Dev Anomalies Consortium - Nick Greene.pptx - MRC Mouse Network

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14 Δεκ 2012 (πριν από 4 χρόνια και 10 μήνες)

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Developmental Anomalies
Consortium

Nick Greene

UCL 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

Genetic

causes

Developmental

mechanisms

Novel therapies

Clinical trials

Population

studies

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

Human

35 days

Eye

Sowden

Skull

Pauws

Palate

Stanier

Branchial arch arteries

Scambler

Heart

Riley

Pituitary

Martinez
-
Barbera,
Dattani

Kidney

Long, Winyard

Choroid
plexus

Ferretti

Neural tube (Brain
& spinal cord)

Copp, Greene

Gonad, adrenal

Achermann

Syndromes
(Ciliopathies)

Beales, Mitchison,
Hammond

Embryos from Human Developmental
Biology Resource

Enteric nervous system

Burns

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 Network

Experimental 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 bifida

Cleft lip/palate

Coloboma

Internal

organ defects

Hirschsprung’s disease

Tracheo
-

oesophageal

fistula

Ventricular septal defect

Polycystic kidneys

Diaphragmatic hernia