Molecular genetics and brain in the Tc1 mouse model of Down syndrome

Lead Research Organisation: University College London
Department Name: Institute of Neurology

Abstract

Babies with Down syndrome account for about 1 in 700 births. The syndrome arises because people with Down syndrome have an extra copy of chromosome 21. Down syndrome is the most common known cause of mental retardation, and occurs along with many other more variable features, such as specific heart defects or abnormalities of the immune system.

To try to find out which genes on human chromosome 21 give rise to the different aspects of the syndrome, we created a mouse model of Down syndrome. This is a unique mouse strain, and it does recapitulate the features of Down syndrome.

We are now applying for funding to work out exactly which genes are present in this mouse, and when and where they are switched on. We then want to refine the mouse model by adding in a marker that allows us to tell which cells contain the extra chromosome. We also want to go to study the brain of these mice, to see how closely the mouse parallels human Down syndrome, and ultimately to try to work out which are the important genes for producing some of the specific brain changes that are seen in Down syndrome.

This research will help us understand more about why Down syndrome occurs, with a long-term view to therapy for some aspects of the syndrome, and will also tell us about exactly the same disorders that occur in the non-Down syndrome population.

Technical Summary

DS is the most common known form of mental retardation, and also has at least 80 other phenotypic aspects in different tissues. We have created a unique mouse model of DS, the Tc1 transchromosomic mouse. We now wish to investigate the molecular genetics of this mouse in detail and to go on to improve the model and start to study the brain in this animal.

Publications

10 25 50
 
Description Down syndrome research in UK
Geographic Reach National 
Policy Influence Type Gave evidence to a government review
 
Description ART Research Grant
Amount £30,000 (GBP)
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2009 
End 12/2011
 
Description Alzheimer's Research UK PhD Studentship
Amount £105,000 (GBP)
Organisation Alzheimer's Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2013 
End 09/2016
 
Description Alzheimer's Society PhD studentship
Amount £84,990 (GBP)
Organisation Alzheimer's Society 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2014 
End 09/2017
 
Description Biochemical Society Summer Vacation Studentship
Amount £1,600 (GBP)
Organisation Biochemical Society 
Sector Charity/Non Profit
Country United Kingdom
Start 06/2013 
End 07/2013
 
Description Pilot Project ERUK
Amount £29,897 (GBP)
Organisation Epilepsy Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2013 
End 03/2014
 
Description Synaptic, Cellular and Neural Circuit Dysfunction in Down Syndrome
Amount £2,444,366 (GBP)
Funding ID 217199/Z/19/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2019 
End 08/2024
 
Description Wellcome Trust Joint Senior Investigators Award
Amount £1,258,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2013 
End 12/2019
 
Description Wellcome Trust Strategic Award
Amount £838,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2013 
End 12/2017
 
Title A panel of mice with partial trisomies, with Dr Victor Tybulewicz 
Description Panel of 12 new mouse strains for modelling human Down syndrome and finding genes underlying the syndrome 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2015 
Provided To Others? Yes  
Impact Papers and new research collaborations and new research in external groups. Also depositing the mice in the European Mutant Mouse Archive so they are freely available to others. 
 
Title Mouse models of Down Syndrome 
Description We have generated 14 new mouse strains with duplications or deletions of large regions of mouse chromosomes orthologous to human chromosome 21. 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Year Produced 2016 
Provided To Others? Yes  
Impact Multiple collaborations and requests for use of the animals. 
 
Title Tc1 mice 
Description Mouse model of Down syndrome 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? Yes  
Impact Allow study of Down syndrome 
URL http://www.ncbi.nlm.nih.gov/pubmed/16179473
 
Title Chromosome 21 map 
Description Interactive chromosome 21 map that shows human sequences and mouse homologs, and shows breakpoints for the various engineered mouse partial trisomy strains. Ours and others. 
Type Of Material Database/Collection of data 
Year Produced 2013 
Provided To Others? Yes  
Impact Offered to various research groups internationally, but need an informatics curator, which we do not have. 
 
Description Analysing the metabolome Griffin, Cambridge 
Organisation University of Cambridge
Department Department of Earth Sciences
Country United Kingdom 
Sector Academic/University 
PI Contribution Access to novel mice and mouse crosses
Collaborator Contribution Analysis of the metabolome including lipidomics
Impact No outputs yet
Start Year 2016
 
Description Cardiff DS mouse models behaviour 
Organisation Cardiff University
Department School of Psychology
Country United Kingdom 
Sector Academic/University 
PI Contribution Mouse models of Down syndrome and Alzheimers disease
Collaborator Contribution In depth behavioural analysis
Impact Papers and research
Start Year 2014
 
Description Down Syndrome 
Organisation University College London
Department Institute of Neurology
Country United Kingdom 
Sector Academic/University 
PI Contribution Joint grant applications, joint research program, joint publications
Collaborator Contribution Joint grant applications, joint research program, joint publications
Impact PMID: 16987872; PMID: 18047653; PMID: 18626093; PMID: 18771760; PMID: 18787134; PMID: 19001410; PMID: 19181682; PMID: 19726804; PMID: 20154221; PMID: 20535211; PMID: 20697343.
 
Description Down syndrome and cancer 
Organisation Queen Mary University of London
Department Barts Cancer Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution Contributing mouse resources and expertise in pathology
Collaborator Contribution Expertise in cancer and angiogenesis
Impact Papers and ongoing research.
Start Year 2009
 
Description Down syndrome and heart development 
Organisation Medical Research Council (MRC)
Department MRC National Institute for Medical Research (NIMR)
Country United Kingdom 
Sector Academic/University 
PI Contribution Mouse resources and a postdoc
Collaborator Contribution Expertise in heart development and imaging
Impact Papers, new experimental paradigms, studentships
Start Year 2008
 
Description Engineering new mouse models of Down syndrome 
Organisation Medical Research Council (MRC)
Department MRC National Institute for Medical Research (NIMR)
Country United Kingdom 
Sector Academic/University 
PI Contribution Research ideas input and resources such as mouse tissues and crosses.
Collaborator Contribution Intellectual input and a wider base of collaborators to help analyse our mice.
Impact Publications, joint grants, a PhD student.
 
Description Heart development in Down Syndrome 
Organisation Medical Research Council (MRC)
Department MRC National Institute for Medical Research (NIMR)
Country United Kingdom 
Sector Academic/University 
PI Contribution Mice, joint research planning
Collaborator Contribution Joint publication. PMID: 20558441
Impact PMID: 20558441
 
Description Imaging 
Organisation University College London
Department Centre for Advanced Bioimaging
Country United Kingdom 
Sector Academic/University 
PI Contribution Mouse models
Collaborator Contribution High resolution imaging
Impact Papers, studentships.
Start Year 2006
 
Description LonDowns 
Organisation Birkbeck, University of London
Country United Kingdom 
Sector Academic/University 
PI Contribution Six labs working jointly to understand the link between alzheimer disease and down syndrome.
Collaborator Contribution We bring in mouse expertise, which is compared with the groups studying infants and adults with down syndrome, and also with cell models and genetics of people with down syndrome.
Impact Major meeting taking place in 2014 that we are organising.
Start Year 2013
 
Description LonDowns 
Organisation Medical Research Council (MRC)
Department MRC National Institute for Medical Research (NIMR)
Country United Kingdom 
Sector Academic/University 
PI Contribution Six labs working jointly to understand the link between alzheimer disease and down syndrome.
Collaborator Contribution We bring in mouse expertise, which is compared with the groups studying infants and adults with down syndrome, and also with cell models and genetics of people with down syndrome.
Impact Major meeting taking place in 2014 that we are organising.
Start Year 2013
 
Description LonDowns 
Organisation Queen Mary University of London
Country United Kingdom 
Sector Academic/University 
PI Contribution Six labs working jointly to understand the link between alzheimer disease and down syndrome.
Collaborator Contribution We bring in mouse expertise, which is compared with the groups studying infants and adults with down syndrome, and also with cell models and genetics of people with down syndrome.
Impact Major meeting taking place in 2014 that we are organising.
Start Year 2013
 
Description Looking at gliosis in neurodegeneration 
Organisation University of Queensland
Country Australia 
Sector Academic/University 
PI Contribution Access to unique mouse models and crosses
Collaborator Contribution Analysis of gliosis and potentially the inflammasome
Impact No outputs yet
Start Year 2017
 
Description Mouse Aß species and trisomy of chromosome 21 
Organisation Johnson & Johnson
Department Janssen Pharmaceuticals
Country United States 
Sector Private 
PI Contribution Based on our finding that trisomy of chromosome 21 exacerbates the accumulation of Abeta in the brain, we have supplied mouse brain tissues from our models for an investigation of the accumulation of mouse Abeta in brain.
Collaborator Contribution Highly sensitive mouse Abeta ELISA.
Impact Data generated from this collaboration has furthered our understanding of the effect of trisomy of chromosome 21 on the development of Alzheimer's disease.
Start Year 2013
 
Description Mouse mapping zoo 
Organisation Mouse Clinical Institute
Country France 
Sector Academic/University 
PI Contribution Mouse resources for mapping genes involved in Down syndrome.
Collaborator Contribution Mouse resources for mapping genes involved in Down syndrome.
Impact Papers, grants.
Start Year 2006
 
Description NIMR and mouse engineering 
Organisation Medical Research Council (MRC)
Department MRC National Institute for Medical Research (NIMR)
Country United Kingdom 
Sector Academic/University 
PI Contribution a postdoc, grant funding, expertise.
Collaborator Contribution expertise in manipulating ES cells.
Impact grant and papers
 
Description Prion collaboration 
Organisation University College London
Department MRC Prion Unit
Country United Kingdom 
Sector Academic/University 
PI Contribution Mouse resources, neurodegeneration expertise
Collaborator Contribution molecular biology expertise
Impact Papers
Start Year 2011
 
Description Transcription analysis in mouse model of Down syndrome 
Organisation University of Cambridge
Country United Kingdom 
Sector Academic/University 
PI Contribution Access to mouse tissues.
Collaborator Contribution Entirely novel approach to analysing the biology of our mouse model of Down syndrome.
Impact So far, PMID: 18787134
Start Year 2007
 
Description electrophysiology of DS and AD-DS mice (Pishan/Walker) 
Organisation University College London
Country United Kingdom 
Sector Academic/University 
PI Contribution A unique panel of mice that model human Down syndrome and allow us to map genes
Collaborator Contribution Expertise in EEG and behaviour, and therefore the ability to determine behaviour and see how aberrations correlate with EEG in our different models.
Impact No outputs yet.
Start Year 2016
 
Title New mouse trisomy models 
Description New mouse strains subject to Material Transfer Agreements. 
IP Reference  
Protection Copyrighted (e.g. software)
Year Protection Granted 2011
Licensed Yes
Impact Papers should come out of using thise resource.
 
Description 2019 Down syndrome day event 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Patients, carers and/or patient groups
Results and Impact World Down Syndrome Day event, organised with talks, activities, refreshments, for people with Down syndrome and their carers to meet to understand our research and hear updates.
Year(s) Of Engagement Activity 2019
 
Description Co-organised Keystone Meeting on the Biology of Down syndrome. 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Other audiences
Results and Impact An academic meeting on DS and AD, but it included representatives from several charity and government funders.
Year(s) Of Engagement Activity 2016
 
Description Crick talk 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Talk to general public interested in our research.
Year(s) Of Engagement Activity 2015
 
Description DS Lay talk, Cardiff 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Presentation of our work to a patient and carer group.
Year(s) Of Engagement Activity 2015
 
Description Down Syndrome Cognition Workshop 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact Highly specialist audience. Chaired session and lab and collaborators presented several posters. Audience consisted of scientists and also parent organisations and interested lay people from the Down syndrome community.

Disseminating our research, presenting our work to a North American lay audience who did not know about it, making the point that our mouse model is freely available worldwide.
Year(s) Of Engagement Activity 2013
URL http://finance.yahoo.com/news/linda-crnic-institute-down-syndrome-221500144.html
 
Description Down syndrome association annual meeting 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? Yes
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Talk to audience of people with Down syndrome and their families and the UK Down syndrome association

Raising research as an issue for the public to join in with.
Year(s) Of Engagement Activity 2007
 
Description Funders visit 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact approximately 5 lay members from a dementia association attended two talks from our group to present our work to them.
Year(s) Of Engagement Activity 2015
 
Description Interviewed on BBC Radio 4 for 'The Life Scientific' 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Interviewed by Professor Jim Al-Khalili for a BBC Radio 4 broadcast on the 'Life Scientific'.
Year(s) Of Engagement Activity 2019
 
Description Lay talk at World Down Syndrome Congress 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Participants in your research and patient groups
Results and Impact 600 people largely of either with Down syndrome or their families attended this meeting and I talked about our research and the importance of animal models for understanding Down syndrome. World Down Syndrome Congress, Cape Town, South Africa, 2012.

Great enthusiasm from audience and many requests for more detailed information. Also new connections to a handful of other scientsts who were in the audience.
Year(s) Of Engagement Activity Pre-2006,2012
 
Description Public talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Talk to memebres of the public about Down Syndrome research
Year(s) Of Engagement Activity 2017
 
Description Radio and newspapers interviews over new Down syndrome article from jeanne lawrence 
Form Of Engagement Activity A press release, press conference or response to a media enquiry/interview
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Media (as a channel to the public)
Results and Impact Gave several interviews as an 'expert' on an important paper on Down syndrome that was published.

Wider discussion of the issue.
Year(s) Of Engagement Activity 2013
 
Description School Talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Talk to Y11-Y13 students about Down Syndrome research
Year(s) Of Engagement Activity 2017
 
Description World Down Syndrome Day 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Patients, carers and/or patient groups
Results and Impact Open Day, with activities and talks, for people with Down syndrome and their friends/relations/carers.
Outcome scored anonymously by attendees, positive for all scores.
Year(s) Of Engagement Activity 2018