A+ Nn

 Grading table of the team: Virtual screening C1 C2 C3 C4 C5 C6 A+ A

Grading

Once the visits for the 2012-2013 evaluation campaign had been completed, the chairpersons of the expert committees, who met per disciplinary group, proceeded to attribute a score to the research units in their group (and, when necessary, for these units' in-house teams). This score (A+, A, B, C) concerned each of the six criteria defined by the AERES. NN (not-scored) attached to a criteria indicate that this one was not applicable to the particular case of this research unit or this team. Criterion 1 -C1 : Scientific outputs and quality ; Criterion 2 -C2 : Academic reputation and appeal ; Criterion 3 -C3 : Interactions with the social, economic and cultural environment ; Criterion 4 -C4 : Organisation and life of the institution (or of the team) ; Criterion 5 -C5 : Involvement in training through research ; Criterion 6 -C6 : Strategy and five-year plan.

With respect to this score, the research unit concerned by this report and its in-house teams received the following grades:   Grading table of the unit: Recherche de Molécules à visée Thérapeutique par approches in silico C1 C2 C3 C4 C5 C6

Management team

• Successful unit recently created, and showing a significant attractiveness locally, nationally and also internationally for both young and senior scientists.

• Leading laboratory in France and in particular at the INSERM, in an emerging and multidisciplinary field combining bioinformatics, statistics and chemoinformatics.

• Recognized expertise in the field leading to (and now reinforced by) the opening of European Master for 'in silico Drug Design'. Teaching is an essential commitment for the whole community and an excellent opportunity to establish connection with leading scientists in the area of research.

• Number and quality level of the publications by members of the unit is on average very good and including methodology papers in recognized journal in the field (N.A.R., Bioinformatics, PLoS Comput. Biol., Drug discovery Today, ...) and application papers often in collaborations with biologists (P.N.A.S., ...).

• Several good national and international collaborations as well as a convincing networking within the national communities of bioinformatics and chemoinformatics.

• There is a good potential to increase the collaborations at international level and participate to European projects.

• The unit benefits from a strong support from both the INSERM and the university Paris 7-Denis Diderot.

Weaknesses and threats

• Peptide modeling and protein-protein interface are two fields with high international competitions.

• The lack of papers published in journals with very high impact factors may limit international visibility and therefore involvement in international network or research programs (FP7, ...). The productivity of some teams might be improved.

Recommendations

• The committee fully supports the project and may recommend:

• strengthen connection/collaboration between teams (e.g.: for validation purpose, target analysis).

• keep improving teaching excellence locally and at the European level (master isDD).

• strengthen collaborations in bioinformatics at the international level possibly within the ELIXIR/OPENSCREEN/... infrastructures or through grant applications to FP7 projects.

• keep attracting additional scientists possibly with complementary skills in aim at strengthening experimental applications (teams 1 and 2).

• Extend the current SAB to an international level.

Recherche de Molécules à visée Thérapeutique par approches in silico, MTi, Paris Diderot and INSERM, Mr Bruno VILLOUTREIX 3  Detailed assessments

Assessment of scientific quality and outputs

Over the last period, the MTi has reinforced its main lines of research:

• extending structural alphabet development toward efficient peptide conformation prediction;

• developing original approaches for ab initio ligand conformation and structure-based protein pocket predictions;

• continuing the development of state-of-the-art ADME-Tox predictions and starting to adapt this topic to Protein-Protein Interface.

On top of these topics, it is now adding, in due time, the emerging field of pharmaco-profiling thanks to new professor recruitment.

All this is bringing together a large panel of expertise in bioinformatics and chemoinformatics backed by an impressive amount of theoretical and technical skills in statistics.

All these complementary aspects are nicely connecting each other in the current project of the unit.

The maturation of these fields and the growth of the unit led to a relevant organization into three teams.

The publication level of the entire unit is very good in number (103 in the period 2007-2012) and quality with both methodology papers, application papers and numerous book chapters (20) or invited reviews (18). Lab members are often first and/or corresponding authors of these publications.

In parallel, the involvement in the development and maintenance of two well-established platforms, RPBS and CDiThem, is also a strong and important commitment to the nation-wide scientific community.

Assessment of the unit's academic reputation and appeal

Since its recent creation (in 2009), the MTi has been growing successfully, showing a great attractiveness to both young and senior scientists. This gave the opportunity to become a national leader in its research field by combining complementary topics including bioinformatics, biostatistics and chemoinformatics in a rather unique manner in France.

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

The unit has developed and maintained various software, freely available to the academic community through the IBISA platform RPBS.

Several original and up-to-date tools (e.g.: PEP-FOLD, FROG, FAF-DRUG, ...) achieved high access rate (~ 10000/year) world-wide.

The unit has developed a unique protocol, Mobyle, to disseminate rapidly a plethora of bioinformatics and chemoinformatics tools (Collaboration with Institute Pasteur, Paris).

The integration and the efficient networking through the MobyleNet platform, gathered most of the French laboratories in the field of bioinformatics and also chemoinformatics.

Seven patent applications (2007-2012) have been deposited and several contracts with the industries are ongoing or under investigations.

Assessment of the unit's organization and life

The three teams are scientifically sound and coherently dealing with the new arrivals (4 assistant professors, one professor, two researchers ...) that bring complementary expertise.

During the committee visit, an excellent atmosphere was evidenced as well as a strong trust in the unit leadership.

Regular lab meetings (once a month) are scheduled and opened to all members during the former period and now involve elected delegates due to the rise in the number of unit members.

Assessment of the unit's involvement in training through research

The unit shows an excellent commitment to teaching at various levels (L3 and M1 "Biology-informatics" and the European M2 "in silico Drug Design") and a similar trend regarding training of master (22 M1 and 15 M2 from 2007 to 2012), doctoral students (6 defended and 5 on-going) and also several post-doctoral fellows (6).

All the PhD students publish in good journals in the field and also attend a national/international meeting during the time course of the thesis.

Teaching and training benefit from the various tools developed and made accessible by the unit through the platform RPBS.

Assessment of the five-year plan and strategy

Based on the results from the previous period and the new recruitment in the unit, a new project has been established through a long and thorough process of self-evaluation. Within the global context of in silico drug design, three main axes have been delineated:

•

Structure-Based Peptide Design;

• Computational Pharmaco-Profiling;

• Virtual Screening and design of protein-protein interface inhibitors.

The new lines of research push forward the limits and scope of the current methodologies developed in the Unit. The three main focuses will provide an original framework of efficient methods for tackling the problem of developing drugs targeting protein-protein interactions. This represents a risky and highly competitive area of research. The experiences and the skills gathered at the unit suggest that is a timely move.

In parallel, to this methodology development, several applications studies are planned through collaborations and this would provide challenging and interesting validations.

Team 1 :

Structure-based peptide design Name of team leader: Mr Pierre TUFFERY In the previous four years the members of this proposed team have demonstrated clear successes in developing and making available competitive methods for predicting the structure of relatively large peptides (PEP-FOLD) and also protein pocket detection (Fpocket) and ligand conformation (Frog-2). The external adoption of PEP-FOLD has been significant, with the implementation on the RPBS web platform becoming the most used method with over 11,000 hits in 2012.

Workforce

A number of papers associated with these methods have been published in journals with relatively high impact factors (9 in Nucl. Acid Res., I.F. ~ 8). The PEP-FOLD method stands out as the key development having been shown to be able to compete with complementary methods from other groups, some of which are fortunate to possess significantly more resources than that available to this team, historically.

The MobyleNet web platform represents an unusually well-integrated and federated set of chemoinformatics, bioinformatic and computational chemistry tools which show significant numbers of hits both nationally and internationally. Additionally, a number of publications, of varying impact (2 PNAS, 1 Hepatology, 1 Genome Biol.), have resulted from this platform.

In general the number of publications authored by members of this group is reasonably good (39), for a methods-development team.

Assessment of the team's academic reputation and appeal

The well-used Paris-wide RPBS web platform have ensured that the work of this proposed team is well-known and well used at an international level.

In parallel, the team manage the development of the national MobyleNet connecting several important French web-based platforms. Team 1 leads the RPBS effort and motivated the implementation of MobyleNet.

The proposed group have been successful in becoming part of the national Bip:Bip bioinformatic project.

There have been a relatively low number of invited external talks given over the previous four years which is surprising given the apparent utility of the PEP-FOLD method, for example.

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

The free and unrestricted release of all methods and software either as standalone downloads (open-source) or via the RPBS/MobyleNet web platform has meant that the work of this proposed team has had a direct and immediate availability to others in the field both nationally and internationally.

PEP-FOLD has in the past been licensed to at least one company and discussions are underway with a number of other biotech companies with regard to licensing of MTi's software and datasets.

The head of Team 1 is a member of a number of national committees related to bioinformatics and also heading the axis 'Structural Bioinformatics' at the French Infrastructure for Bioinformatics.

Assessment of the team's involvement in training through research

The level of teaching by members of the proposed group is good, with involvement with the organisation and teaching of the MTi-designed in silico drug design masters course as well as teaching in other local courses at various levels.

Assessment of the five-year plan and strategy

The proposed plan involves the focusing of effort upon two complementary themes:

•

. peptide folding and design;

• . further development of the MobyleNet platform.

These two directions make sense given the previous success with PEP-FOLD and also the federated bioinformatics web platform.

It is intended to continue developing PEP-FOLD to explore the possibility of predicting protein:peptide interactions by folding peptides close to the cognate protein surface. In parallel, effort will be placed on identifying 'hotspots' between peptide & protein, and then designing de-novo fragments which are then linked together either via PEP-FOLD, fragment mining from the PDB or via stable, well-defined, peptide sections. The ability to identify the hotspots is well-established and the idea of creating linkers is not entirely novel, although in the context of 'large' (up to 50 residue) peptides this is clearly challenging. The fast mining of existing fragments from protein structures is something this team have enough experience with to ensure that the method they are developing shall be competitive within the field.

Deducing possible interactors for targets identified by team 3 should provide a useful parallel set of 'hints' to prioritise. The proposed work, whilst not entirely novel, is timely and appropriate for the scientific questions posed and has a good chance of success.

The group intend to extend the functionality of MobyleNet to include more complex, multi-scale workflows. Furthermore, there is work planned on 'semantic' approaches to enable MobyleNet to be more accessible to nonstructural biologists/bioinformaticians. These are two complementary and important developments for this platform in order to continue to extend its use broadly.

Conclusion



Strengths and opportunities:

A very professional approach to software and web platform development should ensure a high quality of the developed products.

Assuming sufficient IT resources can be provided, it should be possible to develop MobyleNet to become a clear leader in providing ad hoc structural bioinformatics to the community both nationally, and internationally.

 Weaknesses and threats:

There is quite some competition in the field of protein : peptide interaction modelling It will be important that web-based tools and workflows are clearly discoverable by non-specialists both via search engines and social media.



Recommendations:

The team will have to increase their visibility and the visibility of the developed methods to make an impact at the international level.

To demonstrate method efficiencies, it will be important to branch out and attempt demonstration on various targets, so that the method can be shown to be generic and not biased towards one particular target/family/classification. Assessment of scientific quality and outputs

Overall Team 2 members made significant contributions in their respective fields of expertise i.e chemoinformatics, structural bioinformatics and data analysis. They developed original computational approaches integrating statistical, geometrical and network biology considerations towards profiling of ligands, targets and ligandtarget interactions.

The recent and original contributions in the area of druggability of targets and developing field of multi-scale pharmacology is to be highlighted as it is expected to impact substantially research in pharmacology.

The six permanent scientists of this newly formed team co-authored 53 original articles in the 2007-2012 period, all of which were published in average or relatively high impact journals (Nucl. Acid Res.; PLoS Comput. Biol.). Half of this production was done by new MTi members before they joined this lab showing good attractiveness of this unit.

Assessment of the team's academic reputation and appeal

The team members have many ties collaborations with several external teams or collaborators, most of which are experimental-, clinical-or pharma-based which is of outstanding value to team 2.

Team 2 successfully attracted funding from national agencies (ANR Piribio, Bip-Bip) and team 2 is involved or heading several EU-based consortia (OpenPHACTS, eTOX, ...) and the Danish-based INDICES consortium.

Members of Team 2 belong to editorial boards of specialized journals, have been solicited on conference boards and have been recruited as scientific experts at national and international levels (ANR, FP7).

Assessment of the team's interaction with the social, economic and cultural environment Team 2 members through their interactions with members of team 1 and Team 3 have been involved in developing several software and methodology made available through Web-based servers.

As part of its contribution towards translational medicine, team 2 is now involved in the development of the database ChemProt. This huge database was developed towards integrating relationships between drugs, targets and diseases using clinical data and translational technologies and has been made available publicly. This has potential for high clinical and social outreach.

Assessment of the team's involvement in training through research

MTi members from team 2 have outstandingly played a leading role in nurturing training in bio-informatics at the University Paris7-Denis Diderot (at license L3 and master M1 level).

Team 2 members led the creation and are now coordinating a unique European MSc degree in Drug Design.

In addition, a substantial number of students were provided training through research internship by MTi members from team 2.

Team 2 members are also actively involved in Doctoral Schools from higher education institutions in Paris.

Team 2 will be focusing on the development of new computational approaches towards pharmacological profiling through three complementary directions:

• ligand space profiling and target space profiling;

• pharmacological network profiling.

Their main objective is to develop innovative platforms and new methods by considering network and systems biology towards knowledge enrichment about mechanism of diseases, drug safety and activity.

These original resources and methods will allow prediction of drug side effects and potential off-target. They will be integrated in a "systems pharmacology" approach with the aim to develop "hybrid" models to improve pharmacological profiling of drugs with special emphasis on drug safety. Collaboration with team 3 on mechanistic ADME-Tox prediction is foreseen.

The proposed work relies on the adequate combination of complementary scientific expertise. The question of druggability and ligand profiling is a very competitive area.

Conclusion



Strengths and opportunities:

Team 2 involvement into EU projects (eTOX, OpenPHACTS) and heading of the development of one of the largest databases in chemical biology, will provide the unit with a leading position at the international level.

Combination with structural analysis for ligand and active site profiling shall bring additional advantage in the emerging but already highly competitive field of integrated pharmacology/chemical biology.



Weaknesses and threats:

The plans are very ambitious compared to available human resources.

The cooperation between scientists in team 2 is low  Recommendations:

Additional dedicated technical personnels would be critically needed to keep team 2 moving forward in a timely fashion.

Strong interactions between team 2 scientists should be encouraged (with aim of joint publications) as it is expected to positively consolidate the team as a whole.

Recherche de Molécules à visée Thérapeutique par approches in silico, MTi, Paris Diderot and INSERM, Mr Bruno VILLOUTREIX Assessment of the five-year plan and strategy Team 3 has defined a plan and strategy for the coming five years with a strong focus on identifying and optimizing (potency, ADME-Tox) modulators of protein-protein interaction (PPI). Three main themes have been defined:

•

Chemical space for modulating PPI;

• Hit Optimization & 3D Mechanistic ADME-Tox prediction;

• Applications to selected PPI targets.

Team 3 project works in a highly relevant and timely area of research in which the team has an excellent expertise, placing them in an excellent position to successfully carry out the proposed research.

Team 3 has already built a unique database of PPI modulators, iPPI-DB in order to initiate a global categorization of PPIs and to determine some class of PPI targets for which a clear and homogenous chemical subspace can be established. This project also involved a more methodological part on software development for the docking of flexible peptides, and identification of binding pockets, building on the in-house MS-DOCK approach. This is potentially a part where the competition will be high and the team will have to demonstrate their performance to make an impact internationally. This part has direct links to team 1, the two teams working in synergy.

In addition, dedicated protocols will be developed for multi-parameter optimization for potency and ADME-Tox properties. This project will benefit from the available results of the experimental screening of a 40,000 compound library on 4 selected PPI targets (screening performed at the Institut Pasteur de Lille/Inserm U761 in the context of the funded ANR Piribio project (coordinated by the director of the unit).

Conclusion



Strengths and opportunities:

This is a timely project with promising preliminary results likely to enhance significantly the international visibility and impact of the team.

In general, the already existing expertise and the access to experimental data should give this project a head start for some aspects of the project. Maintaining and further developing collaborations with experimentalists will be crucial to ensure success since the team is dependent on experimental input and work from other parties. The collaborations in place are already very good which gives a good confidence that the team will meet the defined objectives in the coming period.



Weaknesses and threats:

Lack of participation in EU networks and projects. Je vous prie de recevoir, Monsieur le Président, l'expression de mes salutations distinguées.

Bruno Villoutreix

Dear Colleagues, Please find enclosed our comments about the AERES evaluation of our research unit.

Ref number for the report: S2PUR140006436 -Recherche de Molécules à visée Thérapeutique par approches in silico, MTi -0751723R

Director UMR-S 973: BO. Villoutreix

Overview of the research unit

First we would like to thank the AERES committee for providing very positive and constructive feedbacks about our research unit. Our group is indeed rather unique in France, as mentioned in the report, as it combines skills in the areas of chemoinformatics, bioinformatics and biostatistics. One of our goals is to develop new in silico approaches and protocols to assist the rational design of therapeutic molecules and to apply these tools and expertise in several therapeutic areas. As stated in the report, our group is well recognized in the field, is very active in terms of publications, grant applications, teaching, and is attractive to young and senior scientists and has numerous national and international collaborations. We were up to now organized in one single team but the committee is very supportive of our proposal for the next contract to work in 3 teams, each focusing on a well defined topic (team 1: structure-based peptide design, team 2: computational profiling and team 3: in silico screening of protein-protein interactions under ADMET constraints) but with a common goal (methodological developments in the area of in silico drug design with applications on selected therapeutic areas). The committee acknowledges the two platforms associated to our laboratory and the fact that they provide support to the scientific community. The continuous support from Inserm and Paris Diderot is also highlighted in the report and we would like to take this opportunity to here thank both, our institute (and corresponding ITMOs) and the university.

Points to improve in the unit • The committee notes important international competitions in the field of protein-protein interaction and peptide modeling. We agree with this observation and it is also clear that the competition is fierce in the area of profiling. In fact the topics that we address are timely and critical and therefore, competition will be strong. However, we are already well established in these areas of research, we have the skills, the right collaborations, the financial supports to carry out our projects and each team has convincing publications on the addressed topics. As such, we believe that we will be able to face competition. The new organization of the laboratory in 3 teams should also have positive impacts. • The committee mentions the lack of publications in very high impact factor journals. This is correct, as for the time being most of our papers have impact factors between 5 and 11. First, we all know that the best journals in the field of computational biology and chemistry tend to have impact factors in this range, as the community is smaller. Yet we also think that the new organization of the lab in 3 teams will help us to improve this point, as projects will be more focus. Further, the publications of some data is being postponed, as we want to accumulate sufficient in silico and experimental data prior to submitting papers in very high impact journals. At present, with the data at hand, we believe this should be possible for two unpublished projects since we have discovered compounds that are acting in relevant animal models.

Recommendations for the unit • The committee suggests strengthening collaborations between the teams. If we look at our previous work (up to 2007), we note 14 publications that involve many scientists of the unit. We also have projects involving all members of the lab and as such, internal collaborations are favored in our group. • The committee also mentions to keep improving our teaching and we are indeed paying attention to this point. To succeed here, we have international scientists involved in our trainings from all over Europe as well as industrial partners from pharmaceutical companies. • The committee suggests becoming more involved in FP7 or other European projects. In fact, one recently appointed professor in our lab is involved in 2 FP7 projects and we have submitted an application in the area of drug discovery in January 2013, the work passed the first review and we are now awaiting the final decision. • The committee talks about keeping attracting additional scientists to the laboratory, especially in teams 1 and 2. In fact, a candidate who would like to join team 1 sent one Avenir application and we are very likely to get a new assistant professor position to join team 2 in September 2014. One foreign young scientist is also applying to Inserm to join team 3. We are thus actively working on this specific point. • The committee suggests that we should extend our current scientific advisory board and invite international scientists. This is in fact ongoing and is indeed easy as we have many international contacts with leading scientists in the field.

Answers from team 1 (head: Dr. P. tuffery) General

We first would like to thank the AERES committee for its assessment, highlighting that we are a team of developers, sharing our efforts between the RPBS platform (and the technological developments associated with it) and more fundamental efforts on peptide protein interactions and peptide design. As stated in the report, the RPBS platform is largely used in France and abroad, and some actions that we have initiated such as the MobyleNet project have resulted in the federation of web-based platforms in France. Our developments of methods have in the past tackled various areas of interest for the UMR-S 973, including pocket detection, ligand 2D/3D conformation generation, and also peptide de novo modeling, an important contribution for the team for the future project.

Points to improve and recommendations

The committee mentions a number of publications reasonable for developers: the number reported by the committee is 39 but is different from the one reported in our report and now validated by INSERM and the number should be indeed 44. Several of our publications have been published in the high impact factor journals of the field. The committee relates few participation/invitations in international events. We agree that our participation in international meetings should be improved. Yet we would like to point out that, for instance, PEP-FOLD has been the subject of oral presentations in international meetings each of the past three years including the European Peptide Society meeting, at the end of 2012.

The competition in the field of protein-peptide interactions is high. In addition to the answers made above at the level of the Unit, we would like to point out that our project is Structure-based peptide design, i.e. not only protein-peptide interactions, and we intend to focus on structural aspects for which we have demonstrated skills validated by many publications.

The committee points out the need to increase the team visibility to get an impact at the international level. We are actively working to improve our visibility. Our participation to international meetings and the several contacts made should result in some new international collaborations. In addition, RPBS is also involved in the ongoing French application to ELIXIR.

The committee suggests us to work on attracting additional scientists possibly with complementary skills with the aim of facilitating experimental applications. We fully agree to increase our interactions with experimental teams. Contacts have been taken with NMR, X-ray and SPR expert teams in Montpellier, Nancy and Lyon, and one young scientist with an experimental background has been applying to the Avenir program. The committee suggests demonstrating the method developments on various targets to avoid a bias towards specific application. The in silico methods that we develop are general and validated on protein/peptide data-sets that encompass much more than one particular target/family. It is for instance a point mandatory for de novo peptide structure predictions that have been validated over all folds experimentally available.

Answers from team 2 (head: Profs. AC. Camproux & O. Taboureau) General

We acknowledge the reviewers for their discussions during the presentation of the newly formed team 2 during the visit of our unit and for their comments about the team in the written report. We appreciate that the reviewers were enthusiast about the leading role of team 2 in training in bioinformatics and in silico drug design and we will continue to provide relevant, and of quality, course in this area.

We thank them about their positive assessment regarding the scientific quality and outputs in the area of druggability of targets, ligand profiling and multi-scale pharmacology.

Points to improve and recommendations

We recognize that pharmacology profiling is a very competitive area and the plan might appear ambitious compared to the available human resources present in the team. We would like to emphasize that we agree with the reviewers and to achieve our objective we will have to pursue our involvement into national and EU projects, in international and industrial collaborations with the leaders in our area of research in order to attract new grants and new scientists in our team. For example since the visit of the reviewers, we have a new engineer (IE for technical helps for three years from the "investissements d'Avenir" grant) that starts to work on chemogenomics and we are top-ranked by the university to hire a new assistant professor in 2014. We aim to pursue our collaborations with external teams, experimental-, clinical-or pharma-based, highlighted as outstanding value by the AERES committee.

We understand that the reviewers think that the cooperation between scientists in team 2 seems low, but we would like to remind the committee that the team 2 got partially started in September 2012 with the arrival of a new professor and of an assistant professor. However, we would like to note that we have already started strong intra team interactions resulting, for instance, in publications in preparation based on a PhD co-direction involving different themes of team 2. Finally, grant applications are on going with the involvement of the 2 professors inside the team 2. We hope that this clarifies the situation inside team 2.

NB

We also noted some minor typos in the AERES table workforce. The number of permanent professors and similar positions as of June 2012 mentioned in the table is 4 but should be 3, the number of other EPST researchers noted is 2 but should be 1, the number of theses defended should be 2 (and not 3), the number of postdoctoral students having spent at least 12 months in the unit is 3 (and not 2) and the number of supervisors with an HDR should be 2 (and not 3). The numbers for the future project are correct.

Answers from team 3 (head: Dr. M. Miteva) General

We would like to thank the AERES committee for the strong appreciation of the high quality of the past work and the timely research project. The acknowledged visibility of the team at the national and international level is highly appreciated. During the last few years we have been developing and successfully applied in silico screening protocols with the goal of identifying new potent hits for cancer, cardiovascular and rare diseases. We continue to work in the same therapeutic areas but we will now focus on modulating protein-protein interactions with drug-like molecules under ADMET constraints in order to develop high quality optimized hits. We strongly believe that we have the required experience, right skills, funding (both public and from private companies) and collaborations to fulfill successfully the objectives of our ambitious project.

Points to improve and recommendations

The committee notes that we are not currently involved in EU networks and projects. In fact, we have submitted a EU FP7 Innovation proposal in the area of drug discovery in January 2013, the work passed the first review stage and we are now awaiting the final decision. We intend to continue our efforts in this direction.

We would also like to underline our strong international collaborations with recognized scientists, for instance: -cardiovascular diseases, the coagulation and complement cascades with Dr. Nicolaes, Netherlands; Prof. Dalback and Prof. Bloom, Sweden (PI from the silico side: the unit director).

-rare diseases with Prof. Alexov and Prof. Schwartz, USA; Dr. Ikeguchi, Japan (PI from the silico side: the team leader) -ADMET predictions with Pr. Pajeva, Bulgaria; Prof. Wiese, Germany; Prof. Baell, Australia (PIs: the team leader and the unit director).

Indeed, these fruitful interactions resulted in a total of 22 joint publications with our collaborator scientists since 2007.

NB

We would like to note that the correct number of HDR supervisors expected in 01/01/2014 is 3 (2 is mentioned in the Table ).

Also, it is written in the AERES report that Cdithem is a bioinformatics platform, in fact it is larger and is a Consortium for Drug Discovery & Chemical Biology dedicated to protein-protein interaction modulation employing several complementary methodologies: medicinal chemistry, cellular bioassays and protein chemistry and in silico predictions (the latter are ensured by members of the MTi team 3).

N3: 9 N4: 1 N5:

 91 Other permanent staff (without research duties) 8 Other professors (Emeritus Professor, on-contract Professor, etc.) 1 Other researchers from Institutions (Emeritus Research Director, Postdoctoral students, visitors, etc.spent at least 12 months in the unit Number of Research Supervisor Qualifications (HDR) taken Qualified research supervisors (with an HDR) or similar positions 8 2  Assessment of the unit Strengths and opportunities

N2: 1 N3: 1 N4:N6:TOTAL

 11 Pharmacologic profilingName of team leader: Ms Anne-Claude CAMPROUX & Mr Olivier TABOUREAU Workforce Permanent EPST or EPIC researchers and similar positions 1 1 Other permanent staff (without research duties) 1 1 Other professors (PREM, ECC, etc.) N5: Other EPST or EPIC researchers (DREM, Postdoctoral students, visitors, etc.) 1 2 Other contractual staff (without research duties) 1 students having spent at least 12 months in the unit 3 Number of Research Supervisor Qualifications (HDR) taken 0 Qualified research supervisors (with an HDR) or similar positions 3 3

  non-national networks (EU,…) Recherche de Molécules à visée Thérapeutique par approches in silico, MTi, Paris Diderot and INSERM, Mr Bruno VILLOUTREIX 5  Conduct of the visit Brion, 75013 Paris Conduct or programme of visit: 08:00 Welcome to the committee (15 min) 1. Centering of the committee 8:15 Preliminary meeting of the committee (closed hearing) (30 min) Attending: Committee members, AERES scientific delegate 2. Scientific part 8:45 Presentation of AERES evaluation and of committee members (Jacques BARATTI and Gilles LABESSE) 8:55 Presentation of the unit project: Bruno VILLOUTREIX (30 min + 30 min discussion) Attending: Committee members, AERES scientific delegate, representatives of Institutions and unit members 9:55 Scientific Presentation Team 1 -Pierre TUFFERY (20 min + 20 min discussion) Attending: Committee members, AERES scientific delegate, representatives of Institutions and unit members 10:35 Scientific Presentation Team 2 -Anne Claude CAMPROUX & Olivier TABOUREAU (20 min + 20 min discussion) Attending: Committee members, AERES scientific delegate, representatives of Institutions and unit members 11:15 Break (15 min) 11:30 Scientific Presentation Team 3 -Maria MITEVA (20 min + 20 min discussion) Attending: Committee members, AERES scientific delegate, representatives of Institutions and unit members 3. Meeting with representatives of Institutions 12:10 (30 min discussion with committee members) Attending : Committee members, AERES scientific delegate, representatives of University Paris Descartes (Marc BENEDETTI) and of INSERM ( Marie-Josèphe LEROY-ZAMIA and L LOMME) 12:40 Lunch -buffet / discussion (90 min)

Team workforce Number as at 30/06/2012 Number as at 01/01/2014

				2014-2018
				Number of
				project producers
	N1: Permanent professors and similar positions	1	1	1
	N2: Permanent EPST or EPIC researchers and similar positions	2	1	1
	N3: Other permanent staff (without research duties)	3	2	2
	N4: Other professors (PREM, ECC, etc.)
	N5: Other EPST or EPIC researchers (DREM, Postdoctoral students, visitors, etc.)	1	1
	N6: Other contractual staff (without research duties)	2	1
	TOTAL N1 to N6	9	6	4

Team workforce Number as at 30/06/2012 Number as at 01/01/2014

	Recherche de Molécules à visée Thérapeutique par approches in silico, MTi, Paris Diderot and INSERM, Mr Bruno VILLOUTREIX
		 Detailed assessments
		Assessment of scientific quality and outputs
		Doctoral students	5
		Theses defended	3
		Postdoctoral students having spent at least 12 months in the unit	3
		Number of Research Supervisor Qualifications (HDR) taken
		Qualified research supervisors (with an HDR) or similar positions	2	2

  (Segers et al. PNAS 2007; Dahlback c est un J Biol Chem 2008; Lagorce et al. Bioinformatics 2011; Blom et al., J Immunol. 2008; Zhe et al. J Am Med Inform Assoc 2013; Martiny et al. in "Predictive ADMET: Integrated approaches in Drug Discovery and Development", J. Wiley & Sons, Inc. 2013; etc).

Team-by-team analysis

 Statistics by field: SVE on 10/06/2013

In between the unit was moved

Assessment of scientific quality and outputs

This is a strong team with as research focus virtual screening and rational design of protein-protein interaction modulators with balanced ADME-Tox properties. The team comprises the unit director, who is clearly the most senior and recognized scientist in the unit.

The team has a number of national and international collaborations (although no direct involvement in EU projects at this time). They are involved in the Cdithem bioinformatics platform (IBISA label) to which they have contributed a rather unique resource about protein-protein interaction inhibitors.

The research output of the team over the last five years is very good. All team members are actively publishing (67 as a whole) and their work is well cited, indicating a good international impact. They have also published several key reviews that are being (and will most likely be) highly cited (3 in Drug Discovery Today; 1 Curr. Opin. Struct. Biol.). This is a highly visible team at the international level, publishing excellent quality research, both on methodology and application. Their expertise is well recognized as indicated by numerous oral contributions at conferences, editorial memberships of various journals and referee activities.

Assessment of the team's academic reputation and appeal

The team has quite a number of collaborations, both at the national and international level, in most case bilateral ones.

They have been successful in national funding and got support from industry as well. Although, their strong national network is not reflected in participation in large EU projects, they do have however connections to various EU projects/networks (e.g. eTOX).

The team members are also active as reviewer for well-known journals in the field and for funding agencies, including various EU programmes. All this is indicative of a good visibility and reputation of the team.

Young and senior members of the team have a well-established international reputation and visibility, with significant contributions to the field, as reflected in citation analysis.

Assessment of the team's interaction with the social, economic and cultural environment Team 3 members deposited several patents, and manage several collaborations and support from the industry. Team 3 has developed, published and made available to the whole community several original softwares dedicated to ligand docking (MS-Dock) or ADME-Tox predictions (FAF-Drug). Similarly, their original database will be essential for the emerging field of protein-protein interface inhibition.

The research topics concentrate around human health and as such have are socially highly relevant.

The targets they choose to concentrate on for the coming years are all highly relevant and associated with various important diseases.

Assessment of the team's involvement in training through research

All team members are deeply involved in teaching including the European master for in silico drug design, and in the doctoral school on drugs which is an inter university school.

The head of the unit is board member of this doctoral school and will take co-directorship in the future.

The team has further trained several PhD students and post-docs over the last years.


1 Introduction History and geographical location of the unit

The Inserm unit U770 entitled Hemostasis and vascular cell dynamics was created in 2006 under the direction of Mr Jean-Marie FREYSSINET and is linked with the Université Paris 11. This unit was a continuation of the Inserm unit 143 Hemostasis and thrombosis created in 1987 under the direction of Ms Dominique MEYER. It is currently under the direction of Ms Cécile DENIS since September 2010 and is organized into two teams: team 1, devoted to Structurefunction relations and regulation of hemostatic proteins (Ms Cécile DENIS), and team 2 focused on Cellular Physiopathology of Hemostasis (Mr Jean-Philippe ROSA).

The unit is located on the ground floor of the Gregory Pincus Inserm building in Bicêtre Hospital and has a surface of 995 m 2 . An additional 35 m 2 is allocated to a L2 laboratory for tissue culture and 10 m 2 to a radiation-safety laboratory, both on the third floor of the building. A common Institut Fédératif de Recherche (IFR 93) animal facility is located in the basement of the building.

The team EA4531 Engineering of hemostasis protein with therapeutical potential was created in 2010 under the direction of Ms Delphine BORGEL. This team is located at the Faculty of Pharmacy of the Université Paris 11 in Chatenay Malabry and has slowly grown between 2010 and 2013 to reach its current composition.

The team led by Ms Delphine BORGEL will join the Inserm unit U770 in January 2015 in the Gregory Pincus Inserm building (Bicêtre Hospital). The proposed new research unit entitled Hemostasis-Inflammation-Thrombosis will be directed by Ms Cécile DENIS and is the result of a complete re-organization of current research groups leading to the proposal of two new research teams. The future team 1, Integrative hemostasis: from fundamental aspects to hemorrhagic disorders (Ms Cécile DENIS), will encompass current U770 team 1 and part of current U770 team 2. The future team 2, Thrombosis and inflammation: from pathophysiology to therapeutics (Ms Delphine BORGEL) will be formed by the fusion of EA4531 and part of the current U770 team 2.

Management team

The management committee comprises all permanent researchers and one elected representative of each of the following categories of personnel, administrative, research technicians and engineers, students and post-docs. The committee meets at least once a year to discuss the budget, and more frequently if required.

There is no formal management committee for EA4531 given the small size of the team and the main decisions are discussed with all members.

Individual teams and the U770 unit have weekly meetings to discuss scientific results with all personnel. Every year a general health and safety meeting is organized by the risk prevention assistant.

AERES nomenclature 2  Overall assessment of the interdisciplinary unit

The Inserm unit U770 has a long standing experience in the field of hemostasis and thrombosis with a strong implication in von Willebrand (vWF) related diseases and hemophilia. The scientific output of the unit is excellent and the published work has clearly advanced the field, in particular on vWF structure-function analysis and clearance as well as on the physiopathology of platelets. The unit benefits from a strong national leadership and was able to maintain an excellent international reputation over time by developing both original and competitive basic research and useful clinical applications (diagnosis/prognosis tools and therapeutic interventions). Despite the fact that EA4531 is a relatively young team, the strong orientation to translational research has produced important achievements transferable to medicine, in particular modified antithrombins as antidotes active against heparin derivatives. Altogether, the new combined unit will take a place of excellence in the field of hemostasis and thrombosis.

Strengths and opportunities related to the context

The scientific production is excellent, considering the impact factors of the publications, the citations and medical impact of the discoveries in the field of hemostasis and thrombosis.

The complementarity between the two teams of the Inserm U770 group is remarkable and is strenghtened by constant re-organization to favor the emergence of new themes while keeping a strong focus on structure-function relationships and regulation of hemostasis and cellular physiopathology of hemostasis.

The unit has been able to attract and recruit 1 foreign senior researcher and 1 young full time researcher, as well as one new group leader by the arrival of the team 4531 for the next contract.

The academic reputation is emphasized by regular invitations of several members of the unit to major national and international conferences and active participation in national groups and to the prestigious International Society on Thrombosis and Haemostasis.

The unit has developed an excellent level of international academic collaboration and strong interactions with companies, giving the unit an excellent efficiency to raise external funding.

The unit is involved in two national reference centers for rare diseases, and in patient's organizations.

There is a very good balance between the different research axes as well as a good balance between experimental and clinical research and this is supported by a highly efficient management. The director deserves encouragement in her leadership as regards the definition of priorities and the balance between authority and delegation of responsibilities and in her availability for all personnel.

The unit actively participates in the training of PhD students and the recruitment of post-doctoral fellows is impressive.

The new organization is interesting and coherent. The projects are solid, original and well-focused. The unit will be composed of two well-balanced and complementary teams and the reorganization proposed to integrate the team EA4531 has been well prepared. The future strategy is defined by paying attention to maintain an excellent interaction between experimental and clinical research and to further improve the competitiveness of the unit through the next contract.

Weaknesses and threats related to the context

As mentioned in the strengths of the Inserm unit U770, the recruitment of post-doctoral fellows is excellent but few PhD students have completed their theses so far. The retirement of experienced technicians and engineers during the next contract may also participate to weaken the teams.

Despite important investments to obtain expensive equipment and access to outside platforms, some difficulties to develop state-of-the art technology in imaging and analysis of transgenic animals remain. Such ambitious platforms may be shared with the Federative Research Institute.

Recommendations

Given the ability of the unit to develop external collaborations and connections with international groups, the establishment of international networks leading to collaborative publications in top general journals and european funding should be considered.

Diversity of the research themes may be a concern, especially because projects of future team 1 are very solid and successful and projects of future team 2 are original and more risky. It would appear essential that team 2 have a huge benefit of reciprocal interactions with team 1 to more clearly identify and focus on competitive projects, in particular clearance of natural anticoagulants and implication of platelets in vascular permeablity and sepsis.

 Detailed assessments

Assessment of scientific quality and outputs

The main research scope of the unit is to identify new molecular mechanisms involved (I) in the biology of the vWF/factor VIII complex, (II) in the cellular physiology and pathology of hemostasis focusing on platelets, and (III) in the relation between structure and function of main inhibitors of the coagulation system. Although the search for molecular mechanisms of hemostasis is a very competitive and busy field today, the projects are very original mainly because of the development of appropriate relevant animal models and the opening up of basic research discoveries towards new specific therapeutic strategies in hemophilia, von Willebrand diseases, platelet-related diseases, heparin therapy and severe sepsis.

The scientific production is excellent, with a total of 193 publications and 9 book chapters. In accordance with the aim to privilege quality over quantity, 34 original articles have been published in journals with IF>9 (including 13 articles with members in leading positions) and around half of the articles are published in journals with IF>5. Among these papers, some publications merit being highlighted based on their originality, methodological breakthroughs and impact: the association of type 2B von Willebrand disease with thrombocytopathy (J Clin Invest 2013), identification of LRP1 as a clearance receptor for vWF under flow (Blood, 2012), development of mouse models for type 2B von Willebrand diseases using hydrodynamic gene transfer (Blood 2010 and Blood 2013), identification of new mutations inducing quantitative and qualitative defects in vWF (Blood 2013), development of a recombinant antithrombin with a potent antidocte activity to heparin derivatives (Blood 2011).

Remarkably, the high level of research published in top hematology journals is evenly balanced between the different groups.

Assessment of the unit's academic reputation and appeal

Members of the EA4531 team participated in two Leducq transatlantic research networks and the team is partner to an ERC advanced grant.

The attractiveness of the research groups is excellent: 16 post-doctoral fellows and 3 visiting scientists have been hosted since 2008. The Inserm unit U770 has succeeded in recruiting two full time researchers, one high level foreign senior scientist and one young scientist. The arrival of the EA4531 group from the faculty of Université Paris-Sud for the next 5-year contract also illustrates the attractiveness of this unit.

All team leaders and several collaborators are regularly invited worldwide to give scientific seminars, with 22 national and 29 international conferences including one plenary lecture at the World Federation of Hemophilia, two state-of-the-art lectures and two symposium lectures at the International Society on Thrombosis and Haemostasis (ISTH) and one symposium lecture at the American Society of Hematology.

Several scientists from the unit have obtained prizes and distinction awards.

The head of the unit is a member of a specialized scientific committee at Inserm and co-chair of the subcommittee of the ISTH on animal models. A team leader is also a member of the board of the ISTH.

The scientists from the unit have developed a network of collaborations with all research groups in France in the field of hemostasis and thrombosis, and internationnaly with prestigious academic research groups and companies, leading to a high number of collaborative publications in high ranking journals in the field.

Assessment of the unit's interaction with the social, economic and cultural environment Four European patents have been filed during the past contract, and 5 international patents have been published, among which one has been licensed to a major pharmaceutical company.

Many recent discoveries have clear potential for medical impact, e.g. the development of a modified factor X molecule as a bypassing agent in hemophilia A and B with inhibitors, the demonstration of the negative regulatory role of apelin on platelet reactivity, and the development of a recombinant antithrombin as an antidote for all heparin derivatives.

Several members are involved in patients' organizations which are very important in the field of hemophilia and in rare disorders. The fact that the unit is associated with two national reference centers for rare diseases, the reference center for von Willebrand disease and the reference center for thrombotic microangiopathies, is of major interest for the development of clinical projects.

The fund raising is excellent (around 750 000 euros/year). There is a long lasting collaboration with biotech and pharmaceutical companies (18 contracts during the period 2008-2013, among which 2 CIFRE Contracts for PhD students).

Assessment of the unit's organisation and life

The unit benefits from a highly efficient management. The unit has experienced important changes during the past contract due to relocation of several members and recruitment of permenant Inserm researchers. Organizational transitions have occurred swiftly to successfully preserve a competitive, productive and well organized unit concerned with coherent, focused and highly connected projects. There is a good equilibrium between the different research axes and the level of interaction between groups within the unit is excellent as demonstrated by high level joint publications.

The personal interactions appear also very good and are favored by the group discussions with the students/post doctoral fellows and technicians. The unit has made the strategic choice to organize itself into groups focused on a research axis with their dedicated technicians to ensure the continuity of essential and specific know how. Although a potentially unfavorable approach for the development of ambitious platforms with new state-of-theart technologies, it provides a good, friendly and collegial atmosphere between each of these key players.

A strong point of the unit is that it houses a genetically-modified animal facility and it has access to unique cohort of patients, thus providing adequate resources for the integration and interaction of basic and clinical research initiatives.

The financial rules are clear in terms of distribution of recurrent funding between transverse activities and between teams, and established at the level of the management committee.

Assessment of the unit's involvement in training through research

During the past contract, the unit hosted 15 PhD students, over 10 have defended their thesis so far, and 34 master students were trained. PhD students are affiliated to the doctoral school Innovation thérapeutique: du fondamental à l'appliqué (ED 425) or Signalisation des réseaux intégratifs en biologie (ED 419,BIOSIGNE). The unit has successful access to different sources for post doctoral fellows (16 since 2008) and PhD students.

The meeting with the students revealed a high satisfaction regarding the unit, its organization and their position. Their guidance is favored by the organization of weekly meetings with all members, and group discussions with their supervisors.

The impact of the unit on academic appointments is excellent as demonstrated by the recruitment of an Inserm researcher in 2011 and identification of 2 motivated and talented young scientists for future recruitments.

Assessment of the strategy and the five-year plan

Convergence of the scientific interests of the U770 Inserm unit and the EA4531 and the wish to foster research within the field of hemostasis and thrombosis in France have primarily driven the proposal for a new merged research unit composed of two complementary teams with a definitely original, important and ambitious project. This dynamic appears evident and timely, and complementary inputs should provide synergy and cross-fertilization to respond to a strong international competition.

The unit will be composed of two complementary teams, one focused on the pathophysiological aspects of hemostasis, particularly hemorrhagic disorders related to coagulation and platelet defects and the other on the reciprocal interactions between inflammation and coagulation in vascular diseases such as sepsis and ischemiareperfusion. The unit proposes a strategy well balanced between the pursuit of ongoing, validated and solid projects, and riskier innovative and challenging projects, with a genuine attention being given to the translational aspects, interaction between experimental and clinical research and valorization of the findings.

General feasibility is high and secured by the past year's achievements of the unit in terms of reaching the proposed goals and raising funding from several agencies and private companies. Feasibility and overall quality of the projects are also well supported by existing technical facilities, in particular for genetically modified animal models and by a growing network of external collaborations for new technologies, and access to patients. The planned research has thus the potential to deliver pivotal results and breakthroughs in the next 5 years. The projects will be developed by internationally recognized leaders, but an expansion of the currently limited human resources in terms of PhD students and technicians should be pursued.

The SWOT analysis is extensive and adequate. The unit has shown that it can adapt to the evolution of the research in its field to maintain its leading international position.

4  Team-by-team analysis The team has a long standing expertise in the field of hemostasis and is internationally renowned in the search for molecular mechanisms of hemorrhagic disorders related to vWF/factor VIII proteins and platelet defects, with projects ranging from basic in vitro and in vivo approaches to human applications.

The research has produced major breakthroughs and led to the emergence of inventive concepts and tools for experimental models and therapeutic strategies. The most innovative findings include:

1) The opening of the hydrodynamic gene transfer technique towards the development of mouse models for type 2B von Willebrand disease (1 Blood in 2010 and 2 Blood in 2013). Such methodological research has paved the way for the in vivo analysis of vWF function.

2) The demonstration that the von Willebrand disease type 2B mutation p.V1316M alters platelet signaling through inactivation of Rap1 small G protein and inhibition of the inside-out activation of the integrin (J Clin Invest 2013).

3) The identification of the protective role of N-glycosylations in the activation peptide of factor X on rapid clearance (PloS ONE 2012), of the involvement of Siglec-5 in the catabolism of factor VIII/vWF complex (Haematologica 2012) and of LRP1 as a clearance receptor for vWF under flow (Blood 2012).

4) The identification of new mutations in the A3 domain inducing quantitative and qualitative defects in vWF (Blood 2013) and the construction of a human-murine chimeric vWF to evaluate the anti-thrombotic potential of monoclonal antibodies to vWF (Blood 2012).

5) The development of a thrombin-activatable factor X protein with a long half-life for hemophilia A and B treatments (international patent with exclusive license).

The elucidation of the key role of the JNK1 signaling pathway in platelet secretion and thrombus formation (Blood 2010) and the analysis of platelet morphological (macrothrombocytopenia and abnormal granule distribution) and functional (altered adhesive and secretory properties) anomalies in filaminopathy A (Blood 2011 and Arterioscler Thromb Vasc Biol 2013).

The output is very stable at a high level and the recent paper in J Clin Invest illustrates the ambition of the team. The reports include 119 original articles (28 in journals with IF>9 and 50 in journals with IF>5). Members of the team are first/last authors of 47 papers, including 9 in Blood and 1 in J Clin Invest. In addition, results have been communicated at several top international meetings.

Assessment of the unit's academic reputation and appeal

The senior scientists are all opinion leaders at the international level in their respective research fields and they have set up a large number of pertinent national (20) and international collaborations (15), in basic science and also in clinical investigation. The team leader co-chairs the Scientific and Standardization Committee Animal, Cellular and Molecular Models of the International Society of Thrombosis and Hemostasis (ISTH). Another team scientist is member of the ISTH council and chairs the World Health Organization (WHO) -ISTH Standards Liaison Group. A third team scientist is member of the organizing committee of the Groupe d'Etude sur l'Hémostase et la Thrombose (GEHT) and member of the organizing committee of the Société Française d'Hématologie (SFH).

Members of the team have been invited to give 19 conferences at national meetings and 28 lectures or conferences at international congresses of prestigious societies, the ISTH (2 state-of-the-art lectures, 2 symposium lectures and 3 conferences at the Scientific and Standardization Committees), the World Federation of Hemophilia (1 plenary lecture and 1 symposium lecture), the American Society of hematology (1 symposium lecture), the International Society for laboratory Hematology (1 symposium lecture) and the Bari International Conference (3 plenary lectures and one conference). Members of the team have received 9 inter(national) awards for the quality of their research and presentations including the Prize Danièle Hermann de la Fondation de Recherche Cardiovasculaire, the valorization prize of the Université Paris-Sud, 1 young investigator award from the ISTH and 3 young investigator prizes of the GEHT.

The quality of the work has also been highlighted by a high rate of success in getting funded by excellent and highly visible agencies. Members of the team have been or are coordinators of 5 ANR grants (2 ANR Blanc, 1 ANR Emergence Bio, 1 ANR chaire d'Excellence and 1 ANR Programme Cardiovasculaire, obésité et diabète (COD)).

The team leader is a member of the CCS4 Inserm committee and is a member of the ethical committee for animal experimentation n°26. Two scientists are manager and member respectively of the animal facility committee of the IFR 93. Another scientist of the team is member of the pilot committee of l'institut thématique multiorganisme (ITMO) Immunology-Hematology-Pneumology. Members of the team have been working as reviewer of grants or experts for several national and international institutions (ANR, AERES, health ministry, …).

The team was able to attract and recruit a high-level full-time foreign researcher and a French young scientist (the latter will joint team 2 for the next contract) and is very appealing for post doctoral fellows (14 since 2007). In the period 2012-2013 the team also welcomed 3 visiting foreign scientists for one or two months.

In the period 2009-2013, the team authored 31 reviews in qualified international journals and 9 book chapters. A team member is also an academic editor of PloS ONE. All senior scientists act as reviewers for several internationalscientific journals.

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

Their research has led to 8 patents:

-The work on the thrombin-activatable factor X protein for the treatment of blood coagulation disorders has been used to generate an international patent that has been licensed to a major pharmaceutical company and a phase I clinical trial is scheduled for the end of 2014 or at the beginning of 2015.

-The team is the inventor in 3 European patents that are focused on anti-vWF antibodies exhibiting antithrombotic potential.

-Two international patents related to polypeptides as apelin inhibitors and an apelin receptor agonist for preventing platelet aggregation respectively have been filed in 2012.

-The 2 last inventions relate to furin as a marker for rheumatoid arthritis and the quantitation of cell-derived microparticles.

The research of this team has had strong impact on the clinical and public health environment. The coordination of the French Reference Center for von Willebrand disease and of the national laboratory for ADAMTS13 investigation of the Reference Center for Thrombotic Microangiopathies (National Plan for Rare diseases supported by the French Ministry of Health) allowed a privilieged access to a wide range of patients' data and thereby (I) the validation of a new commercial ELISA for the diagnosis of type 2N von Willebrand disease, (II) the identification of vWF mutations and (III) the establishment of a predictive score of ADAMTS13 severe deficiency and of a predictive model for death in patients with thrombotic thrombocytopenic purpura linked to a severe ADAMTS13 deficiency. The work on microparticles has led to the development of an enzymatic assay to measure blood-borne tissue factor activity, licensed to Hyphen Biomed.

The team is involved in 5 clinical studies focused on inflammation and dysregulation of hemostasis, and Postpartum hemorrhage and is affiliated to the DHU (Département Hospitalo-Universitaire) TORINO (Thorax Innovation).

Five members of the team are involved in the "Association Française des Hémophiles". The team has also interactions with the association "Vaincre la Mucoviscidose" and the association ADIRAL.

The team had 7 contracts during the period 2009-2012 with LFB Biomédicaments and 8 contracts with other non-academic partners. These connections with industrial partners represent a substantial financial support for the team without unbalancing the research activity.

The fact that several members of the team are respected as international leaders in the field of hemostasis and thrombosis is of major importance for the development of proficient national and international collaborations, also providing academic fund raising.

Assessment of the unit's organisation and life

The team is well organized into coherent and logical scientific objectives and benefits from distinct experience that are shared among the subgroups. For the future contract, the team will result from the merging of former U770 team 1, highly focused on von Willebrand disease and hemophilia, and two members of former U770 team 2 who are specialists in platelet physiopathology and signaling. The principal scientists of the previous teams are developing different but highly connected projects. Thus, the scientific potential and complementary inputs are great as well as the promises for medical impact and valorization.

Recruitment of young researchers is actively addressed. The number of PhD students (1 full time and 1 half time) is low for five full time senior researchers.

Interactions with non-permanent young investigators are based on regular group meetings together with individual discussions. A weekly meeting gathers all the staff of the team in which ongoing work and future research are presented either by students or post-docs and discussed by everyone.

Assessment of the unit's involvement in training through research

The team is affiliated to the doctoral schools ED 425 (Innovation thérapeutique: du fondamental à l'appliqué) and ED 419 (Signalisation des réseaux intégratifs en biologie). Seven PhD theses have been completed between 2008 and 2013.

The team has trained 13 post-doctoral fellows over the past years. One of them has been recruited as an Inserm researcher in 2011, another has been presented for recruitment at Inserm in 2013 and his ranking is promising, finally a third one has been identified for future recruitment and is now in a research laboratory in the USA to expand her expertises.

Looking at the list of PhD students and post-doctoral fellows, it seems that few of them are of foreign countries. The team has the infrastructure and competence to host foreign researchers in the future.

Assessment of the strategy and the five-year plan

The new team now entitled Integrative hemostasis: from fundamental aspects to hemorrhagic disorders maintains a focus on hemorrhagic disorders related to coagulation and platelet defects and the translational aspect is very important. The merging of the current U770 team 1 and part of current U770 team 2 will lead to the formation of an ideal platform of expertises on factor VIII/vWF complex, vitamin K-dependent proteins and platelets. The five-year plan is built on strong existing track records and the proposal is thus appealing and competitive at the international level.

The scientific project has four major axis:

1) The pathogenesis of congenital or acquired von Willebrand disease: one of the main objectives is to further examine the effect of VWF-type 2B mutants on megakaryocytopoiesis and thrombocytopoiesis as well as on platelet function, and thereby to design novel strategies against the bleeding tendency; a second translational objective is to identify new mutations in von Willebrand disease and their impact on functional assays; the two last main objectives are to unravel the role of LRP1 in vWF clearance, and to propose therapeutic approaches for patients with excessive vWF degradation.

2) The pathogenesis of hemophilia. The objectives are focused on the mechanisms of clearance of factor X or factor VIIa, and the expression of factor VIII variants in factor VIII-deficient mice to evaluate their hemostatic potential in bleeding and thrombosis models.

3) The pathogenesis of inherited platelet disorders. The objectives are derived from previous work and encompass the analysis of platelet function and signaling in patients with mutations in the FLNA gene, the genotypephenotype relationship of mutations in the NBEAL2 gene in the gray syndrome platelet, the molecular analysis of the impaired activation of the small GTPase Rap1 in the von Willebrand disease type 2B with the mutation p.V1316M, the functional impact of the deletion in the Ca 2 +-activated anion transporter involved in anionic phospholipid scrambling associated with the Scott syndrome and the identification of platelet signaling and secretion defects in patients with unknown thrombopathies.

4) The role of von Willebrand factor beyond hemostasis. The aim is to invetigate the absence of vWF-induced apoptosis of tumor cells via the generation of genetically modified animals, and to examine the role of the interaction between vWF and osteoprotegerin in bone protection.

The project is straightforward and ambitious but also realistic and feasible. The team will benefit from original methodologies or technologies running in the laboratory such as the hydrodynamic gene transfer approach to the development of relevant in house animal models, an efficient network of local, national and international collaborations, and direct access to patients through internal interactions with physicians. The project shows high feasibility in terms of financial resources since the team has raised funding from several agencies and industrial partners. The project has great potential considering the preliminary data already obtained. So all the conditions are gathered to search for breakthroughs.

The team leader identified clearly the potential and limitations of the project and proposes some solutions in the SWOT analysis.

Conclusion  Strengths and opportunities:

Research team internationally recognized for its high standards and long-standing experience in the field of hemostasis and thrombosis. Substantial contribution to knowledge and strong implications for treatment of von Willebrand disease and hemophilia.

Highly focused, original and translational research with molecular, cellular, animal and clinical approaches.

Very effective leadership and organization of the team as indicated by the national and international network of collaborations and the excellent training of post-docs leading to recruitment of young researchers.

Important valorization of research and interactions with non academic partners.

Excellent level of external funding.

 Weaknesses and threats:

Limited support by permanent technical staff due to the retirement of experienced technicians and engineers may be a danger for research continuity.

Crucial requirement for animal experimentation in a context where animal handling will become more and more controlled and restricted.

Relative lack of state-of-the art new technologies platforms on site.

 Recommendations:

The team deserves encouragement in its strategy to recruit young researchers.

Attention should be paid to the application for European grants through the network of international collaborations.

An additional effort needs to be made to reinforce the team with PhD students.

The team may start thinking about the creation of a start-up given the number of patents issued by team leaders.

 Detailed assessments

Assessment of scientific quality and outputs

During the past contract, the team has developed very well with translational projects focused on coagulation inhibitors, the protein C/protein S pathway and antithrombin, to address important questions on the relations between inflammation, hemostasis and thrombosis.

The research has generated original findings disclosing the role of protein S deficiency and Gas6 in pathology and highlighting the therapeutic potential of antithrombin-derived variants. The major contributions are:

1) The identification of protein S gene mutations (Human Genet 2009 and2010) and viral infection (AIDS 2009) as mechanisms of protein S deficiency and the generation of the first protein S conditional deficient mice (Blood 2009).

2) Evidence of an anti-atherogenic role of Gas6 through the reduction of the pro-inflammatory phenotype of vascular smooth muscle cells (Thromb Haemost 2012).

3) The demonstration of extensive vascular damage with multifaceted prothrombotic local imbalance and bacterial pathogen adherence at sites of maximal damage in adult purpura fulminans (Am J Respir Crit Care Med 2013).

4) The production of modified antithrombins devoid of intrinsic anticoagulant activity and with increased heparin affinity as specific antagonists of heparin analogs (Blood 2011 and J Thromb Haemost 2013).

In the period 2008-2013, the team published 35 original research articles (7 in journals with IF>9 and 9 in journals with IF>5). Members of the team are first/last authors of 11 papers, including 2 in Blood and 1 in Am J Respir Crit Care Med.

Assessment of the unit's academic reputation and appeal

Several members of the team have international connections in their field. The team participated in two transatlantic networks, the Leducq Transatlantic Network of Excellence on Atherothrombosis Research (LENA) and the Leducq International Network Against Thrombosis (LINAT) both including 3 European and 3 American teams. The team was also invited to participate in an ERC advanced grant TERNANOMED (Terpenoylation: an original concept for the discovery of new nanomedicines). The team leader is member of the committee Pharmacology and therapeutics of the GEHT.

Members of the team have been invited as speakers in national (3) and international congresses (3). The team leader has been the organizer of the Annual Scientific Meeting of the European Society for Clinical Investigation (2008) of the GEHT Meeting in March 2013.

Members of the team have received distinctions for their innovative research (prize from the Fondation SGAM pour l'innovation thérapeutique and the valorization prize of the Université Paris-Sud) and the quality of their presentations (2 young investigator awards of the ISTH).

The team leader is coordinator of an ANR project (RPIB grant; recherches partenariales et innovations médicales). She is also a reviewer of grants for the ANRT.

A team member is the manager of the gestion committee of the L2 facility of the IFR 93 and a member of the regional and national committee for health, security and working conditions. The team leader and another scientist of the team are members of different councils or committees of the Université Paris-Sud.

The team has published 4 reviews in the evaluated period. Several members are reviewers of internationalscientific journals in the field of hemostasis (Blood, J Thromb Haemost, Arterioscler Thromb Vasc Biol).

Assessment of the unit's interaction with the social, economic and cultural environment Three patents have been filed in the past 5 years: the inventions related to mutated antithrombins has led to 2 international patents and the work focused on nanoparticles based on bioconjugate of glycosaminoglycans has been submitted to the European office in 2012.

The follow-up studies for the patent on mutated antithrombins for treating or preventing coagulation disorders are supported by a partnership with industry (LFB Biotechnologies) together with an ANR grant (RPIB) to generate recombinant antithrombin-derived variants. The team has a contract also with another non-academic partner. Most of the funding of the team is provided through these interactions.

The team leader is a senior consultant for a pharmaceutical company since 2011 (pharmacology of rivaroxaban) and for LFB (Protein C and severe sepsis).

A professor, who joined the team in September 2012, is vice-president of the foundation Martine Midy (for cancer research).

Assessment of the unit's organisation and life

The team is led by the former team leader of EA4531 and is well balanced in terms of staff composition. The team has coherent scientific objectives, with complementary research projects focused on coagulation inhibitors and the interaction between inflammation and hemostasis in the pathogenesis of severe sepsis and ischemia/reperfusion injuries.

The team is going to experience changes for the next contract due to the relocation of two young researchers of former U770 team 2. It is anticipated that this alliance will work very well and allow the emergence of new research directions based on their current research themes and/or their expertise on platelets.

Given the small size of the team, the main decisions are discussed by all members.

A weekly meeting with all the staff is organized for the presentation and discussion of ongoing work and future plans either by senior scientists or by students.

Assessment of the unit's involvement in training through research

The team is affiliated to the doctoral school ED 419 (Signalisation des réseaux intégratifs en biologie). The team has trained 2 post-doctoral fellows and 5 PhD students. These are excellent results given the small number (2) of effective PhD student supervisors. Therefore it would be important for the young full time researchers to obtain their "Habilitation à diriger des recherches".

The team is fully involved in young student training. Six 2 nd year Masters students, 13 first year Masters students and 1 3 rd year License student have been trained over the past years.

The team leader actively participates in teaching tasks. She is responsible of the Chair of Hematology at the Faculty of Pharmacy of the Université Paris Sud. All the members of the team participate actively in the teaching of hematology (more than 750 hours a year). They also participate in the teaching of different courses (M2 level) of the specialities Biologie Vasculaire, Athérosclérose, Thrombose, Hémostase and Biologie, Physiologie et Pharmacologie de la Circulation et de la Respiration in the Master Biologie Cellulaire Physiologie et Pathologies (BCPP) at ParisDescartes/Paris Diderot.

Assessment of the strategy and the five-year plan

The team entitled Thrombosis and inflammation: from pathophysiology to therapeutics will benefit from the reorganization of the unit and the relocation of two young motivated full time researchers to propose an original and challenging project from the molecular scale to the development of diagnosis and therapeutic approaches.

The project reveals a relatively broad scope including four main axis, taking advantage of genetically modified animals and of the clinical activity of members of the team:

1) The role of endothelial sarco-endoplasmic Ca 2+ -ATPase SERCA3 in severe sepsis and ischemia/reperfusion. This part of the project aims at characterizing the regulation by SERCA proteins of calcium dependent pathways involved in endothelial cell dysfunction, and is based on an in vitro cellular approach along with an in vivo approach with mice invalidated for SERCA3.

2) The second axis goes in line with the previous work of the team on antithrombin and is focused on the identification of the molecular network responsible for the protective role of antithrombin on endothelial glycocalyx and the characterization of the ability of recombinant antithrombin-derived variants to increase this cytoprotective effect. Another objective is to evaluate whether neutrophil extracellular traps modulate the concentration and/or activity of antithrombin and thereby coagulation in sepsis and inflammation.

3) The third axis consists of deciphering the role of the protein Z/protein Z-dependent protease inhibitor system on the endothelial glycocalyx and as a modulator of the thrombogenic potential of neutrophil extracellular traps.

4) The last axis is devoted to exploring the role of platelet heparanase in platelet adhesion and in vascular permeability and glycocalyx integrity during inflammatory responses.

The project shows high feasibility in terms of financial resources. The team will benefit from academic and non-academic funding and is a member of an IDEX (Initiative d'Excellence). The only problem is to assess the feasibility of maintaining all new research lines simultaneously while remaining well positioned in international competition. However, the team leader has a very good capacity for adaptation and change in strategic directions in response to results of ongoing research and for managing the team's expansion. Some potential problems and limitations have been well identified in the SWOT analysis. It is emphasized that a significant part of the project is new, ambitious and highly competitive.

Conclusion  Strengths and opportunities:

Important contributions in the field of coagulation inhibitors.

Strong interactions with physician scientists whose clinical responsabilities are critical for the translational nature of the research.

Timely reorganization to take advantage of close collaboration with top full time researchers of team 1 and their expertise in animal models and platelets.

Important valorization of research.

Excellent fund raising.

 Weaknesses and threats:

The projects on endothelial glycocalyx and neutrophil extracellular are original and ambitious but may be considered as being of a high risk since they are currently based on limited preliminary data.

The number of different projects is elevated given the relatively small size of the team.

High competition in the field so that the objectives could be out-dated when they are reached.

 Recommendations:

It is important for the team to better establish the priorities of the projects considering the critical mass of researchers in the team.

A strong interaction with team 1 and other international leaders in the field of inflammation and thrombosis should help reaching the fixed obejctives in a context of high international competition.

The team should aim at attracting post-docs.

The team is advised to reinforce its international position.

  The involvement of the unit at various levels in teaching and in international training networks is remarkable. Several members of the unit are involved in the coordination and/or teaching of the specialities Biologie Vasculaire, Athérosclérose, Thrombose, Hémostase and Biologie, Physiologie et Pharmacologie de la Circulation et de la Respiration in the Master Biologie Cellulaire Physiologie et Pathologies (BCPP) at Paris Descartes/Paris Diderot. The unit has created a teaching module Initiation à la Biologie vasculaire (UEM 95H) in the Master Médicaments et autres produits de santé at Paris-Sud. The unit is also partner of the Princeton International Internship Program.

  Hémostase intégrative : des aspects fondamentaux aux maladies hémorragiqque Name of team leader: Ms Cécile DENIS Workforce Permanent EPST or EPIC researchers and similar positions 3 5 N3: Other permanent staff (without research duties) 3 (2,5) 7 (4,8) N4: Other professors (PREM, ECC, etc.spent at least 12 months in the unit 11 Number of Research Supervisor Qualifications (HDR) taken Qualified research supervisors (with an HDR) or similar positions 5 6  Detailed assessments Assessment of scientific quality and outputs

  The team is fully involved in young student training. Twelve 2 nd year Masters students, 3 first year Masters students and 4 3 rd year License students have been hosted over the past years. Three bachelor students coming from Princeton University have been trained during the summers of 2010-2012.Several researchers actively participate in teaching tasks in different Masters and "Diplôme d'Université" (DU) courses. The team leader coordinates the speciality Biologie Vasculaire, Athérosclérose, Thrombose et Hémostase in the Master Biologie Cellulaire Physiologie et Pathologies (BCPP) at Paris Descartes/Paris Diderot and a member of the team organized a module Biologie cellulaire et moléculaire des plaquettes in this speciality (M2 level). All members of the team also actively participate in the courses of this Master. The unit has created a teaching module Initiation à la Biologie vasculaire (UEM 95H) in the Master Médicaments et autres produits de santé (M1 level) at Paris-Sud. A member of the team also coordinates a DU dedicated to Hematology (120 hours a year including 70 hours focused on hemostasis) at the Medical School of the Université Paris Sud.

 Supervising bodies' general comments