Disease Model Discovery and Translation

Group Leader : Paul Potter

The central role of the Disease Model Discovery and Translation (DMAT) group is to develop and characterise models of age-related, late onset, or chronic disease. The group manages the Harwell Ageing Screen and collaborates with research groups both within MRC Harwell and externally. The overall aim of this project is to generate new models of age-related disease, thus identifying genes/pathways associated with these pathologies. Given the growing burden of age-related disease there is an increasing need for models that will eventually lead to therapeutic interventions.

Research Themes:

The Genetics of Ageing. We are investigating the role of genes associated with adverse or beneficial effects during the ageing process. Currently we are studying the role of CISD2 in age-related disease. This gene has been associated with early onset of phenotypes commonly associated with ageing and in aged mice the expression of CISD2 reduces, thus implicating CISD2 as a key regulator of disease susceptibility in ageing (Chen et al, Genes and Development, 23, p1183-1194, 2009).

Renal Disease. In collaboration with the Renal Group at Imperial College we are characterising and mapping a number of mutants exhibiting spontaneous renal disease, both early onset and age-related. We are investigating a model of Alport Syndrome and modifiers of disease in these mice.

Macrophage Signalling Pathways. In order to determine signalling pathways affecting macrophage responses, with a particular interest in the poorly characterised IL-10 signalling pathway, a research group led by Dr. Phillip Kong and Prof. Sir Mark Feldmann (Kennedy Institute of Rheumatology) have been screening macrophages derived from pedigrees of mutagenised mice for abnormal responses to a variety of stimulation. We are working to map and characterise mutants identified in this screen.

Immunosenescence. As part of the ageing screen we are undertaking a screen of peripheral blood lymphocytes to identify mutant pedigrees with altered cell surface antigen profiles. We are initially focussing on T cell subsets as these have been demonstrated to change with ageing and may be linked with susceptibility to disease (Miller et al, FASEB J. 11, p775-783, 1997; Jackson et al, Genes and Immunity 4, p30-39, 1993; Selma et al, Science 326, p140-4, 2009). Combined with the comprehensive phenotyping platforms being applied to the ageing mice we aim to identify novel genes and pathways regulating immunosenescence.

Vision. In collaboration with Prof Ian Jackson (FGU, Edinburgh) we are undertaking screening of mice to identify models with visual phenotype including cataracts and retinal degeneration.

Overall, DMAT are characterising and mapping mutants with phenotypes potentially relevant to human disease for a wide variety of systems. We are currently characterising mutants with abnormal mineral density, tumour susceptibility, heart disease, and are constantly identifying new models or early onset and age-related disease.