Resource for innovation and application of genetic engineering strategies in embryonic stem cells

The aim of this research programme is to innovate experimental genetic approaches to investigate the regulation and role of genes in blood development in both normal and diseased states. By using sophisticated genetic engineering strategies genes can be altered in numerous ways (to inactivate them or modify their function or expression) in mouse embryonic stem (ES) cells. Mouse ES have the capacity for both unlimited cell division and differentiation into almost all cell types, and can create an entire organism. These cells therefore provide an experimental system for studying the effect of any genetic alterations both at cellular and physiological levels. A major focus of the programme is to build more accurate models of human blood diseases by introducing large regions of human DNA sequence into mouse ES cells. These human DNA sequences can be altered to recapitulate known human disease-associated mutations and thus it is possible to create an experimental animal model for evaluating human disease pathology and potential drug therapies. In addition, a parallel approach is being followed applying genetic engineering strategies to human ES cells. Genetically altered human ES cells can be differentiated in the culture dish to generate blood cells and therefore allow the effects of genetic alterations to be studied and evaluated.

This Resource aims to innovate genetic engineering strategies in mouse and human embryonic stem cells, and apply these strategies to address contemporary questions in molecular and developmental haematology. Application of these strategies includes: 1) monitoring and controlling stem cell self-renewal and commitment to differentiation by use of reporter transgenes and inducible expression systems; 2) facilitating functional analyses using both forward and reverse genetic approaches to understand the regulation of gene expression and the role and interaction of genes in haematopoietic development; 3) constructing new sophisticated models of human blood diseases for both in-vitro and in-vivo analysis, and for drug screening and development. In addition, this Resource is using its expert knowledge and newly developed technologies to assist other research groups in the MRC Molecular Haematology Unit in their individual Programmes.