Supporting Enlarged Motor Units in Mouse Models of Childhood Motor Neuron Disease

This project is fully funded by Spinal Muscular Atrophy UK and Muscular Dystrophy UK. Application deadline is the 28th of February. Please see below for application process. Please email [Email Address Removed] for informal inquires.

Spinal muscular atrophy is a childhood motor neuron disease with a genetic origin. When motor neurons are lost, the remaining motor neurons undergo compensatory enlargement. In milder forms of SMA, enlarged motor units become progressively dominant. Furthermore, although current treatments can dramatically slow motor neuron loss, remaining motor neurons will exist in a chronically enlarged state. The enlargement of motor units in SMA is central to the disease process, yet it is remarkably understudied.

Enlarged motor units are thought to encounter heightened oxidative stress due to their increased metabolic demands, which negatively impacts upon their longevity. In this project, we will determine whether administration of drugs which can reduce oxidative stress can confer additional benefit to SMA mouse models. We will give mice one of the approved therapies for SMA and then also give another pro-survival drug (there are 4 to test). We will quantify the effect on survival and neuropathology.

In parallel to this, we will also induce motor unit enlargement in wild-type mice, by a L4 spinal nerve injury. RNAseq will be performed on laser captured motor neurons 12 months later. This will reveal the pathways which are disrupted following chronic enlargement of motor unit size, and will identify novel therapeutic targets which could be exploited to support large motor units.

This work will give important insight into the therapeutic potential of decreasing oxidative stress to support enlarged motor units in SMA and identify novel pathways which could be therapeutically targeted to support motor units and extend the effective therapeutic time window. 

Applicants should send a CV and 2 references to [Email Address Removed] by the 28th of February. Please also include a cover letter which details your experience and motivations.