Targeting Neuromuscular Ageing using Novel Synthetic Retinoids and Chrono-pharmacological Approaches

Project summary (maximum of 4000 characters including spaces/returns) -from original proposal Ageing is characterized by a loss of neuromuscular function and muscle mass/strength, which contributes to frailty and lower quality of life. This poses a significant socio-economic burden on the UK healthcare as well as globally. Retinoic acid (RA) signalling has recently emerged as an important regulator of neuromuscular repair/regeneration. Most of its effects are mediated by nuclear RA receptors (RAR a/b/y) through binding to RA-responsive elements (RAREs) to regulate target genes and through non-genomic pathways. Active vitamin A, retinoic acid (RA), has been known to have profound effects on neuromuscular function. However, one of the main drawbacks of vitamin A metabolites for clinical use is their short half-life and photic instability. Our SME partner, Nevrargenics, has developed a panel of dual-acting synthetic retinoids with improved potency and increased light stability. In addition, supervisory team has recently characterised some of the lead compounds using peripheral motor neuron models (Durham) and time-of-day effects on muscle cell differentiation (Liverpool).

Circadian timing regulates many physiological processes in the body, including timely activation of signalling pathways and drug metabolism. Preclinical and clinical data show that optimal circadian timing is an important determinant of drug success-it modifies up to tenfold the extent of tolerability and doubles the extent of efficacy for >500 drugs. >85% of drugs with half-lives <15hrs show time-of-day dependency, and most synthetic retinoids have short to moderate half-lives. However, the optimal dose and timing of administration regimens of lead retinoids is yet to be formulated to improve drug efficacy and avoid undesirable side effects.

This project will investigate the following hypotheses that: 1) skeletal muscle and motor neuron cells show circadian regulation of RA signaling, which is altered with age and 2) Time-scheduled retinoid administration improves RA signaling target engagement and 3) Neuromuscular changes with age can be partially rescued using time-scheduled retinoid treatments.

This project has the following main aims:
1. Determine the circadian regulation of RA signalling in skeletal muscle and motor neurons from young and old animals.
2. Characterize the effects of time-scheduled retinoid treatments using clock reporter cells and tissue explants.
3. Investigate the effect of time-scheduled retinoids on age-related neuromuscular changes and model interactions between circadian clocks and RA signaling to predict their mutual interactions.

In this PhD project we will gather essential proof-of-concept data as to the optimal timing of Nevrargenics lead retinoids, which will form a framework for drug testing in in vivo models of neuromuscular ageing and in silico modelling of retinoid effects.