Disease model discovery
Our group established and manage the Harwell Ageing Screen, a unique large-scale project to study the genetics of ageing and age-related diseases. Faced with an ageing population, there is a pressing need to improve our understanding of age-related diseases so that new treatments can be developed. We screen for mice with relevant phenotypes to investigate the underlying genetics.
The biggest problem currently facing UK healthcare is ageing. We have an ageing population and the incidence of the majority of diseases – cancer, heart disease, diabetes - goes up exponentially with age. We are using mice to determine the genes that specifically give rise to such age-related conditions, an enormous challenge and the first attempt of its kind. The idea is not to learn how we can live longer, but to extend the period of our lifespan when we are healthy. In addition to studying the genetics of ageing itself, our group focuses on four main disease areas; vision, kidney disease, bone disorders, and cardiac problems.
Vision and eye diseases
We are interested in visual problems and eye diseases, including cataracts and retinal degeneration. Our collaboration with Professor Ian Jackson at the MRC Human Genetics Unit in Edinburgh provides us with an understanding of both mouse and human genetics, so enabling us to determine how mutations in certain genes cause these conditions to develop.
Chronic renal disease is a serious condition associated with ageing where the kidneys stop functioning properly. We are collaborating with the Renal Unit at Imperial College to study an inherited form of kidney disease called Alport syndrome, as well as using our own mouse lines with a late onset renal disease to investigate dysfunction of the glomerular basement membrane.
As part of the screen, we look for any abnormalities in bone development and any bone disorders that develop as the mice age. We also focus on the most common form of arthritis in the UK, osteoarthritis, which mainly affects people over the age of 50, and are screening for genes that influence the course of this disease. This research is funded through the Oxford-based Arthritis Research UK Centre for Osteoarthritis Pathogenesis.
We are collaborating with Amsterdam Medical Centre to investigate the genetics of heart problems and cardiac conditions. Heart disease is one of the main killers in the UK, and the incidence rises with age. We study the underlying genetics to understand how certain mutations can increase the risk of developing such conditions.
The Harwell Ageing Screen uses ENU-induced mutagenesis to create mice with a wide range of genetic mutations. The mice live for 18 months, relatively old for a mouse, and are closely observed throughout their lives. The mice undergo tests at various ages to detect any behavioural, cognitive or physiological problems. In addition to tests for the diseases described above, there are ones developed for other research groups at MRC Harwell and some specifically requested by researchers at other institutions.
Once a mouse line of interest has been identified, we use next generation sequencing to identify the gene in which the mutation occurred. We then conduct more detailed analysis to investigate the role of this gene and the effect of the mutation on its function. We preserve the DNA or sperm of the mouse line in our ENU DNA archive and FESA for use by other researchers, and all screen results are made available in our database MouseBook.
We can therefore use the screen to study the role of genetic mutations in a very wide range of diseases and provide a valuable resource for the scientific community. Our ultimate aim is to identify the underlying causes of age-related diseases so that we can develop new treatments for patients.