Primary supervisor: Dr Lyndsay Murray
Other supervisors: tbc
Location: University of Edinburgh
Project description
Spinal Muscular Atrophy (SMA) is a motor neuron disease with predominantly childhood onset caused by low level of SMN protein. Untreated, this disease can cause death before the age of two years. The SMA field has recently been transformed by the advent of new treatments which act by increasing SMN levels. Although these treatments have conferred dramatic benefit to many people, a significant number of patients continue to experience chronic weakness and fatigue, and difficultly in fundamental motor tasks such as walking, eating or breathing. There is a need to understand the defects which persist after treatment, and to find ways to target them with the next generation of drugs.
In my lab we use mouse models of SMA and track the recovery of the motor unit following administration of SMN up-regulating drugs. In the conduit of this work, we have identified persistent defects in motor unit structure, specifically a persistent loss of axons and anomalies at the neuromuscular junction. We have identified some strategies which can offer further protection to the structure of the motor unit, but their affect of motor unit function is unknown. This is critical to assess the translational relevance.
In this project, we will using in vivo electrophysiology to profile the recovery of the motor unit following administration of Smn up-regulators in mouse models of SMA. We will subsequently trial a range of strategies to improve the recover of the motor unit and use a combination of structural and functional studies to assess their efficacy.
This project is designed to target unmet needs in an important patient group. However, since SMA sits at the translational forefront, findings here will have broad implications for other disorders of the nervous system and will identified the next generation of therapeutic strategies which could help improve recovery of the nervous system after injury or disease.
References
Comley LH, Kline RA, Thomson AK, Woschitz V, Landeros EV, Osman EY, Lorson CL, Murray LM. Motor unit recovery following Smn restoration in mouse models of spinal muscular atrophy. Hum Mol Genet. 2022 Sep 10;31(18):3107-3119. doi: 10.1093/hmg/ddac097. PMID: 35551393; PMCID: PMC9476628.
