A UK resource of new models of bone and mineral disorders
Lead Research Organisation:
University of Oxford
Department Name: Medical Sciences Divisional Office
Abstract
Genetic abnormalities are important in the causation of many common human diseases of bones, joints and the minerals important in their makeup. These conditions combined affect nearly all humans. Studies of mice are important in understanding the role of genes in these diseases, as there are many experiments that can be performed with mice that are impossible in humans both ethically and for practical reasons. Currently there are many conditions for which no mouse model has been identified. This programme will systematically breed new mouse strains to identify mice developing phenotypes relevant to conditions such as osteoporosis, osteoarthritis, gout, cancer and kidney stones. Identifying the genes involved in these mice will help us to understand what causes the same conditions in humans. This knowledge will lead to the development of new treatments for these conditions in humans.
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.
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.