Functional genetics in multiple sclerosis: determining the translational potential
Supervisor: Prof Lars Fugger
Multiple sclerosis (MS) is the most common disabling neurological condition in young adults in the developed world, and has major personal and socioeconomic consequences. Disease susceptibility is jointly determined by genetic predisposition and environmental contributions. Through our past work we have demonstrated how the first indentified MS genetic determinants can interact with each other (Nature, 443, 574-577; Nature Medicine, 14, 1227-1235) and with environmental factors (Immunity, 30, 348357) to modify or drive disease development.
Better understanding the pathogenesis of MS and how each of its contributing factors increases disease risk alone and in concert is critical: current therapies for MS have very broad effects and are thus associated with severe side-effects. Therefore, there is an urgent need to develop new, more refined therapeutic strategies that are efficacious but that result in fewer adverse responses.
One of the most significant developments in MS research in recent years has been the identification of over 100 different genetic factors that confer risk for the disease. These genetic findings have the potential to provide a wealth of information regarding the specific mechanisms involved in the key processes that drive MS, but taking advantage of these so-called ‘big data’ requires functional analyses to interrogate the biological consequences of the genetic factors. We have recently shown through a proof-of-principle study that investigating the functional consequences of MS-associated genetic variation can be clinically informative (Nature, 488, 508-511; The New England Journal of Medicine, 367, 2370-2371; Nature Medicine, 19, 138-139).
Further expanding on this concept, the DPhil project will be based on a broader translational programme (see schematic below) that incorporates the latest technologies in a tiered approach that assesses how the smallest of genetic alterations may change specific properties of immune and nerve cells, right through to how the interactions of these altered cells are orchestrated in an entire organism, thereby leading to the inflammation and neurodegeneration that cause MS (Nature Reviews Immunology, 9, 408-417; Nature Review Neurology, 10, 225-238). Particular consideration will be given to pathways amenable to drug repositioning, whereby key disease mechanisms are targeted by clinically safe drugs already licensed for the treatment of other conditions (Nature Medicine, 12, 1483-1489; MS Society Award 2012). This interdisciplinary project is at the crossroads of genomics, neuroimmunology and translational medicine, and will incorporate a range of cutting-edge experimental approaches, including CRISPR genetic microsurgery methods, Capture-C technology, in vitro human primary cell and stem cell-based assays, polychromatic flow cytometry, in vivo transgenic models, and next generation optical imaging.
For further information please contact: Prof Lars Fugger