Molecular Characterisation of novel candidate genes for spinal muscular atrophy

Ref: S2017SHLS006

Background.
Spinal muscular atrophy (SMA) is a neuromuscular disease that primarily causes muscle wasting and respiratory problems. SMA is the leading genetic cause of infant mortality in humans; 1 in every 6,000 to 10,000 births are affected in the UK. Despite a full understanding of the genetic cause of the disease (mutations in a single gene known as survival motor neuron 1, SMN1, resulting in loss of the SMN protein), there is currently no cure. Severe SMA patients will usually die within 2 years.
Current therapies in development for SMA specifically target the central nervous system (CNS), but we know that multiple tissues outside the CNS (systemic tissues) are affected by SMA. Recent research carried out by us and our collaborators showed that therapeutically targeting a gene downstream of SMN1 results in improvements to neuromuscular, but not systemic, pathology. We now aim to identify further novel pathways that could be therapeutically targeted to improve all aspects of SMA pathology.

Aims.
• To identify novel genes downstream of SMN with altered expression in SMA affected tissues
• To identify novel genes with therapeutic potential for SMA

Methods. This studentship will use mouse tissue (from a mouse model of SMA used by our collaborators at the University of Edinburgh) and patient tissue (available from existing BioBanks). A range of approaches will be used, including quantitative real-time PCR, methylation analyses, quantitative immunoblotting and transient in vitro assays (such as quantitative measurement of apoptotic markers and the ER stress response). We will assess candidate gene expression in multiple tissues, including systemic and CNS tissues. We will also perform microarray and methylation analyses of SMA mouse muscle to identify novel SMA genes and pathways. In vitro analyses will be used to establish whether gene expression can be therapeutically manipulated.

Outcome.
The student will gain experience in a range of state-of-the-art molecular assays and will perform extensive characterisation of genes that are potentially downstream of SMN.

Training.
The student will gain experience in a range of state-of-the-art molecular assays and will benefit from collaborations through involvement in a network of UK SMA researchers (Prof Tom Gillingwater, Edinburgh; Prof Simon Parson, Aberdeen; Dr Tom Wishart, Roslin Institute) and the Euan MacDonald Centre for Motor Neuron Disease research. The student will be encouraged to attend collaborative meetings and to present research findings where appropriate.

Timelines.
Year 1. Literature review and quantitative gene/protein analysis of genes of interest
Year 2. In vitro work and microarray analyses to identify novel genes
Year 3. Completion of research work and attendance at the CureSMA conference in June 2020 to present results.

Specific requirements of the project:
A background in molecular biology and quantitative gene analysis would be advantageous.