Institut Clinique de la Souris (PHENOMIN-ICS)

PHENOMIN-ICS (Mouse Clinical Institute) is a research infrastructure of excellence providing a comprehensive set of specialised services to academic and industrial scientists. PHENOMIN-ICS services will ultimately help the scientific community in the use the mouse model, first to develop a complete functional annotation of the human genome and second to better understand human diseases and their underlying physiological and pathological basis. PHENOMIN-ICS offers to generate genetically modified mouse models on a high-throughput and large scale basis, and then to provide a first phenotyping characterisation, either standardised or more specific, for a better understanding of disease mechanisms and for the development of new therapeutic treatments.
Since its founding in 2002, more than 1300 mouse models have been created, PHENOMIN-ICS being therefore the most important transgenic mouse production unit in France. To date, PHENOMIN-ICS is able to generate around 200 genetically modified mouse models per year. The phenotyping platforms of PHENOMIN-ICS area, adapted to study genetically modified mouse models, can also be used for preclinical studies, including the validation of therapeutic targets, as well as pharmaceutical and toxicological studies in mice.


PHENOMIN-ICS consists of three highly interactive departments :

  • Genetic Engineering and Model Validation : engineering and generation of customised genetically modified mouse models, generation of genetically modified ES cells, genotyping, analysis of gene expression, model validation by molecular analysis, CRISPR/Cas9 nucleases technology
  • Mouse Supporting Services : ethics and animal welfare, microinjection (ES cells, DNA), husbandry, state-of-the-art breeding, mouse cohorts production, archiving by cryopreservation of embryos or sperm, mouse rederivation, in vitro fertilisation (IVF), distribution
  • Phenotyping : neurobiology and behaviour, cognition, cardiovascular system, exploration of lung functions, haematology and clinical chemistry, metabolic exploration, histopathology and embryology

 

PHENONIM-ICS is the co-founder of PHENOMIN infrastructure, founded by a future investment grant in 2011, together with PHENONIM-TAAM (Orléans) and PHENOMIN-CIPHE (Marseille), enabling a coordination of their complementary activities dedicated to phenogenomic. Through this involvement, PHENOMIN-ICS contributes to European consortium InfraFrontier I3, to the International Mouse Phenotyping Consortium (IMPC) and to the International Knockout Mouse Consortium (IKMC).

In the last 12 years, PHENOMIN-ICS has been a key player in several European and international programs. PHENOMIN-ICS is also a key player in the development and the characterisation of new mouse models for many academic laboratories or big pharmaceutical groups, and  contributes to European and international leading projects. In 2015, PHENOMIN-ICS has been partner of 8 European projects of mutagenesis and high scale phenotyping, (EUCOMMTools - EMTRAIN - InfraFrontier I3 - InfraFrontier GmbH - GENCODYS - InfraCoMP - InterReg - AgedBrainSYSBIO), in the frame of big European and international programs, therefore placing the French scientific laboratories at the forefront of mammalian genome deciphering in an organism model. Thus, PHENOMIN-ICS resource is able to meet the needs of new models creation, from the punctual mutation to the big chromosomal rearrangement, as well as the needs in high-throughput or specialised phenotyping, for research teams either mouse specialists or not.


PHENOMIN-ICS has been approved by Lloyd's Register Quality Assurance to the following

Quality Management System Standards NF EN ISO 9001:2015 and NF X50-900. The certification guarantees the requirements international standard of the quality system management for Fee-for-service and research and development activities in the following areas:

  • Genetic engineering for the generation of mouse models
  • Custom management and experienced breeding of mouse lines
  • Comprehensive, high-throughput and integrative phenotypic analysis of mouse models

Dual certification NF EN ISO 9001:2015 & NF X50-900 and scope extension to all our activities reinforces the professional recognition at the scientific level. The integration of long term strategic objectives in our policy will consolidate the continuous improvement of our services. PHENOMIN-ICS is IBiSA certified.

Engineering and model validation

  • Design and production of genetically modified mice:
    ◊ by targeted mutagenesis : Knock-out (KO), conditional Knock-out (cKO), Knock-in (KI), conditional mutations, deletion and duplication of genomic fragments ...
    ◊ by pronuclear injection : injection of plasmids, PAC or BAC
    ◊ genome editing using CRISPR/Cas9 nucleases technology
  • Generation of genetically modified ES cells (C57BL/6N, 129Sv/Pas and BALB/cN, initiated at PHENONIM-ICS)
  • Genotyping
  • Analysis of gene expression for model validation

Breeding and management of mouse model lines

The Animal Facility, a 2100 m2 area comprising 12 housing rooms, allows a housing capacity of 50 000 mice. The mouse lines housing area comprises 10 rooms of 60 m2 and 2 rooms of 45 m2, in biosafety level BSL1, and 2 experimental rooms in biosafety level BSL2 (embryo implantation).

  • Microinjection (ES cells, DNA)
  • Husbandry and breeding, production of transgenic and mutant mouse cohorts
  • Archiving by cryopreservation (embryos, sperm)
  • Rederivation by embryo transfer
  • In vitro fertilisation (IVF)
  • Distribution of mouse lines

Phenotyping

The phenotyping platforms of PHENOMIN-ICS area, adapted to study genetically modified mouse models, can also be used for preclinical studies, including the validation of therapeutic targets, as well as pharmaceutical and toxicological studies in mice. These platforms enable to explore the whole physiological systems and the related diseases with more than 250 validated tests covering 500 different parameters. The 900 m2 phenotyping area of the animal facilities comprises 7 breeding rooms (with a housing capacity of 1600 cages) and 26 experimental rooms.

This department is departed in four main platforms :

Metabolism and biochemistry

  • Energy metabolism : body composition and body weight, diets, food intake, obesity, energy expenditure, metabolic cage, indirect calorimetry
  • Glucose tolerance test, insulin sensitivity test, glycaemia
  • Obesity models, atherosclerotic models, inflammatory disease models
  • Intestinal and digestive functions: metabolic cages, calorimetric bomb
  • Endocrine function tests
  • Renal functions
  • Bone metabolism

 

Cardiology and lung function

  • Cardiovascular system: telemetry, ECG, EKG, hypertension, cardiac hypertrophy, vascular exploration, blood flow, thrombosis models
  • Spontaneously breathing, inflammatory models

 

Anatomy, histopathology and embryology

  • Histology, histopathology
  • Autopsy, necropsy
  • Embryology

 

Neurobiology, cognition and behaviour

  • Cognitive functions
  • Motor, locomotor, sensori-motor functions
  • Muscular functions by non-invasive sensors
  • Sensory functions : vision, audition
  • Pain sensitivity, depression, anxiety
  • Learning and memory
  • Schizophrenia, epilepsy

Another mission of PHENOMIN-ICS is to promote internal and external users training, thus to ensure processes in accordance with ethics and animal welfare.

Phenogenomics international school

  • 3rd European Advanced School for Mouse Phenogenomics
    Good practices: use of mouse models for biomedical and scientific research
    Learn how to choose, create and analyze your best mouse model. Get a sufficient background in mouse functional genomics to lead at best your research.
    This international training of excellence provides engineers, PhDs and researchers with an innovative program focused on best practices in the use of the mouse model biomedical and scientific research.You will gain crucial skills required to use the best mutant mice and to support you in your research!
    It provides a wealth of information on good practices in the use of mouse model (standardized techniques, ethics, regulations, analysis, data and resources ...) to support attendees in their research.
    ▪ School in Liebfrauenberg (North of Alsace) in 2019 (5 days): May 20-24
    Detailed information

Genome editing

  • In vivo CRISPR-Cas9 genome editing (in ENGLISH)
    This training given in English aims to provide a general framework to get scientists started using CRISPR/Cas9 for in vivo gene editing in rodents. It will include lectures, practical workshops and interactive discussions. The training is open to graduate students (PhD), post-doctoral scientists, researchers and engineers.
    The main topics are:
    ① Learn more about gene editing and how it works
    ② Hear about current advances on many technical aspects
    ③ Optimize the RNA guide design to the genotyping analysis (Bioinformatics workshop)
    ④ Highlight crucial issue in your own scientific project
    Training "CNRS formation entreprises": 2 days
    ▪ Session in Illkirch (outskirts of Strasbourg) in 2019: October 9-10
    ▪ Session in Illkirch (outskirts of Strasbourg) in 2020: October 8-9

    Description

Trainings specific to the mouse model

  • Mouse embryology (practical training course in ENGLISH)
    This training, given in English, is aimed at providing a theoretical and practical background knowledge to researchers and engineers willing to acquire primary expertise in mouse development. The topics will cover dissection of post-implantated embryos, histology, whole mount Lac Z staining and confocal imaging of whole embryos.
    The training is open to researchers, engineers, scientists having the basic knowledge in mouse physiology and able to handle mice.
    Objectives:
    ① Acquire primary expertise in mouse development
    ② Be able to design primary phenotyping experiment on mouse embryos
    ③ Learn about all the primary phenotyping analysis on mouse embryos
    ④ Be able to dissect post-implantated embryos
    ⑤ Be able to determine the window of lethality in utero
    ⑥ Be able to evaluate embryos viability at neonatal stage
    ⑦ Increase awareness of relevant technics to image embryos
    Training "CNRS formation entreprises": 3 days
    ▪ Session in Illkirch (outskirts of Strasbourg) in 2019: October 15-17
    ▪ Session in Illkirch (outskirts of Strasbourg) in 2020:
    March 10-12

    Description
  • PATHBIO Imaging mouse master class
    This training consists of one of the three intensive courses from PATHBIO consortium. The PathBio project brings together an ERASMUS+ Knowledge Alliance consortium from across the globe to cooperate on pooling resources and expertise in order to build the framework for a European post graduate degree in Precision pathobiology for disease models.
    The training is composed of theoretical courses [animal handling, ethics and regulation, image Analysis (quantitative analysis, visualisation, 3D analysis,..), X-rays, µCT imaging, MRI, echography, opto-acoustic imaging, nuclear imaging Spect-CT/PET, bioluminescence, specialized / new imaging, optical imaging, embryo (HREM /OPT)] and practical courses devoted to hands-on experience and demonstration for trainees
    ▪ Session in Strasbourg in 2019: November 4-8
    Program in progress
    Registration not open yet

Ethics

  • The 3 Rs in practice, refinement, endpoints
    This training, which is intended for designers, practitioners and keepers in animal experimentation, entitles them to 3.5 hours of training to maintain their skills (decree n°2013-118).
    Objectives:
    ① Update your knowledge of animal experimentation
    ② Validate your practices in compliance with the regulations relating to decree n°2013-118
    ③ Be aware of the endpoints to optimize their implementation and application in experimental procedures
    Training "CNRS formation entreprises": half a day
    ▪ Session in Orleans in 2020: March the 3rd
    Description

Cell culture

  • Contamination in cell cultures
    This training is intended for engineers and technicians using cell lines or having a project in cellular biology.
    Aims of the training:
    ① To realise how important are traceability and quality control in cell culture
    ② To grasp the issue of contamination in cell culture
    ③ To be aware of the diversity of mycoplasma detection methods and to be able to choose the appropriate techniques for each case
    ④ To prevent contaminations by mycoplasms and to know the attitudes to have in case of proven contamination
    Training "CNRS formation entreprise": 1 day
    ▪ Session in Illkirch (outskirts of Strasbourg) in 2019: September 17
    ▪ Session in Illkirch (outskirts of Strasbourg) in 2020: June 9
    Description

Contribution to regulatory trainings

The objective is to acquire the mandatory qualification to practice animal experimentation in accordance with the transposition of the new European Directive 2010/63.

  • Contribution to the regulatory trainings to use "rodents" for staff designing experimental procedures (formerly level I)
    Regulatory training for researchers and research engineers with direct scientific responsibility for animal experimentation, designing or carrying out experimental procedures.
    CFE trainings "CNRS formation entreprises": 7 days (no e-learning)
    ▪ 2 sessions in Gif-sur-Yvette in 2019: May 20-28, November 18-26
    ▪ 2 sessions in Gif-sur-Yvette in 2020: May 11-19, November 16-24
    Description

    Trainings exclusively limited to CNRS employees or non-CNRS employees working in a CNRS unit: 5 days + e-learning
    ▪ 4 sessions in Paris en 2019: March 11-15, April 15-19, September 9-13, October 21-25
    ▪ 1 session in Bordeaux in 2019: June 17-21
    Registration procedures
  • Contribution to the regulatory trainings to use "rodents" for staff applying experimental procedures (formerly level II)
    CFE trainings "CNRS formation entreprises": 5 days (no e-learning)
    ▪ 4 sessions in Gif-sur-Yvette in 2019:
    April 8-12, June 3-7, September 16-20, October 7-11
    ▪ 3 sessions in Gif-sur-Yvette in 2020:
    March 30 to April 3, June 8-12, October 12-16
    Description
    Training description
  • Regulatory training session in ENGLISH for staff designing experimental procedures and projects on "rodents" organized by CE2F-PRIM and CELPHEDIA
    Training limited to non-Francophone students and researchers working in a CNRS unit: 7 days
    ▪ 1 session in Marseille in 2019: July 1-9
    ▪ 1 session in Strasbourg in 2019: October 10-18
    Registration procedures

The mission of PHENOMIN-ICS is to initiate and promote relevant research and development programs to be at the edge of technology in the areas of mutagenesis, phenotyping, bio-informatics and analysis data.

The strong interaction with the Institute of Genetics, Molecular and Cellular Biology (IGBMC), one of the most prestigious biomedical research center in Europe, greatly contributes to the design and development of new techniques and tools for functional studies.

Genetic engineering

  • Design and production of genetically modified mice and rats :
    ◊ by targeted mutagenesis in ES cells: Knock-out (KO), conditional Knock-out, Knock-in (KI), conditional mutations, deletion and duplication of genomic fragments ...
    ◊ by pronuclear injection : injection of plasmids, PAC or BAC
    ◊ genome editing using engineered nucleases
  • Generation of complex models via the engineered nucleases technology
  • Development of mouse libraries: CreERT2 and reporter models
  • Creation and supply of innovative genetic tools:
    ◊ Cre and Flp ubiquitous lineages (Birling et al.2012)
    ◊ karyotype analysis by Droplet DigitalTM PCR (ddPCRTM)
  • Process optimization, such as obtaining a germline transmission rate of 80% per clone injected

Phenotyping

The phenotyping department of PHENOMIN-ICS is advancing a technical platform for functional characterization of preclinical models of human diseases with respect to both genetic understanding of pathophysiological mechanisms and the assessment of drug therapies.

Our new developments include:

  • Advanced imaging techniques (Echography, X-ray microtomography) for orthotopic tumour grafting and longitudinal monitoring of cancer in vivo;
  • Various in vivo assays for assessment of neuromuscular and muscular functions;
  • New neurobehavioral assessment:
    o Fine-tuned motor abilities (MoRaG, digigait)
    o Social interaction analysis (eg. affected in autism or other psychiatric disorders)
    o Novel learning & memory paradigm and circadian activity in a social environment with Intellicages
  • An expanding panel of histological stainings and improved techniques;
  • New cardiopulmonary investigations:
    o Echographic examination of atherosclerotic plaques,
    o Hypoxia-induced pulmonary hypertension,
    o New lung stress models, e.g. cigarette smoke, bleomycin, elastase, mites;
  • New metabolic investigations:
    o Energy expenditure with various challenges (temperature, exercise, fed or fasted state)
    o Intestinal inflammation model
  • Three-dimensional visualization of embryonic development using comprehensive image reconstitution of two-dimensional sections.

National and international projects

Since it was founded, PHENOMIN-ICS has always been an active partner in most European/international mouse phenogenomic programs, which includes :

  • The creation and the high-throughput phenotypic characterization of about 20,000 mutant mouse lines until 2020: IKMC/IMPC project
  • The first line phenotyping of 500 mutant mouse lines: EUMODIC project.
  • Archiving and distribution of genetically modified models, essential for basic biomedical research: EMMA project.

PHENONIM-ICS is also a founding member of INFRAFRONTIER Gmbh whose aim is to implement two complementary networking infrastructures: a high-throughput exhaustive phenotyping and mouse models archiving for the needs of the scientific biomedical research community to benefit human health; the iPad program in terms of cooperation and coordination between the European infrastructure INFRAFRONTIER, American and Asian infrastructures, in connection with the IMPC project. Moreover, PHENONIM-ICS is involved in European projects presenting a strong impact on human health : Interreg CARDIOGENE (Genetic mechanisms of cardiovascular diseases), GENCODYS (Genetic and epigenetic networks involved in cognitive dysfunctions), AgedBrainSYSBIO (Basic studies of brain aging), as well as projects in partnership with industry : MAGenTA (an Industrial Strategic Innovation project supported by Bpifrance about the treatment of major urogenital diseases) and CanPathPro (H2020 program), to develop a predictive modeling platform of signaling pathways involved in cancers.

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