Genetic variation and altered leukocyte function in health and disease (GANDALF) – Generation of induced pluripotent stem cells as cellular models to study the effects of genetic variation in FOXO3A (substudy)
Dr Paul Lyons
Institution or company
University of Cambridge
The immune system is a complex network of cells, tissues, and organs that work together to protect the body from infections and maintain health. Occasionally, the immune system can hit the wrong target and attack normal parts of the body, giving rise to autoimmune diseases, like systemic lupus erythematosus, type 1 diabetes and rheumatoid arthritis.
The immune response varies a lot between different people, and the underlying mechanisms are only partially understood. We are especially interested in how genetic variation influences immune responses, affecting individual predisposition to diseases and, once diseases are established, modulating their severity.
In particular, this study will focus on a gene, called FOXO3A, that plays a key role in regulating inflammation. Variants in this gene have been associated with clinical outcome in malaria, Crohn’s disease and rheumatoid arthritis. Gaining insights into the underlying biological mechanisms promises to facilitate the development of novel treatments and personalised medical management. However, performing these studies requires significant amounts of cells from individuals that carry different variants of the gene. This means that multiple blood draws would be required, and some experiments would not be feasible at all. This important limitation can be circumvented using inducible pluripotent stem cell (iPSC) technology. iPSCs are generated by “reprogramming” adult cells into a pluripotent state that enables the development of any type of human cell.
In this study we will generate iPSCs from volunteers carrying known variants in the FOXO3A gene. This will establish an unlimited source of differentiated cells (such as immune system cells) to investigate how genetic variation in FOXO3A affects different biological pathways and, ultimately, modulates health and disease.