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MRC Mouse Network Meeting – Jan 2012. Developmental Anomalies Consortium. Nick Greene UCL Institute of Child Health. Developmental anomalies/birth defects. Defects of structure (malformations) Present at birth (congenital) Originate during pregnancy (usually early) - PowerPoint PPT Presentation
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Developmental Anomalies Consortium
Nick GreeneUCL Institute of Child Health
MRC Mouse Network Meeting – Jan 2012
Developmental anomalies/birth defects• Defects of structure (malformations)• Present at birth (congenital)• Originate during pregnancy (usually early)• Can be caused by genetic and/or environmental
factors
Genetic
Environmental
What is the size of the problem?
• 1 in every 40 infants has a birth defect• 360,000/year new birth defects in Europe• 286,000 progress beyond 1 week of age• ~ 40% of children at GOSH have a birth defect
Dolk et al, 2010, Adv Exp Med Biol 686, 349
Aims & Objectives
Analyse IMPC mouse models in order to:
• Understand the genetic and developmental origin of birth defects
• Establish tools for translation to clinical diagnosis, therapy and prevention of human birth defects.
Birth defects research: a multi-disciplinary approach
Geneticcauses
Developmentalmechanisms
Novel therapies
Clinical trials
Populationstudies
MRC Centre of Epidemiology for Childhood Disease
Clinical Research Facility (GOSH), Clinical Trials Unit (UCL)
Research teams working on defects of CNS, palate, skull, eye, kidney, heart, gut Links to Centre for Advanced Bioimaging
GOSgene, UCL Genomics
Developmental Anomalies Consortium
Gene & stem cell therapies, tissue engineering, small molecules (UCL)
ICH/UCL/GOSH
Developmental Anomalies Consortium
Human35 days
Eye Sowden
SkullPauws Palate
Stanier Branchial arch arteries Scambler
HeartRiley
PituitaryMartinez-Barbera,
Dattani
KidneyLong, Winyard
Choroid plexusFerretti Neural tube
(Brain & spinal cord)
Copp, Greene
Gonad, adrenal Achermann
Syndromes (Ciliopathies)
Beales, Mitchison, Hammond
Embryos from Human Developmental Biology Resource
Enteric nervous systemBurns
Cerebral cortex
Jacques
Imaging Lythogoe (Centre for Advanced Bioimaging)
Research Plans• Selection of genes:
– Relevance to aims & objectives of Consortium– Preliminary data to suggest role in birth defects (eg. altered expression in
existing model, candidates for human conditions from patient screens)– Lack of existing knockout or conditional
Consortium activity within the NetworkExperimental approaches for analysis of prority gene models• Phenotyping:
– Gross morphology, histological analysis– Gene expression (lacZ staining, in situ hybridisation, immunohistochemistry)– Micro MRI (also micro-CT or OPT in selected models)
• Culture methods:– Whole embryo culture - Organotypic culture - Stem cell culture
• Genomic, molecular & cellular analysis– Many Cre-deletor lines available UCL/ICH– Transcriptomics (UCL Genomics) - FACS core facilty (eg, cell sorting for
microarray)
Additional models from other Consortia• Expected that birth defects will arise in additional models, many
will be pre-natal lethal (homozygote sub-viable)• Phenotypes include:
– Externally visible defects (NTDs, cleft palate, craniofacial & limb)– Internal organ defects (ENS, kidney, heart, tracheo-oesophageal fistula)
• Mechanism to identify to identify birth defects in pre-natal lethal models?
Research plan• Selection of genes
– Relevance to aims & objectives of Consortium– Preliminary data to suggest role in birth defects (eg. altered expression in
existing model, candidates for human conditions from patient screens)– Lack of existing knockout or conditional
• Developmental phenotypes examined by teams focused on particular organ systems
• Analysis of tissue & stage-specific gene function• Gene-environment interaction (eg, nutritional folate deficiency)
• Functional/mechanistic analysis
• Development of biomarkers and therpeutic interventions
Holoprosencephaly with cyclopia
Phocomelia Synpolydactyly
Craniofacial disorder
Externally visible defects
Spina bifidaCleft lip/palate
Coloboma
Internal organ defects
Hirschsprung’s disease Tracheo-oesophageal
fistula
Ventricular septal defect
Polycystic kidneys
Diaphragmatic hernia