How motor neurone disease affects metabolic substrate transport and utilisation.

We have developed a phenotypic screening assay (Biolog) which screens MND patient lines to discover novel areas of dysfunction. Working in collaboration with Biolog, we will screen induced neuronal progenitor cell (iNPC) derived iAstrocytes from patients with MND using Biolog’s emerging 96 well plate technology to metabolically characterise cell models and identify energy substrates that are dysfunctional in disease models. We will use functional screening to assess whether the energy substrates identified have disrupted transport or metabolism defects and how the iAstrocytes respond to mitochondrial inhibition and metabolic effectors. We will then identify which enzymes are involved and assess whether metabolic supplementation restores the pathways of interest and ameliorates pathogenic processes in the cell. The project will involve extensive primary iNPC tissue culture and differentiation, 96 well plate based screening assays using an OmniLog™ phenotypic screening system, western blot, ATP assays, InCell assays and XF metabolic flux assays. The prospective candidate will work in the Sheffield Institute for Translational Neuroscience (SITraN) a world class research facility in the centre of Sheffield (http://sitran.org).