Project No. 2318

STANDARD PROJECT

Primary Supervisor

Prof Nullin Divecha – University of Southampton

Co-Supervisor(s)

Prof Anastasia Callaghan – University of Portsmouth

Prof K Lillycrop – University of Southampton

Summary

Many adults spend the last decade of life in poor health.

One major feature of ageing is loss of muscle mass and function (sarcopenia), leading to impaired mobility, physical disability, increased insulin resistance and associated co-morbidities, and mortality. Sarcopenia occurs through decreased satellite cell number and decreased capacity to differentiate and regenerate muscle fibres. Identifying druggable factors that maintain the number and function of muscle satellite cells is a priority that will directly impact quality of life.

Nuclear polyphosphoinositide (PPIns) signalling is composed of highly druggable lipid kinases and phosphatases controlling messenger PPIns lipid levels. Nuclear-PPIns are key nodes impacting DNA damage and epigenetic signalling pathways to control cell fate decisions, such as myogenic differentiation.

Using a muscle stem like cell model of ageing induced loss of muscle differentiation, we discovered that altering nuclear PPIns dramatically reinvigorates muscle cell differentiation. Furthermore, we have discovered that RNA splicing factors containing RNA binding motifs are key regulators that control the levels of nuclear PPIns suggesting an important link between nuclear PPIns, splicing factors and maintenance of muscle stem cell vigour during ageing.

The challenge for the PhD student will be to combine cellular biology, signalling technologies and PPIns pathway inhibitors (Divecha) with novel RNA array technologies and biophysical molecular interaction approaches (Callaghan lab) to reveal how nuclear PPIns/RNA binding motifs modulate muscle stem cell biology. The student will also utilise a panel of satellite cells derived from young, middle, and old aged patients to study how nuclear PPIns manipulation impacts on muscle stem cell function (Lillycrop).

We expect the student to develop expertise in:
• Muscle stem cell biology
• High-definition cell microscopy
• Transformative PPIns-modulation technologies
• CRISPR-CAS9 mediated gene editing
• Large data bioinformatic analysis
• RNA, RNA binding motifs, PPIns and their interactions
• Biophysical and structural techniques; including application of the novel RNA array technology