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The
German Mouse Clinic
Helmut Fuchs,
and the GMC-Consortium
Helmholtz Zentrum München Institute of Experimental Genetics
The 2 strategies: BU and TD
Bottom up
Top down
Requests from the scientific comunity
Bilateral collaborations
Centrally organized projects
• offers systemic phenotypic analysis of mouse mutants
on the basis of scientific collaboration
• Runs a primary screening of more than 500 parameters
in 14 different screens
• offers detailed analysis in secondary screening
• GMC II genome meets environment
• GMC III Systemic analysis of compound and drug action
The German Mouse Clinic
• Open access
• logistics developed for open access of scientific community
• experts from different research areas work together in one
facility (consortium)
• systemic interpretation of results
Unique concept
Selection: Nat Med (2005, 2012, 2015), Nat Com 2014, Hum Mol Genet(2012, 2014), EMBO J (2010, 2014), BBRC (2013), Development (2013),
Acta Neuropathol (2012), Nucleic Acids Res (2010, 2014). PLoS Genet (2012, 2014), PLoS Biol (2010), Blood (2011), Bone (2013), Histol
Histopath (2013), J Cell Science (2011), J Biol Chem (2011, 2013), Methods (2011), Faseb J (2012), Eur J Endocrinol (2012), J Comp Neurol
(2012), Science (2010), BMC Neurosci (2012), (Diabetes 2015), Nat Genet (2015,2016) JCI (2013)
Age [weeks] 7 8 9 10 11 12 13 14 15 16
Screens Methods
Behaviour Open field
Acoustic startle response & PPI
Neurology Modified SHIRPA, grip strength
Rotarod
Dysmorphology Anatomical observation
Energy Metabolism Indirect calorimetry
Cardiovascular Awake ECG / Echocardiography
Clinical Chemistry IpGTT
Neurology ABR (Auditory brain stem response)
Dysmorphology X-ray, DEXA
Nociception Hotplate
Eye Scheimpflug imaging, OCT, LIB, drum
Clinical Chemistry Clinical Chemical analysis, hematology
Immunology FACS analysis of PBCs
Allergy BIOPLEX ELISA (Ig concentration)
Pathology Macro & microscopic analysis
Molecular Phenotyping (optional) Expression profiling
B) Pipeline anxiety, depression or schizophrenia
A 4
Acoustic
startle&P
PI
A1 Open
field
B2
Elevated
plus maze
B2 Social
interaction
B4
Swimabilit
y test
B5 Tail
suspensi
on
B1 Light/
dark box
B6 Acute
stress
C) Pipeline learning and memory
D) Pipeline motoric abilities
A5
Rotarod
A3
SHIRPA
D2
Ladder
walk
D3
Vertical
pole
D4
Inverted
grid
D1 Beam
walk
D5 Gait
analysis
E) Pipeline sensoric abilities
A20 ABR A7 Hot
plate
E2
Electro-
retino-
gram
E3. nerve
conduc-
tance
E4
Seizures
E1 Eye
pressure E5 EEG
Pipelines for secondary analyses
Behaviour and Neurology
C2 Social
discrimina
tion
C1 Y-
maze
C4
Intellicage
C5 Olfakt.
discrimina
tion
C6 Neuro-
genesis
C3 Object
recogni-
tion
C7 pharm.
Antagon.
F) Pipeline kidney function
G) Pipeline glucose metabolism
A5 Blood sample A11 Body composition
(NMR)
A12 Glucose
tolerance test
G1 Insuline
tolerance Test
A5 Blood
sample
G2 Glucose-
Clamp
A5 Blood
sample F1 Analysis of kidney function A21 Histo-pathology
H) Pipeline energy metabolism
I) Pipeline non-invasive imaging technologies
I2 MRI I1 Micro CT
Physiology, energy metabolism and diabetes
A5 Blood
sample
A11 Body
composition(NM
R)
H2 Energy
balance
H3 Breath
gas analysis
A5 Blood
sample
A10 Ind.
calorimetry
H4 Cold
challenge
H1
Implantation
of sensor
Pipelines for secondary analyses
MRT-Applications
• Brain imaging
• Heart imaging
• Knee joint
• Body composition
• Liver spectroscopy
Immunology, Allergy and lung diseases
M) Analysis of progressive phenotypes
Repetition of special analyses
J) Pipeline Immunity
K) Pipeline Allergy
L) Pipeline lung function: Either Acute lung injury test, Elastase-induced lung-emphysem, Cigarette induced lung-emphysem or bleomycin-induced lung-fibrosis
L Lung function
analysis
K1
OVA
sensitation
K2
OVA aerosol
provocation
K3
Blood sample and
histo-pathology
A5
Blood sample
J1 Primary
infection
resistence
J2
T-cell
response
J3
Protective
immunity
A5
Blood sample
J4
Inflammation-
test
Pipelines for secondary analyses
• sensimotor neurological disorder • urge to move the legs • symptoms occur exclusively during rest, evening and
night • Age – dependent prevalence of up to 10% in
western societies
• GWAS identified Meis 1 (homeobox transcription factor (TALE family)) locus for Restless Legs Syndrome (RLS)
• SNP in risk allele of MEIS1 highly conserved non-coding
region (intron 8)
• Leads to reduced gene expression in the future basal ganglia in the forebrain - pathophysiology of RLS includes aspects of neurodevelopmental disorders
Disease model Restless Legs Syndrome (RLS)
Spieler et al., 2014 Genome Research
Motor restlessness/hyperactivity in adult heterozygous Meis1tm1Mtormice
7
Systemic phenotyping of mice with
reduced Meis 1 expression revealed
motor restlessness and hyperactivity
Behavior Screen:
• Alteration of the behavior
phenotype towards hyperactive
locomotion in a novel
environment (Open Field)
Metabolic Screen:
• Hyperactivity in home cage
conditions and increased energy
expenditure (Indirect Calorimetry)
Spieler et al., 2014 Genome Research
http://www.mouseclinic.de/
Publically available phenotyping data
Phenomap
16
Reporting • GMC phenomap • Bottom-up projects: PDF-reports
MausDB – reporting
Standardized Mouse Phenotyping
Envirotype “Challenge” Tests
Systemic Analysis of Compounds & Drugs
Envirotypes
Beckers et al. Nature Reviews Genetics 2009
air stress
immunity/ inflammation
nutrition, diet
exercise physical activity
envirotype platforms
Tread-mill Jump
exercise
Infection Challenge Allergen exposure
Light exposure Restraint Oxidative
stress
High fat diet fasting
Instillation of diesel particles
Standardized challenge tests and their combination
The 2 strategies: BU and TD
Bottom up
Top down
Requests from the scientific comunity
Bilateral collaborations
Centrally organized projects
Hrabě de Angelis…. Brown
Nature Genetics 2015
New phenotypes revealed – genes with no prior annotations
www.mousephenotype.org
IMPC activities • Undertake broad-based phenotyping of 20,000 mutants
(genes) from the IKMC resource
• Phase 1 (2011-2016): Phenotype up to 5,000 lines
• Phase 2 (2016-2021): Phenotype 15,000 lines
• Data freely available through a Data Coordination Centre
• Mice available through the global network of mouse
repositories
IMPC pipeline
IMPC phenoview
6
www.infrafrontier.eu
INFRAFRONTIER – Access to mammalian
models for biomedical research Pan-European Research Infrastructure
How to contact us?
Neurology Lore Becker Ingrid Vargas P. Thomas Klopstock IEG, HMGU/LMU München Allergy Juan Antonio Aguilar-Pimentel Carsten Schmidt-Weber Markus Ollert IEG, HMGU/TU München/Institute of Health Luxembourg/University of Southern Denmark Bioinformatics/Statistics Manuela Östereicher Anja Hurt Christine Schütt Ralf Schneider Elida Schneltzer Ralf Steinkamp Karlheinz Schäble Christoph Lengger Holger Maier IEG, HMGU Mouse production Susan Marschall and team Andreas Hörlein and team Ralf Kühn and team IEG/IDG, HMGU
Martin Hrabě de Angelis (Director) Valérie Gailus-Durner (Scientific Administrative Head) GMC Management Team Claudia Stöger Stefanie Leuchtenberger Christine Hutterer Sandra Greißel Cindy Gonda IEG, HMGU Behavior Sabine M. Hölter Lillian Garrett Annemarie Zimprich Wolfgang Wurst IDG, HMGU Dysmorphology Robert Brommage Martin Hrabě de Angelis IEG, HMGU Diabetes Jan Rozman Martin Hrabě de Angelis IEG, HMGU
Clinical Chemistry Birgit Rathkolb Eckhard Wolf LMU München Immunology Irina Treise Dirk H. Busch IEG, HMGU/TU München Cardiovascular Kristin Moreth Raffi Bekeredjian Hugo A. Katus IEG, HMGU/University of Heidelberg Pathology Julia Calzada-Wack Pathology, HMGU Lung Function Tobias Stöger Ali Önder Yildirim Oliver Eickelberg iLBD, HMGU
Energy Metabolism Jan Rozman Monja Willershäuser Martin Kistler Martin Klingenspor IEG, HMGU/TU München Steroid Metabolism Cornelia Prehn Gabriele Möller Jerzy Adamski IEG, HMGU Eye Oana Amarie Jochen Graw IDG, HMGU Nociception Lore Becker Andreas Zimmer IEG/HMGU, University of Bonn Molecular Phenotyping Johannes Beckers IEG, HMGU Infrafrontier Michael Räß IEG, HMGU
Thanks to