A UK resource of new models of bone and mineral disorders

Lead Research Organisation: University of Oxford
Department Name: Clinical Medicine

Abstract

Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.

Technical Summary

We propose to establish a UK consortium to perform an ethyl-nitrosourea (ENU) mutation screen to provide models of human musculoskeletal diseases including disorders of: bone quantity and mineralisation (e.g. osteoporosis and Paget‘s disease), bone mineral homeostasis (e.g. parathyroid disease); urate metabolism; ectopic calcification and ossification; osteoarthritis; skeletal dysplasias, and tumours.

ENU mutagenesis is an established method for the rapid, efficient development of novel mouse models for a better understanding of the genetic basis and the genetic pathways involved in human disease. Using efficient screening by digital radiography, dual-energy X-ray absorptiometry, microCT and serum biochemistry, mice will be screened for a wide range of musculoskeletal disorders. ENU gene-driven screens will also be performed to identify mice with mutations in ~ 12 candidate genes of interest. Over three years, 8,000 mice will be screened as part of the Harwell dominant mutagenesis programme. 3,000 mice will be screened as part of the Mary Lyon Centre‘s (MLC) standard production pipeline of mutagenised mice for dominant genome-wide screens, involving mating mutagenised C57BL/6 males to C3H females and scoring the hybrid offspring. However, for bone mineral density (BMD) screens there are large differences in BMD between the BL/6 and C3H strains reflecting allelic variation at a variety of QTLs around the genome governing BMD. Therefore for these studies we will initially screen the F1 from mutagenised BL/6 males mated with BL/6 females, and following demonstration of heritability perform subsequent gene mapping employing two strains with similar whole body BMD e.g. BL/6 and DBA. A further 5,000 mice will be screened in this part of the study. In addition, we will screen approximately 50 lines from the MLC‘s recessive genome-wide mutagenesis pipeline.

Through this program we aim to establish a valuable resource for future research into the genetic causation of common heritable musculoskeletal disorders.

Publications

10 25 50

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Esapa CT (2012) A mouse model for spondyloepiphyseal dysplasia congenita with secondary osteoarthritis due to a Col2a1 mutation. in Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

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Gorvin CM (2019) An N-Ethyl-N-Nitrosourea (ENU)-Induced Tyr265Stop Mutation of the DNA Polymerase Accessory Subunit Gamma 2 (Polg2) Is Associated With Renal Calcification in Mice. in Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

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Gorvin CM (2019) Mice with a Brd4 Mutation Represent a New Model of Nephrocalcinosis. in Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research

 
Description Centre of Excellence Award
Amount £2,500,000 (GBP)
Organisation Versus Arthritis 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2013 
End 10/2017
 
Description Collabortive Grant
Amount £120,000 (GBP)
Organisation GlaxoSmithKline (GSK) 
Sector Private
Country Global
Start 10/2011 
End 10/2012
 
Description PhD Studentship - C Gorvin
Amount £60,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 10/2008 
End 09/2011
 
Description PhD Studentship - K Gaynor
Amount £60,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 10/2007 
End 09/2010
 
Description Project Grant
Amount £194,000 (GBP)
Organisation Kidney Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 10/2012 
End 10/2014
 
Description Treat-OA
Amount £500,000 (GBP)
Funding ID 200800 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 01/2008 
End 12/2012
 
Title mouse models 
Description mouse models for musculoskeletal disorders 
Type Of Material Model of mechanisms or symptoms - mammalian in vivo 
Provided To Others? No  
Impact Mouse models for musculoskeletal disease 
 
Description Brown, S 
Organisation MRC Harwell
Department MRC Mammalian Genetics Unit
Country United Kingdom 
Sector Academic/University 
PI Contribution Undertaken molecular genetic studies and mouse phenotyping analysis together with details for publication.
Collaborator Contribution Brought together different expertise and resources to answer a biological question.
Impact 20457824
 
Description Cox, R 
Organisation Medical Research Council (MRC)
Department The Mary Lyon Centre
Country United Kingdom 
Sector Academic/University 
PI Contribution Undertaken molecular genetic studies and mouse phenotyping analysis together with details for publication.
Collaborator Contribution Brought together different expertise and resources to answer a biological question.
Impact Several papers, full details under publications.
 
Description Treat-OA 
Organisation European Commission
Department Seventh Framework Programme (FP7)
Country European Union (EU) 
Sector Public 
PI Contribution Providing models for osteoarthritis and basic science processes.
Collaborator Contribution Greater links with European investigators.
Impact Studies still in progress. Several abstract presented at British Endocrine Societies meeting and American Society of Bone and Mineral Research.
Start Year 2008