ADP-Ribosylation as a regulator of metabolism

The post-translational modification ADP-Ribosylation (ADPR) cleaves the critical cofactor NAD+ (nicotinamide adenine nucleotide). PARP1 is both the cells key source of ADPR and major consumer of NAD+. Existing roles of PARP1 link fundamental biological processes including endocrine signaling, RNA stability and cellular identity. As a result, both PARP1 and ADPR have been shown to be dynamic and sensitive to disease status. However, a lack of understanding remains surrounding the tissue-specific roles of PARP1, the influence of nutritional NAD+, ADPR, and their contributions to health and the transition to dysregulated states.  

Skeletal muscle tissue has specialised features such as contractile organisation and metabolic adaptation, key to supporting vertebrate health. However, a progressive decline in skeletal muscle performance is common in human ageing and occurs in parallel with reduced quality-of-life. Currently, no clinical tool exists to sustain muscle function across the life course.  

We believe that muscle PARP1 is critical to whole body metabolism and the signaling events that determine overall muscle mass.  This project will work to reveal the contribution of PARP1 to in vivo physiology and define the molecular signaling events ADPR commands in skeletal muscle. This work will utilise a range of mouse genetic models, advanced physiology, and cutting-edge molecular techniques, with additional training at University of Texas - Southwestern Medical Center with world-leading collaborators.