Amyotrophic lateral sclerosis: biological drivers of a complex disease
Supervisors: Prof Kevin Talbot, Prof Martin Turner, Dr Alexander Thompson
Background
Amyotrophic lateral sclerosis (ALS) causes progressive weakness due to loss of neurons within the corticomotoneuronal system. Despite decades of preclinical research and clinical trials, there remains only a single globally licensed disease-modifying therapy with a small effect on survival. The upstream cellular and neuronal network-level events that lead to ALS are complex, with genetic evidence indicating that these differ between individuals; this potentially underlies failure of current treatment approaches which do not distinguish causal mechanisms between individuals. The proposed DPhil candidate will be embedded within the Oxford MND Care and Research Centre, led by Prof Kevin Talbot, Prof Martin Turner and Dr Alexander Thompson, which combines providing clinical care to 10% of people with ALS in the UK with a research portfolio spanning preclinical cellular disease models, world-leading longitudinal biofluid, imaging and neurophysiological cohort studies, and large scale epidemiological and genetic research in ALS.
Project overview
The proposed DPhil programme will integrate analysis of cellular phenotype based on induced pluripotent stem cell (iPSC) modelling using motor neuronal and microglial monoculture and coculture to explore cellular mechanisms of disease heterogeneity. Resulting data will be integrated with clinical, biofluid and cortical neurophysiological datasets, including data from experimental medicine interventional studies, to discover the downstream manifestations of biological heterogeneity. There is scope further integrate research at the population level using genomic data from people with ALS through the Project MinE Consortium and UK Biobank.
Training opportunities
The student will be embedded within the MND Care and Research Centre. Dependent upon the eventual direction of the DPhil project, the student will have the opportunity to develop skills in tissue culture, specifically induced pluripotent stem cell modelling or brain organoid modelling as well as cellular neurophysiology under the supervision of Prof Kevin Talbot. They will learn bioinformatic skills under supervision of Dr Thompson, cortical neurophysiology and imaging with Prof Turner, working closely with the bioinformatic core at the GSK-funded Institute of Molecular and Computational Medicine. As a clinical trainee, they will attend the Oxford MND Clinic, developing complementary skills in the diagnosis and management of ALS.