it is still operating several common services and platforms that seem to function satisfactorily, at least for those already running.

Discussion with tenured staff, technical and administrative staff and doctoral students revealed a large degree of cohesion and interaction within these groups and a general contentment in the way the Institute functions.

 Strengths and opportunities

IPBC is the most important research laboratory in the field of biological sciences and health in Poiters as well as in the Region Poitou-Charentes-Limousin and it is highly connected with the University of Poitiers and the CHU La Milétrie. An important strength of the research unit as a whole is its relationships with local authorities which guarantee a significant support from both University of Poitiers and the CHU.

Importantly, practical issues concerning the connections with the CHU and with the unit from Tours were raised during the visit. The answers were convincing : The medical analyses laboratories are located within the same building, the quality of connection and high commitment of people from Tours was confirmed by the meeting with university (including from Tours) and CHU representatives. Consequently, the objections initially raised by the committee with regard to these practical issues have been largely ironed out.

It is important to notice that IPBC members have an enormous involvement in teaching and therefore they are very well supported by the Universities. IPBC efficiently attracts PhD students, who recognize the IPBC as an excellent place for training.

The Director is dynamic and personally has a true international scientific recognition in his field of research (study of CFTR protein). He has made major efforts to restructure the research unit. When he started his leadership the unit was splitted in eight groups, which was reduced to five (including an INSERM « avenir »). The present project has reduced the number of groups to three, which guarantees groups with a stronger internal structure. Moreover, the director has been able to set up or reinforce facilities (Imaging and screening) to assist the research in the institute. Other facilities (proteomics, genomics, bioinformatics, animal surgery) are currently being set up. These facilities represent major tools for most of the current teams inside IPBC and offer services to the external communauty.

The IPBC has good local opportunities for interdisciplinary and translational research, for collaboration with the local hospital area to obtain relevant biological samples and informations. The IPBC has an important technology transfer activity leading to patents, one license and one clinical assay.

A member of the IPBC has set-up a regional council for cancer research, which allowed the connection with clinicians and favored the access to human biological samples.

The committee was convinced that people were happy to work in the unit and appreciated the supportive atmosphere and the strong emphasis on training. Students have the opportunity to present their work at national or international meetings.

Members of the unit play active roles in local and national committees and editorial boards. Some members of the IPBC have developed international collaborations (USA, Canada, Brazil, Liban). A Marie Curie fellowship has been obtained during the previous period.

There is a strong tradition of internal collaborations which reinforce and synergize the local expertise. This is a clear added value.

 Weaknesses and threats

There was a general consensus among the experts to notice a certain degree of self-effacement: i.e., few foreign post-doctoral trainees, limited attendance of the PIs and their younger colleagues to international meetings, a limited number of papers published in journals of broad audience and high impact factor. Some teams are doing better than others in this regard, but globally there is ample space for improvement of these items, and for induction of a virtuous circle that would lead to attract young investigators from all horizons.

The number of full time researchers is low since most of the IPBC members have teaching duties. There were few new recruitments over the past years. In this context, the committee noted the absence of open calls for the recruitment of new teams. This hinders promoting the national and international visibility and recognition of the IPBC.

A difficulty of assessing the general scientific level is the presence of some heterogeneity inside large teams. This was presented in some cases as the willingness to examine the proposed subjects from basic science to bedside (or the opposite). Nevertheless, the committee noticed that it led to include ongoing projects poorly related to the main themes of the team leader. This particular arrangement presents the risk of a dilution of forces and resources, and to reduce competitiveness of teams for funding and publications.

While the number of publications is high, the international recognition of some authors is probably not as good as it should be. This constitutes a threat because application of the « standards of excellence » as presently thought would jeopardize the unit, while its importance both in term of local policy and in terms of originality (relationships with chemists, applications, cutting edge projects proposed) deserves the highest consideration.

The current project also shows a significant emphasis on connecting their current biological projects to pharmacological and medicinal chemistry applications, for instance via drug-screening programs. This in itself is very positive, but care should be taken to secure collaborations and appropriate funding to make this whole endeavour feasible. Hit-to-lead improvement is a difficult track, which requires a lot of workforce and solid partnerships with expert medicinal chemists groups.

 Recommendations to the head of the research unit

The committee recommends that maximum efforts be made at all levels, particularly the Direction and PIs, to improve the visibility of IPBC outside. This may involve several tools:

The IPBC should try to attract new researchers, to promote new teams arrival through AVENIR/ATIP program or other attractive packages.

They have to promote a dynamic policy for recruiting workers on contracts (post-docs).

They should pursue the restructuration effort to focalize on the most promising projects in order to get better ressources.

The committee strongly advises scientists to remain focused on their most promising research projects and also add more mechanistic studies which should help in increasing quality of the journals that they publish in. The relevance and the originality of the research are generally good, but not outstanding compared to the international level. While some groups are at the international standard, others experience some difficulties to reach a sufficient level of visibility and originality. The efficient collaborations with chemists as well as between biologists and clinicians were highly appreciated by the committee, and the developments of these collaborations are strongly encouraged.

Whereas the quantity of publications is high, their quality in general are not very good. The committee encourages team leaders to be more ambitious in their publication strategy. Some PIs do not have enough international visibility since they are rarely invited to international meetings. The fact that the lab produces PhD theses was well appreciated. IPBC efficiently contributes to research training in Poitiers with an average of 4 to 5 PhD and many master degree students coming each year in the laboratoy.

On the research valorization side, several teams have filed patents. One has lead to a license (CNRS/Actelion Pharmaceuticals) and to phase 2 clinical trials, which is very positive.

IPBC benefits from an important and regular support on behalf of the University of Poitiers and the Region Poitou-Charentes-Limousin in particular in terms of funds and technicians' positions.

 Appreciation on the impact, the attractiveness of the research unit and of the quality of its links with international, national and local partners IPBC has a good national visibility as demonstrated by their ability to regularly raise funds from local and national charities (AFM, VLM, Mucovie, ABCF, Ligue contre le Cancer) and also from the national research agency ANR (2010)(2011)(2012). Two teams are doing better in this regard. Funds were also obtained from Actelion Pharmaceuticals and Laboratoire Servier. The committee noticed a good integration into regional and national networks. Thus the visibility of IPBC at those levels is very good. A member of the IPBC has set-up a regional council for cancer research (GPRC) which allows the connection with clinicians and favours access to human biological samples. One drug (Miglustat) developped at IPBC leads to a licence (CNRS/Actelion Pharmaceuticals) and to phase 2 clinical trials.

From an international point of view, IPBC has a rather medium visibility. Some teams have ongoing international or european collaborations but no european or international grants have been obtained except a Marie Curie fellowship for a two-years post-doc position. Members of the institute participate to the EUROCARE network. Some members of the unit, especially the director, are regularly invited to national and international conferences. Whereas IPBC attracts many PhD students from Poitiers and abroad (20-25% of the Ph D student in biology granted by the government in this region), there is a clear deficiency in the recruitment of post-docs and young scientists. This might be attributed to the relative limited international visibility of IPBC. It should be mentioned that this is also likely to reflect a regional problem independent from the intrinsic qualities of the unit as it appears reasonable to assume that scientists from abroad have a modest drive towards such a relatively small city in France.

 Appreciation on the strategy, management and life of the research unit

The general organization of the research unit relies on fully independent research teams (with collaborations between team members), shared core facilities and administrative service. The quality and organization of the governance of IPBC was considered to be good. In its overall description (both of past or project) the written report and presentations showed a realistic and reactive point of view. This might well be ascribed to the dynamism of the director, which constitutes a strength for the success of the future unit.

The action of the Director has been efficient in connecting the activity of the IPBC to the local tissue. The connection with the University of Poitiers is excellent. The positives outcomes of this strong interaction are the financial and technical supports from the university and the attractiveness of IPBC for PhD students, but its drawback is the heavy teaching load for IPBC members. Solutions are envisaged to alleviate the teaching load when requested.

The connection with the CHU and the School of Medecine is also excellent and again financial and technical supports from the CHU have been noticed.

IPBC is a major actor in the SFR project which aims to structure the « Biologie Santé » field in Poitiers.

The Policy of publication had the advantage to allow Ph D students and young tenured scientists to appear in leading positions (first, last). This authorizes the rising of future team leaders."

 Appreciation on the project

The proposed project, while in continuity with the activity during the previous period, shows a profound reorganization of the unit in three teams. The venue of two new groups, one from Tours and one from Poitiers appears as a good strategic choice. From the past records it is expected that the experience of team members will ensure expertise on specific domains amenable to grant applications. The link with chemists is to be mentionned as a very positive point for this unit, but deserves to be strengthened by appropriate co-funding.

A possible threat is that the unit could drift more and more toward application-driven research and progressively looses ground on basic science approaches. This balance will depend on how the director and group leaders will deal with this issue and find means to support « basic science », which is sometimes difficult, but creates the grounds for future progresses. In this respect the arrival of the group working on lipid droplet appears as a positive signal.

While the number of publications is high the international recognition of some authors is probably not as high as it should be. This constitutes a threat because application of the « standards of excellence » as presently thought would jeopardize the unit while its importance both in term of local policy and in terms of originality (relationships with chemists, applications...) deserves consideration and support.  Relevance and originality of the research, quality and impact of the results

Axe1: The team has a longstanding experience in the study of chloride channels, in particular the CFTR , a Clchannel, the mutation of which causes cystic fibrosis (also called mucoviscidosis). In the last few years, the team has contributed to the identification of several other key residues in CFTR, important for its pharmacology, has discovered several activatory or inhibitory molecules, and most importantly, has unveiled the mechanisms of retention of a misfolded mutant of the CFTR protein found in the majority of the patients. This latter discovery was the rationale for the identification of compounds that regulate the retention and compensate for the mutation. One of these drugs (Miglustat) led to a technology transfert (licence CNRS/Actelion Pharmaceuticals) and to phase 2 clinical trials.

Axe2: This medical genetic team already part of the IPBC will join the Axe 1 for the new project. In the last years, the team has, in close relationship with the molecular genetic laboratory of the CHU in Poitiers, developed a program in direct relation with the Cystic Fibrosis group. In particular, the group deciphered some new facets of CFTR trafficking.

Axe3: This group has a strong reputation in the study of calcium deregulation in dystrophin-deficient myocytes in Duchenne myopathy. In particular, the group showed that in the absence of dystrophin abnormal Calcium homeostasis in the muscle cells are implicated in the pathology, probably through Ca++ activated proteases.

Axe4: The group is primarely interested in the pharmacological study of ion channels considered as potential proarhythmic targets in remodeling of cardiac tissue. During the past years, the group identified the pacemaker channel HCN as the target of ivrabadine, a heart rate-lowering drug. The group also showed selective blocking of IKs in the prolongation of the QT interval in patients treated with the anti tumor drug doxorubicin.

Axe5 : The team located at the University of Tours is interested in the genesis of ectopic activity of pulmonary veins (PVs) cardiomyocytes responsible for atrial fibrillation (AF). The group has shown that at variance with atrial cardiomyocytes, PVs cardiomyocytes can generate a catecholamine-induced automatic activity that require the stimulation of both and adrenergic receptors. In the absence of efficient treatment for AF, these observations are important for future investigation.

The overall scientific production of the team is good with a high number of publications but too many are published in specialized journals. . Given the « axe » substructure of this team, a breakdown of the publications over the 2006-2010 period is given below:

 Axe1



Axe5 has published 25 papers, 12 of which with first or last authorship, among which 2 Br J Pharmacol, 1 J Med Chem, 1 Am J Physiol Cell Physiol, 1 Am J Physiol Heart Cell Physiol.

The team has several publications relative to collaborative works with foreign (through EUROCARE, USA) and local (IPBC) partners. The team is also actively involved in translational research, especially in clinical trials of compounds Licensing Miglustat and two phase II clinical trials (2008 & 2010).

 Appreciation on the impact, the attractiveness of the team and of the quality of its links with international, national and local partners

The team has been successful to obtain fundings from a variety of institutions (Mucovie, VLM, ABCF, LNCC, Region Poitou-Charentes, European FP7, AFM, ANR) in the past and also in 2010. Pharmaceutical Industry Actelion Pharmaceuticals, Laboratoire Servier PhysioStim Company, Robert-Giffard). The funding is in good adequation with the scientific projects.

Members of the team gave lectures in several national and international meetings.

Most of the staff is engaged in teaching at the University of Poitiers 4 PhD students were formed during the last contract  Appreciation on the project Axe1: The current project is in direct line with the previous studies on CFTR: i) use of pharmacological and siRNA strategies to study the biogenesis and the degradation of the mutated F508del-CFTR protein, ii) research of molecular partners of CFTR that could account for the impaired Ca++ homeostasis in CF cells and iii) role of CFTR mutations in the perturbation of lipid homeosatsis and ER-stress. The questions are pertinent and interesting and the expertise of the scientists involved in adequation with these aims.

Axe 2: The current project is aimed at further analysing at the molecular and cellular levels new mutations in the CFTR gene and their implication in maturation, trafficking and activity. However, an important activity of the group is the genetic of rare diseases. This part of the program seems too far from the scientific interests of team 1.

Axe 3: The current project attempts to study calcium homeostasis at micro-domain level and to identify and characterize Ca++ channels using Scanning Ion Conductance Microscopy (SICM). Complementary approaches (immunolocalization of membrane and cytoskeletal components, expression of various isoforms of TRP channels, siRNA etc…) are also planned. The main technique (SICM) is already available on site.

Axe 4: The current project is aimed at a better understanding of the role of ionic channels in the pathophysiology of cardio-myocytes and cardiac fibroblasts. Two aspects will be analysed : i) identification of molecular mechanisms involved in activity, trafficking and expression of mutated SCN5A (Brugada syndrome) and HCN channels in sick sinus syndrome. ii) Na+/K+ channels in cardiac fibroblasts : relevance for pathological remodeling upon pathological stresses.

Axe 5: The current project will be focussed on their discovery of the catecholaminergic automatic activity (CAA) associated with PV muscle cells. The project includes i) identification of cellular mechanisms underlying CAA (receptors, ion channels, signalling pathways) in pathophysiological conditions ii) resarch for differences in contractile and electrophysiological properties of atrial and PV cardiomyocytes iii) development and transmission of automatic activity from the PVs to left atrium.

 Conclusion : -Summary

The activity of this team is focussed on ionic channels studies in physiopathological processes. The proposed future work is a logical extension of their projects.

-Strengths and opportunities

The team 1 has a well recognized expertise in ionic channels, originally from the electrophysiological aspects but now much broader, in particular on cellular and molecular aspects. Translational research from patient diagnosis to molecular studies is well developped particularly on CFTR. The team being involved both in fundamental as well as in clinical research, the results of their research will directly benefit to patients. Clinical trials of compounds are under way.

Successful approaches that have been developed for the CFTR studies will be applied to other projects, such as the cardiologic axis. The cooperation between scientific research and clinicians is a strong point. Original approaches have been developped (such as SICM). There are important exchanges with other IPBC teams. The funding is in good adequation with the scientific projects.

-Weaknesses and threats It appears that they are too many projects in this team.

The quality of publications is of average level and should be greatly improved To attract postdocs and young scientists from abroad does not appear as a priority of this team.

The committee was not convinced by the coherence of the non-CFTR topics of axis 2 with the rest of the team projects.

-Recommendations

The synergy between the different axis was not always apparent and should be improved.

Mechanistic analysis using cell biology approaches, such as intracellular trafficking analysis, should be further developed. Along this line, the projects on CFTR of axis 2 should be integrated with axis 1.

Fusion of axis 5 with IPBC makes sense scientifically but geographic implantation of axis 5 in Poitiers should be progressively envisaged (recruitment of a postdoc on this axis in Poitiers).

Project 3 in previous team 1: Regulation of calcium channels by scaffolding proteins. Implication in muscle physiology and myopathy

The group leader was previously working on complexes formed of calcium channels and dystrophin/syntrophin molecules in the membrane of skeletal muscle cells. He was studying their function in normal and dystrophic muscles. He has also a collaboration on the role of mutants of -sarcomeric actin on congenital myopathies with a group in Belgium and collaborations inside the laboratory. He has a well internationally recognized expertise in the field of calcium signalling.

During the period 2006-june 2010, he published 17 articles (8 as co-author with other groups in the laboratory), of which he is last author on 3 research articles in medium to good impact factor journals (Matrix Biology, JBC and Faseb J).

For the new contract the group leader will move to another research field, the analysis of signaling pathways (in particular calcium signaling pathways) in leukeamia with two others members of IPBC coming from the former team 2 and team 4 of the period 2006-20010.

In previous team 4: GTPases signaling and cytoskeleton dynamics in Bcr-Abl-induced leukeamia

This group found that Bcr-Abl activates both Rac1 and RhoA. He studied the effectors involved in Bcr-Ablinduced migration and identified the pathways activated downstream Rac1 and RhoA.

During the period 2006-june 2010, he published 12 articles (8 as co-author with other groups in the laboratory), of which he is last author on 2 research articles (Oncogene and Leuk. Res.)

In previous team 3: Vitamin K-dependent proteins regulate angiogenesis and tumor growth, cell proliferation and phagocytosis

The work of this group was centred on the function of Vitamin K-dependent proteins (VKDPs) which regulates blood coagulation. The research activity is focused on two VKDPs, protein S and Gas6 which interact with tyrosine kinase receptors. These proteins play a major role in the angiogenis process, in neural stem cell biology and in regulating apoptotic membranes phagocytosis.

During the period 2006-june 2010, the team published 11 articles (4 articles from the group, 4 articles in collaboration, 3 reviews) and participates to 1 patent.

Moreover, an European Marie Curie project (2009-2010) implicating a collaboration with a Russian colleague has also been developed. This project dealing with the role of VKDP in non-professional phagocytosis constitutes a link between the different groups of that team. This group has a good publication records with articles published in good quality journals (Oncogene, Stem Cells, Faseb J, JBC) and participates to 1 patent.

Given the « axe » substructure of this team, a breakdown of the publications over the 2006-2010 period is given below :



Axe1 has published 43 papers, 8 of which with first or last authorship, among which 1 JBC and 1 FASEB J.



Axe2 has published 25 papers, 3 of which with first or last authorship, among which 1 Oncogene, 1 Leuk Res and 1 Blood.



Axe3 has published 11 papers, 7 of which with first or last authorship, among which 1 Stem Cells.

7 PhD students were supervised over the past 5 years and one Marie Curie fellowship for a two years post-doc position has been obtained (2009)(2010).

 Appreciation on the impact, the attractiveness of the team and of the quality of its links with international, national and local partners

The team has been successful to obtain fundings from a variety of institutions (LNCC, Region Poitou-Charentes, European FP7, INSERM etc) in the past and also in 2010. No funding was obtained from international funding agencies. The team obtained a Marie Curie fellowship for a two years post-doc position.

Members of the team contributed to national and international meetings and have also been invited to speak at international meetings.

One group leader has a collaboration with a belgian group (universty of Ghent). A member of the team will organize, in 2011, the VIIe national meeting "Small G proteins" in Poitiers.

The projects in the team are well connected.

Five members of the team are involved in teaching. 1 PR, 1 MCU/PH and 3 MCU. The group leader of the former project 3 axis1 is also actively involved in teaching especially at the master 2 degree.

One member of team is involved in the set up of the proteomic plateform.

 Appreciation on the project

There are three projects proposed. Two focus on the role of two vitamin K dependent proteins (VKDP) called Gas 6 and protein S and partners of TAM receptors in neural stem cell maintenance and on phagocytosis (axe 2) and on angiogenesis (axe 3). These projects are the continuity of the data obtained during the previous quadrennial period. However it was not clear in the oral presentation how the axis 3 will be conducted.

The third project (axe 1) aims at analyzing signaling pathways (Rho GTPases, calcium) involved in migration of hematopoietic cells and leukemogenesis.

These projects are well connected. Given the expertise of the scientists involved and the technical facilities requested the projects appear realistic.

These are challenging but feasible and very interesting studies, which should be strongly supported, as the team is in an ideal position to perform this cutting edge research.

 Conclusion : -Summary

The team 2 "Cellular growth, mobility and cancer » results from the association of scientists coming from 3 original teams of the IPBC and with interest for working scientific scopes such as, VKDP-dependent signalling in neural stem cells, phagocytosis and angiogenesis, regulation of calcium channels by scaffolding proteins cell, GTPases signalling and cytoskeleton dynamics in migration of hematopoietic cells and leukemogenesis.

The new team 2 of IPBC will be composed of 7 staff members, 2 engineer/technicians and 4 PhD and post doc students.

The research was organized in 3 projects (groups) which appear well related to each others.

-Strengths and opportunities

The thematic cohesion is convincing. The committee appreciated the dynamism and competence of the project leaders of axe 1 and 2.

Several interesting projects have reached a state where the group can publish them and two publications are currently submitted.

-Weaknesses and threats

One of the potential weaknesses is the limited size of the team compared to the large number of projects proposed.

There are several senior scientists within this team, the reason of the choice of the proposed team leader does not seem obvious and appropriate to the committee.

No Post-Docs are actually mentionned in this team.

-Recommendations

Reinforcing the human potential (with staff scientist, postdoc and predoc) of this team would improve the feasability of the projects. The granting policy should be more agressive.

The committee is less supportive on the studies on the role of VKDPs on angiogenesis and recommends to focus the research on leukeamia and regulation of neural stem cells. The team needs to focus in the future on fewer projects so that they can have a stronger impact.

4-3

Title of the team:  Appreciation on the results

 Relevance and originality of the research, quality and impact of the results

The research is mainly relevant to the domain of cancer as it addresses the regulation and activity of protein controlling cellular interaction during migration and invasion. When compared to the previous unit (2006)(2007)(2008)(2009)(2010) the present team appears in continuity with the original team 3 (with the same leader). However the project proposes a significant re-shaping : ancient theme 3-3 will become autonomous creating the team 2 of the present project. The merging of « old themes (3-1 and 3-4) in the new axis 1. The VIP-hedgehog theme is conserved (axe 3 in project). Two new projects are proposed : 3-2 on prostate cancer which will be mainly driven by physicians and 3-4 (see below).

Accordingly past records will be evaluated according to people involved in the project proposed.

Axis 1: "Intercellular communications and glioma progression" From 2006, the research activity was centered on studying the role of connexin 43 (Cx43) in cell differentiation and proliferation (functional regulation of Cx43-made channels, role of Cx43 in the differentiation of osteoblasts and in cell proliferation and invasion in glioma). Since 2008 the activity of the team was more focused on the involvement of connexin 43 in tumor development.

Another group (former 3-4) focused on semaphorin 3F asking how it functions as a tumor suppressor in the lung and how it is regulated.

Axis 2: "Mechanism of prostate cancer progression" new group with a large number of newcomers (clinicians) Participants of team 3 axis 2 presented report about candidate genes on cancer cell proliferation, with special emphasis on prostate cancer (PCa). Their attention has been attracted by estrogen related protein such as BCAR1 (breast cancer anti estrogen resistance) and members of the EGF-Receptor family. It has to be mentioned that participants of team 3 axis 2 have produced joint publications on connexin 43 with present and future team 3 axis 1.

Axis 3: « VIP-receptor system, hedgehog pathway in cancer of the nervous system» in the future project. The work of group 3-2 deals with the biological effects of the Vasoactive Intestinal Polypeptide (VIP) receptors system in cancer cells of the nervous system, such as neuroblastoma and glioblastoma. The group demonstrated that VIP decreased the expression of MYCN, an oncogene amplified in neuroblastoma. A collaboration with chemists (University of Poitiers) led to molecules targeting the hedgehog pathway in brain tumors. Axis 4: "Lipid droplets in differentiation & proliferation in cancer", new project associating people from the past unit to newcomers.

The past work of the members of this team was (1) to identify mutations that affect the formation of lipid droplets in yeast and ( 2) to analyze the pathways for differentiation of neurons and photoreceptors in the retina using a chicken embryo model.

The overall scientific production of the team is good with a high number of publication but too many are published in specialized journals. Given the « axe » substructure of this team, a breakdown of the publications over the 2006-2010 period is given below :



Axe1 has published 53 papers, 37 of which with first or last authorship, among which 1 Antioxidants and Redox signaling and 1 Cancer Res.



Axe2 has published 50 papers, 29 of which with first or last authorship, among which 1 Nat Rev Cancer and 1 Lancet Oncol.



Axe3 has published 16 papers, 14 of which with first or last authorship, among which 1 Drug Discovery today, 1 Am J Hum Genet and 1 PNAS.



Axe4 has published 17 papers, 4 of which with first or last authorship, among which 1 Free Rad Biol Med.

The reports indicates that 9 Ph D students were involved, out of them 7 did defend their thesis during the 2006-2010 period.

 Appreciation on the impact, the attractiveness of the team and of the quality of its links with international, national and local partners

Members of the team contributed to national and international meetings and have also been invited to speak at international meetings. From past records it is concluded that 3-1 has a long standing collaboration with the University of British Columbia and University of South Carolina including prolonged stays of scientists. 3-2 participate in wide range national networks studying the factors relevant to prostate cancer. 3-3 collaborates with UCLA Los Angeles. 3-4 has settled a collaboration with the university of Cyprus.

If we consider the amount of resources communicated to the committee, the participants to the team 3 raised 22 200 Euros in 2008, 20 000 Euros in 2009 and 40 000 Euros in 2010. This seems not sufficient in regards to the projects presented. However, this negative statement should be balanced by the fact that not all resources were listed because of the important evolution between past unit (funding finally known) and the new one with incoming people whose past/ongoing funding was not detailed.

It must be emphasized that this team (like the rest of the unit) has developed a dense network of relationships with scientists, medics, or associations on a regional basis (West of France). This includes for example the fact that scientists from this team 3 are at the origin of a local network « GPRC ».

Members of the team are involved in teaching at the university and communication to a larger audience with conferences or events. One member is responsible of the license Sciences du Vivant.

 Appreciation on the project

The project proposes a significant reshaping of the team. The past team 3 has been split with scientists creating the team 2 of the project. The merging of past themes (3-1 and 3-4) in a new 3-1 while the original 3-2 project (VIP-hedgehog) is left autonomous. Two new projects are proposed: 3-2 on prostate cancer will be mainly driven by clinicians and involves nation-wide network (cohorts) for medical research, 3-4 is a cutting edge project which was highly appreciated by the committee.

There are four projects proposed (named axes).

3-1: This project aims at analyzing the role of gap junction (connexin 43), semaphorins and neurotransmitters in glioblastoma cell migration and invasion. They observed that CX43 expression in glioma cells increases the secretion of cytokines, proteases and extracellular matrix compounds. They want to analyze the mechanisms by which this occurs and its contribution to invasion of glioma cells. In collaboration with the CHU in Poitiers they will analyze whether molecules previously identified could be markers of tumor prognosis and progression. Since serotonin mediates GJIC, they plan to screen for serotonin expression in glioblastoma cells lines and analyze whether serotonin impacts on CX43-dependent signaling pathways. Finally, the role of SEMA3F, which interacts wit CX43 in liver cell lines and control its localization and function, will be analyzed in glioma. These projects are well connected and focused around CX43 study in glioma. This axe benefits of the presence of researchers who has a long standing experience in gap junction. Scientists with long standing experience (connexin and semaphorin) will constitute a strength for success of the project.

3-2: In the past, genes expressed in PCa having strong clinical interest have been recognized. They propose a transition towards more mechanistic studies and to analyze the function of these genes in prostate cell lines and using mouse models.

ErbB3, member of the EGF-R family, can have a nuclear localization in PCa. Targets of ErbB3 will be identified and their contribution in PCa progression analyzed.

The function of Cx34 in PCa dissemination and heterotypic communication with endothelia and osteoclasts will be analyze (synergy with axe 1).

The projects are interesting and a translational part is proposed. However the committee had the feeling that this transition towards mechanistic issues will raise practical difficulties that have been largely underestimated.

Moreover, they would depend on facilities which are not settled yet and will require a strong financial support.

3-3: The project is the continuity of the activity during the previous period. They will analyze the function of VIP in glioblastoma. In neuroblastoma cell lines, they plan to analyze the VIP receptor and the signaling pathways involved in VIP-induced MYCN decrease.

In collaboration with a chemist team in Poitiers they have developed a pro-drug derived of cyclopamine, an Hh inhibitor. They will test the efficacy of this molecule in vivo. Moreover, they will analyze the connection between VIP and Hh signaling pathways in neuroblastoma and glioblastoma.

The committee rose concerns about the small size of the group.

3-4 Starting from their original expertise: lipid metabolism/dynamics in yeast and formation of photoreceptors which requires formation of a lipid droplet, the participants aim to address the question of lipid metabolism / dynamics in relation with cancer. They will analyze the genes induced after lipid droplet formation and screen chemical molecule for their ability to interfere with this process. Identified molecules will be analyzed for their antitumoral activities using Pca as a model system. This team brings together people having good expertise on the various aspects of the project.

The committee appreciates this very innovative and interesting project.

 Conclusion :

-Summary

During the 2006-2010 period the team 3 "Physiopathology of cellular differentiation and communication", merged into a single team scientists coming from three teams of the previous IPBC working in cell differentiation and cancer. In the present project the original team 3 splits into a new team 2 (see above) and a new team 3 which in addition will host two new groups: One is headed by clinicians who join the IPBC to address more mechanistic issues starting from evidences coming from human genetics and the other presents a cutting edge project on lipids born from the merging between scientist from IPBC and newcomers bringing a « yeast approach ».

The general research theme of team 3 will be more cancer oriented in the future. The team 3 was composed of 17 staff members, many of them with teaching duties, 1 Post-Doc, 4 PhD students and 2 engineers. The size of team 3 will remain constant in the future and will be composed of 20 staff members 2 engineers/techs and 2 PhD students.

-Strengths and opportunities

Expertise in the connexin field is well recognized. The axis 2 has a strong past of medically orientated activities. Axis 4 represents a risky but original and well-designed project that has been appreciated.

GENERAL COMMENT

We noted with satisfaction some recognition by the committee of the effort made to organize our laboratory into three research teams, services and platforms as well as to play an important role locally both for research and for teaching.

We appreciated most of the recommendation of the committee that should help us in improving the quality of our project. Thus, we have modified our project with three major modifications.

First, we fused axes 1 and 2 of team #1. Second, we changed the team leader of team #2. Third, we fused axes 1 and 3 of team #3. These rearrangements will lead to reduce the number of research topics on more focused projects. We will pay a particular attention to preserve the balance between basic science and application-driven research.

Weaknesses and Threats

While the number of publications is high, the international recognition of some authors is probably not as good as it should be. This constitutes a threat because application of the « standards of excellence » as presently thought would jeopardize the unit, while its importance both in term of local policy and in terms of originality (relationships with chemists, applications, cutting edge projects proposed) deserves the highest consideration.

The director and most leaders are very much aware of this fact. We indeed need to pay a particular attention to the quality of our publications and to encourage our leaders and young scientists to better communicate through high IF publications and conference invitation and by any means to promote our research. On the other hand, we also have to take into account the number of publications for our PhD students because national instances such as CNU 66 impose 3 publications for qualification and most universities, including our, impose at least 2 publications to validate the thesis.

Recommendations

The IPBC should try to attract new researchers, to promote new teams arrival through AVENIR/ATIP program or other attractive packages.

This has been done in 2009 by attracting a young scientist with an ATIP program. This will be done in the next coming years by attracting new researchers. We will publish in 2011 an open call to welcome a new research group on our main research topics.

RESEARCH TEAM #1

Weaknesses and Threats

The quality of publications is of average level and should be greatly improved.

To attract postdocs and young scientists from abroad does not appear as a priority of this team.

We do not think that publishing in the best journal in Physiology like Physiological Reviews, Journal of Physiology, Journal of General Physiology, American Journal of Physiology can be interpreted as of "average level" given the fact that most of our colleagues physiologists worldwide also published in such journals and it is clearly established that the quality of the research is always excellent in those journals despite the medium IF (below 5) except for Physiological Reviews (IF: 37.7).

The second sentence is neither fair nor acceptable. In particular axis one (cystic fibrosis) is regularly attracting post-doc fellows among them ANR post doc (3 in 2010-2011).

We noticed a mistake. We indicated in the Table 4.1 page 9 that team #1 hosted a total of 21 PhD students during the past contract and not 4 as indicated page 10. Many of these students came from outside of our University.

Recommendations

Mechanistic analysis using cell biology approaches, such as intracellular trafficking analysis, should be further developed. Along this line, the projects on CFTR of axis 2 should be integrated with axis 1.

We decided to follow the recommendations of the committee by fusing axes 2 with 1 into a single research axis leaded by former axis 1 leader and focused on cystic fibrosis, from genetic analysis to molecular mechanisms of CFTR function, regulation and pharmacology. Other projects will be discontinued (Charge syndrome).

RESEARCH TEAM #2

Weaknesses and Threats

There are several senior scientists within this team; the reason of the choice of the proposed team leader does not seem obvious and appropriate to the committee.

The "proposed team leader" was initially asked by members of team2, leaders of axis 1 and axis 2 and the director of the IPBC to work towards setting up a new team. The "proposed team leader" initiated and implemented within the IPBC some of the topics that are major for team 2 such as phagocytosis and VKDP, opened up these topics to other team members and coordinated the European project proposal "PHAGOCYTOSIS". Within the last 2 years, the "proposed team leader" has worked with other team members in obtaining funding for each of the projects he is involved with: Angiogenesis-tumour growth/VKDP (LNCC/ Soutien Transfer CNRS), Neural Stem Cell/VKDP (LNNC, region PC), Phagocytosis (Europe/ ACI) and was therefore best placed to apply for "équipe labellisée LNCC". Moreover, "the proposed team leader" has worked and still works with other team members for promoting their research topics: (ERC starting grant application for axis 2 topics in 2010 and a project to re-apply in 2012;

proposal on endothelial cell-neural stem cell interaction for our CR CNRS candidate that was granted over 80 000 Euros fund).

The committee noticed however that other senior scientist of the team should be proposed as team leaders.

After discussion with the director of the IPBC and with the members of the new team, we decided to follow the remark of the committee and to propose the group leader of axis 1 as the new team leader. In addition, he will connect axis 1 and axis 2 projects through his expertise on cytoskeleton, calcium signalling and cell motility.

Recommendations

The committee is less supportive on the studies on the role of VKDPs on angiogenesis.

Team 2, Axis 3, is focussed on the role of VKDPs in both angiogenesis and tumour growth. This project has already lead to a patent application and has been supported by a "soutien transfer CNRS" and special funds from University of Poitiers. Following the recommendation of the committee this project will be discontinued unless it benefits from support from an industrial partner or other funding bodies.

The work on VKDP and angiogenesis is part of a European project proposal on VKDP that includes several European partners and for which the group leader is the proposed coordinator.

The team considers that this topic has a great potential both for fundamental and applied research. The European network should allow the development of the project through application for grants and for post-doctoral investigators.

RESEARCH TEAM #3

Weaknesses and Threats

The association of the different axes into a single large team 3 may be questioned and the organisation of staff members in the different groups of team 3 appears sometimes rather artificial and not always supported by scientific criteria.

We understand the statement as an apparent heterogeneity of the team. To prevent such heterogeneity, the number of axes will be reduced. Axis 3 will fuse with Axis 1, which will be entitled "Cellular communication in neural cancers".

The team will then be constituted of 2 major blocks dealing with invasive or metastasizing tumours (Neural tumours: new Axis 1 and Prostate cancer: Axis 2) and interfacing each with a third axis (lipid droplets: Axis 3) studying the role of lipid droplets in cancer cell behaviour for both models (neural tumours and prostate cancer). The criticism about the lack of PhD students in the project is not funded. We have indicated in the Table 4.3 page 15 that team #3 hosted a total of 16 PhD students during the past contract.

While

When we exposed future projects to the Committee, we only mentioned the permanent staff who will lead them. However, as it was in the past, PhD students will be the active components of the projects that have been presented. In fact, a PhD position will be already granted for the emerging Axis 3 (lipid droplets) from September 2011.

Moreover, as it was presented, a particular effort will be made for attracting post-docs and new CNRS staff to the Team 3.

The feasibility of all the projects presented remains questionable in regards of resources.

As mentioned in the report by the Committee, the resources of the new Team 3 were not well estimated (Page 16; Section "Appreciation on the impact"; 2 nd paragraph; last sentence). This statement was the consequence of the difficulty to estimate precisely funding from people sorting out/coming in the new Team 3. Total of our resources for last 3 years were 197 200 Euros (2008), 213 450 Euros (2009) and 123 465 Euros (2010).

Part of resources from CHU was not taken into account in those estimations as well as facilities that will be opened to people of Axis 2 (Prostate cancer) and the rest of the Team 3. Moreover the implication of members of the team in regional glioma network (Axis 1; Canceropole GO) and in national prostate pathology network (Axis 2; CeRePP) will help getting funds as it was in the past. Finally, we will take advantage of this reorganization for applying to more ambitious grant sources (ANR, ARC, etc.).

About the feasibility of the project of Axis 2, it is mentioned in the Committee report that "the transition toward mechanistic issues will raise practical difficulties". In response to such a statement, we can say that cellular models are already available in the laboratory and some animal models will be developed locally or through collaborations. Moreover, the "In vivo" platform of Canceropole GO will permit the use of the model of orthotopic xenograft for prostate cancer.

Recommendations:

Prioritize the projects as a function of financial and technical feasibility

The projects will be developed according to the financial resources they will get.

Professor Frédéric Becq

Director IPBC

The University of Poitiers joins to all the observations made by the Director IPBC.

Poitiers on April 12th, 2011

The Vice-president in charge of the Research Professor Olivier Bonneau



  Date and execution of the visit



  Production results (cf. http://www.aeres-evaluation.fr/IMG/pdf/Criteres_Identification_Ensgts-Chercheurs.pdf) A1: Number of permanent researchers with or without teaching duties (recorded in N1 and N2) who are active in research 44 A2: Number of other researchers (recorded in N3, N4 and N5) who are active in research A3: Ratio of members who are active in research among permanent researchers [(A1)/(N1 + N2)] 0,91 A4: Number of HDR granted during the past 4 years 9 A5: Number of PhD granted during the past 4 years 35 3  Specific comments on the research unit  Appreciation on the results

4 14 

 14 Appreciation team by team and/or project by project 4 -1 Team : Physiologie, pathologie et pharmacologie des canaux ioniques Leader: C. COGNARD  Staff members (on the basis of the application file submitted to the AERES) Past Future N1: Number of researchers with teaching duties (Form 2.1 of the application file) 10 20 N2: Number of full time researchers from research organizations (Form 2.3 of the application file) 3 3 N3: Number of other researchers including postdoctoral fellows (Form 2.2 and 2.4 of the application file) 0 2 N4: Number of engineers, technicians and administrative staff with a tenured position (Form 2.5 of the application file) of Ph.D. students (Form 2.7 of the application file) 21 6 N7: Number of staff members with a HDR or a similar grade 8 Appreciation on the results :

4 

 4 Title of the team: Croissance, mobilité cellulaire et cancer Leader: O. BENZAKOUR  Staff members (on the basis of the application file submitted to the AERES) of engineers, technicians and administrative staff with a tenured position (Form 2.5 of the application file) 0 1,5 N5: Number of other engineers, technicians and administrative staff (Form 2.6 of the application file) 0 0 N6: Number of Ph.D. students (Form 2.7 of the application file) 0 3 N7: Number of staff members with a HDR or a similar grade 0 Appreciation on the results During the period 2006-june 2010, people now constituting team 2 were developing three distinct projects.

  the past record in terms of Ph D was satisfying the project presented to us includes very few Ph D students, another weakness is the absence of Post-Docs. The team involves only 2 staff CNRS scientists (1CR and 1DR) out of 20 staff members.

  has published 50 papers, 30 of which with first or last authorship, among which 1 JBC, 1 Mol Biol Cell, 2 Traffic, 2 Am J Respir Cell Mol Biol, 3 J Pharmacol Exp Therap.

		Axe2 has published 35 papers, 10 of which with first or last authorship, among which 2 Exp Cell Res.
		Axe3 has published 20 papers, 10 of which with first or last authorship, among which 2 FASEB J, 1 JBC, 1
		Am J Physiol Cell Physiol, 2 J Gen Physiol.
		Axe4 has published 25 papers, 17 of which with first or last authorship, among which 1 Br J Pharmacol, 2
		BBA, 1 J Neurophysiol, 2 J Cardiovasc Electrophysiol.

  Communication, différenciation et cancer Leader : M. MESNIL  Staff members (on the basis of the application file submitted to the AERES)

		Past	Future
	N1: Number of researchers with teaching duties (Form 2.1 of the application file)	13	18
	N2: Number of full time researchers from research organizations (Form 2.3 of the application file)	2	2
	N3: Number of other researchers including postdoctoral fellows (Form 2.2 and 2.4 of the application file)	2	2
	N4: Number of engineers, technicians and administrative staff with a tenured position (Form 2.5 of the application file)	2	3
	N5: Number of other engineers, technicians and administrative staff (Form 2.6 of the application file)	1	0
	N6: Number of Ph.D. students (Form 2.7 of the application file)	16	3
	N7: Number of staff members with a HDR or a similar grade	11	16

Statistiques de notes globales par domaines scientifiques

  (État au 06/05/2011)

Sciences du Vivant et Environnement

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

les résultats SVE2 ne sont pas définitifs au 06/05/2011. Intitulés des domaines scientifiques Sciences du Vivant et Environnement • SVE1 Biologie, santé SVE1_LS1 Biologie moléculaire, Biologie structurale, Biochimie SVE1_LS2 Génétique, Génomique, Bioinformatique, Biologie des systèmes SVE1_LS3 Biologie cellulaire, Biologie du développement animal SVE1_LS4 Physiologie, Physiopathologie, Endocrinologie SVE1_LS5 Neurosciences SVE1_LS6 Immunologie, Infectiologie SVE1_LS7 Recherche clinique, Santé publique • SVE2 Ecologie, environnement SVE2_LS8 Evolution, Ecologie, Biologie de l'environnement SVE2_LS9 Sciences et technologies du vivant, Biotechnologie SVE2_LS3 Biologie cellulaire, Biologie du développement végétal Institute of Cellular Physiology and Biology (IPBC, UMR 6187); Comments and responses to AERES report.

-Weaknesses and threats

The association of the different axes into a single large team 3 may be questioned and the organisation of staff members in the different groups of team 3 appears sometimes rather artificial and not always supported by scientific criteria.

While the past record in terms of Ph D was satisfying the project presented to us includes very few Ph D students, another weakness is the absence of Post-Docs. The team involves only 2 staff CNRS scientists (1CR and 1DR) out of 20 staff members.

The feasibility of all the projects presented remains questionable in regards of resources -Recommendations

Prioritize the projects as a function of financial and technical feasibility.


M Yvon

M Vassili Soumelis

M Renato Monteiro

Jean-François Moreau

Ana-Maria Lennon-Dumesnil

Keywords: Cellules Dendritiques, Immuno-modulation, et

The visit was organized on November 30th, 2010 and lasted from 11:00 am to 5:30 pm.

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

This unit is located at the University of Tours and directed by M. Yvon Lebranchu. It was created in 2004 as a "jeune équipe" working on dendritic cells (DC) and kidney transplantation. Ms. Florence Velge-Roussel will take over the leadersheadhip of the unit in 2012. 2  Overall appreciation on the research unit

 Staff members

 Summary

The unit members have built an impressive connection between clinics and basic research, given the limited resources and lack of pre-existing activity in this area. This forms a very good basis for translational research. The prospective database is a very valuable asset for local and collaborative projects.

National and international connections exist for large-scale clinical investigation studies, but are lacking for more basic research projects. There is a common will to continue improving that.

Recruitment of young researchers, including MD/PhD with integrated research background, is an important priority.

The arrival of a new researcher significantly improved the research environment. There is a need to continue and improve doing basic research.

 Strenghts and opportunities

-Very good integration between research and clinical groups;

-Translational research unit in renal transplantation and immunology with an integrated organization between research and hospital groups;

-Interdisciplinary team from basic to clinical research;

-Prospective clinico-biological database for kidney transplant patients;

-Large DNA collection for genomic studies in renal transplantation;

-Important research contributions, for example the role of IL-2 and IFN-gamma on DC maturation;

-Original future research developments: renin-angiotensin system and immune responses;

-Importance of the questions asked in the field of basic and clinical transplantation;

-Appropriate methodologies, in particular in terms of data management and analyses;

-Good potential for growing given the environment, the expertise, and the interest.

 Weaknesses and threats

 Specific comments  Appreciation on the results

The context motivating the initiation as well as most of the current activity of the team is the drop in long-term renal graft survival, with 50% chronic allograft dysfunction, and 50% of death from other complications, including cancer. In addition, there are a large number of side effects related to the use of immunosuppressants. Research activities were established and organized in order to improve these important aspects of renal transplantation, with potential impact on other transplantation settings and for our understanding of graft rejection and inflammation in general. Three themes were defined along those lines (1) DC, innate, and adaptive immunity, (2) Biomarkers and clinical outcomes and (3) Immunosuppressive strategies. Examples of specific questions are the impact of the allogeneic effect on graft survival, development of patient-tailored immunosuppression, better choice of immunosuppression, the role of IL-2 and IFNg on DC activation, and regulatory T cell (Treg) biology.

Research outputs: The unit has produced a significant number of publication in specialty and generalistic journals, including for 2006-2009: 90 papers, among which 24>5 IF. An important output is the prospective database gathering data starting from 1985, and combining immunological, biochemical, and clinical information in order to answer relevant physiopathology and clinical questions. The unit also has an important DNA collection (1500 samples).

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

Unit members are part of various collaborative networks: French network on renal transplant, DNA collection network, Regional cluster on infection and immunotherapy, LabEx project: Therapeutic antibodies; CHU Tours: Inflammatory responses in renal physiopathology A peculiarity of the unit is the very strong integration with the hospital and clinical teams, with many medical doctors involved in the research at various levels. Projects range from fundamental, to translational and purely clinical research, with a strength in the translational aspects.

 Appreciation on the management and life of the research unit

The unit hosts 6 HDR, 3 Technicians, 2 post-doctoral fellows, 5 PhD students, and a variable number of masters students. New members are expected to join, including young researchers. Staff scientists and medical doctors benefit from a good work environment, with a very good connection between research and hospital teams, including common lab meetings. Technical and administrative staff has a good degree of autonomy and is well integrated in the unit. It is actively involved in training young researchers. Students and post-doctoral fellows benefit from a good environment in terms of material, space, and financing. Following discussions with lab members, the committee had the feeling a very positive and interactive environment, encouraging exchanges and learning from others. Younger lab members were very motivated in pusruing scientific careers.

The unit is actively involved in the training of masters and PhD students, as well as in teaching. The head of the unit coordinates the DIU on clinical transplantation that he has himself initiated. He is president of the CNU commission 47-03 "Immunologie". Several unit members participate in teaching at the University of Tours.

 Appreciation on the scientific strategy and the project

The global strategy is well adapted to the environment and to the type of translational research performed. Azs stated above the interdisciplinarity also adds difficulty in being/remaining cutting edge in various disciplines (see above: Weaknesses and threats). The project would be strengthened by an increased focus on basic mechanisms. The critical mass in increasing, which will certainly favor this and other developments. The perspective is under discussion for applying for an Inserm unit in the near future. This would be justified by the increased size of the unit, the very good interdisciplinarity, and the good perspectives of development that would require the appropriate institutional support.

 Appreciation theme by theme

Theme 1:

 3.

General overview of the activity

In the years 2006-2010 the team aimed at understanding certain mechanisms involved in the generation of regulatory DC and T cell subsets with the ultimate goal to translate their findings into effective and specific immune suppression during organ transplantation in patients. Their efforts have generated many publications of which some of great importance. For example, they showed that mycophenolic acid treatment of DCs renders them suppressive (J. Leukoc. Biol., 2008). They also showed that interferon-gamma licenses human DCs to induce CD8+ alloimmunity in the absence of T helper cells (Blood, in press). Moreover, the team demonstrated that anti-CD25 decreases the ability of human DCs to prime allogeneic CD4+ T cells (J. Leukoc. Biol., 2008) and that CD40 engagement on porcine DCs induces CD25 expression (Mol. Immunol. 2010). They have also demonstrated the role of probiotics in the activation of human regulatory DCs (J. Allergy Clin. Immunol., 2006 ;Plos One, 2008). In addition, the team has recently started a project on the role of ion channels in DC maturation and migration.

The projects were presented in a very clear way. The team proposes to continue their research efforts on the topics they have already worked trying to identify the mechanisms and to link these to the human transplantation situation.

In addition, the team proposes to expand their research on the role of ion channels in DC physiology and inflammasome activation. Another researcher proposed the studies of the effects of renin receptors on DCs. They also plan to employ an ischemia reperfusion in vivo mouse model (that already works in their hands) to study the DC-T regulatory networks.

 3.2 Strengths

This is a wonderful example of academic clinicians/researchers collaborating with basic scientists in order to accomplish translational research. The topics of the proposed research are very significant for immunology and transplantation immunology and the approach is appropriate. A newresearcher, who joined in 2006, is an asset for the team. He is a very good and rare example of a clinician with strong background in basic immunology. His expertise in studying the immune response and the DC-T crosstalk is providing the right force for the team to evolve. In fact, increasing level of publication record of the unit in the last years is noticeable. The team's proposed project on DC function and renin receptors is of high impact, novel and promising.

The leadership is excellent as also judged by their decisions on team formation and projects.

The students (Ph.D. candidates and residents) showed a very good grasp of knowledge and understanding and were characterized by great enthusiasm for their projects and their mentors. Of great importance is the fact that the students want to continue carreers in research and academia.



Weaknesses

The unit lacks permanent scientists (from EPST institutes) and permanent technicians for the proposed research needs.

The team would be greatly benefited by limiting the number of projects in order to study the mechanisms involved in depth. Also, it would be important for the researchers to employ transplantation animal models to study fundamental aspects of DC and immune regulation in transplantation in vivo.

Theme 2: Genetic polymorphism and renal transplantation in Humans

Based on the clinical database and DNA collection from the cohort of renal transplant recipients followed at the Tours-François Rabelais University Hospital (Nephrology and Clinical Immunology departments), the laboratory produced already significant data using a "candidate gene" approach. Especially interesting are the impact of IL-12p40 and of PD-1 on graft survival and CMV infection published in Transplantation ( 2008) and J. Med. Genet. ( 2009). Future plans include other candidate gene (ABC transporters) approach but above all a genome-wide project. This will be made possible through a consortium bringing together 8 clinical centers in France and Belgium (notably Tours, Besançon, Bruxelles, Liège with a total of 5000 DNA samples expected). Genetic analysis will be conducted in Bruxelles.

Strong points are the quality of the clinical data collection and of the interactions with Geneticists.

Considering the fierce competition in the field, further improving collaborations at the National and European levels have been encouraged. Also adequate coding of all information facilitating future statistical analyses would secure the high value of this unique database. Focusing Genetic analysis on critical issues in Organ Transplantation, such as the occurrence of post-transplant HLA-specific antibodies, would add a significant value to the project.

Theme 3: Immunosuppressive strategies

Based on a collaborative network including many kidney transplant center, the team develops a translational original research based on analysis of different immunosuppressive strategies in kidney transplantation. Topics include several studies based on the use of inhibitors of the mTOR pathway, the characteristics of the lymphocyte recovery after the use serum antlimymphocytaire, and the analysis of the consequences of the use of Basiliximab on lymphocyte phenotype T regulatory populations. This activity has resulted over the last 4 years to 8 publications in journals with impact factor over 4. The group plans to create a multidisciplinary platform within the CHU of Tours based on the use of monoclonal antibodies in human therapy. The activity and the project are based on original and excellent operating clinical cohorts and databases even if it is essentially a clinical and translational research with few prospects more basic at the moment.

REPONSE DE L'UNITE : CELLULES DENDRITIQUES, IMMUNOINTERVENTIONS ET GREFFES S2ur120001554

Answer to the EARES committee First of all, we would like to thank the committee members for their investment and their useful comments and proposals. We share the majority of your conclusions. Nevertheless we would like to comment some points regarded as a weakness in the analysis.

1 -we totally agree that the interdisciplinarity increases the difficulty of being cutting edge in all areas. Nevertheless, as underlined in the report, the very strong integration between the research team and the clinical staff of the transplant unit strengthens the translational aspect. In the future, we will be cautious to primarily develop research topics that already represent our strengths as underlined in your report.

2 -indeed the number of HDR is low, but increasing steadily in recent years (3 in 2004, 6 in 2010 and will reach 7 in September 2011). In addition, other valuable scientist have just join our team or shortly or will do it: 1) in September 2011, the team will be strengthened by the arrival of a new HDR, Dr Denis Angoulvant as professor of cardiology; he held a post-doctoral position in Toronto, and worked on ischemia reperfusion injuries and inflammation; 2) the research staff of the HLA laboratory of the "Etablissement du Sang Centre Atlantique" has recently joined our team (1 PhD and 1 research engineer); 3) two young surgeons and several young physicians are being trained in our team: we hope that some of them will be part of our team in the future.

3-we agree with the need to increase connections with expert groups, in particular in basic research, and we will do it. First, we have been co-founders -with D Abramowicz from Bruxelles -of a European network for the study of genetic polymorphism in kidney transplantation in connection with a genetic laboratory of international renown headed by Pr M Georges at Lièges. Second, we recently extended this consortium to other European centers and applied for the 2011 EDTA grant along with D. Abramowicz from Bruxelles, F. Claas from Leiden, D. Dragun from Berlin, R. Borrows from Birmingham and several other colleagues. This network aims to coordinate efforts to create large banks of biological samples backed by clinical databases to conduct genome-wide studies in transplant patients. Finally, our team has also proposed a European network focused on "ion channels and dendritic cells" with M. Hoth, from Saarland University, A. Parekh, from Oxford and several well-known colleagues. These projects demonstrate our capacity to develop interactive connections in basic research.

4-we have been surprised that the report mentionned "a low international visibility and attractiveness". Indeed two Brazilian professors joined our team in the last 2 years (Pr N Olsen-Camara from Sao Paulo and currently Pr M Teixeira from Bella Horizonte who has more than 300 publications referenced in Medline). The significant number of international and national invitations for academic conferences attests of our visibility within the field of transplant immunology. In addition, the head of the unit was the past president of the "Société Francophone de Transplantation", the co-president of the last congress of the "European Society for Organ Transplantation and the president of the scientific committee of this meeting" in 2009. We therefore believe that these facts confer to our team an excellent national and a fairly good international visibility in our field of transplant immunology. Our implication as leaders in European Networks (cf 2.) will improve our international visibility.

Madame Laurence VELGE-ROUSSEL Michel ISINGRINI Vice-Président Recherche



  Date and execution of the visit

  Perform more systematic work on mechanism of IS drugs on DC and link to selective pathways;

	o o Develop more connections with basic researchers because of the weak environment in science and
	immunology;
	-Genomics and biomarkers
	o Establish a database, and prospective cohorts;
	o Link to clinical parameters: CMV, immune reconstitution;
	o Important to go towards genome-wide studies;
	o Continue original study based on urine analysis and peptidomics;
	o Need to reinforce data analysis;
	-IS drug
	o Need to be more linked to molecular mechanisms.
	 Recommendations
	-DC networks:
	o Be more selective on the projects in order to work in depth molecular mechanisms;
	o Renin angiotensin is an interesting and cutting edge area;
	o Ischemia reperfusion injury mechanisms;

-Interdisciplinarity increases the difficulty of being cutting edge in all areas; from basic to clinical research; -Small critical mass; -Need to increase connections with expert groups, in particular in basic research; -Low international visibility and attractiveness.

Sciences du Vivant et Environnement

		Intitulé UR / équipe	C1 Statistiques de notes globales par domaines scientifiques C2 C3 Note C4 globale (État au 06/05/2011)
		CELLULES
	DENDRITIQUES,IMMUNOINTERVENTIONS ET	A	A		A	A	A
		GREFFES
		Note globale	SVE1_LS1_LS2	SVE1_LS3	SVE1_LS4	SVE1_LS5	SVE1_LS6	SVE1_LS7	SVE2 _LS3 *	SVE2_LS8 *	SVE2_LS9 *	Total
	C1	A+ Qualité scientifique et production 7 A 27	3 1	1 13		4 20	7 21	6 26	2	2 12	23	30 145
	C2 C3	B Rayonnement et attractivité, intégration dans l'environnement 6 1 6 C 1 Gouvernance et vie du laboratoire Non noté 1	2	8	23 4	3	3	6	58 5 1
	C4	Stratégie et projet scientifique Total 42	5	20		26	36	59	5	17	29	239
		A+	16,7%	60,0%	5,0%		15,4%	19,4%	10,2%		11,8%	12,6%
		A	64,3%	20,0%	65,0%		76,9%	58,3%	44,1%	40,0%	70,6%	79,3%	60,7%
		B	14,3%	20,0%	30,0%		7,7%	22,2%	39,0%	60,0%	17,6%	20,7%	24,3%
		C	2,4%						6,8%			2,1%
		Non noté	2,4%									0,4%
		Total	100,0%	100,0%	100,0%		100,0%	100,0%	100,0%	100,0%	100,0%	100,0%	100,0%
	*

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

  ER V IC E D E L A R E C HE RC H E ET DE S ET UD E S DO CT O RA L E S

	Tours, le 22 avril 2011

S