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 α/β/γ) through binding to RA-responsive elements (RAREs) to regulate expression of target genes as well as non-genomic pathways. Active vitamin A, retinoic acid (RA), has been known for decades 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.
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. Many commonly used drugs have benefited from chronotherapy, >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 signaling 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 exciting PhD project we will gather essential proof-of-concept data as to the optimal timing of retinoids, which will form a framework for drug testing in in vivo models of neuromuscular ageing and in silico modelling of retinoid effects.
HOW TO APPLY
Applications should be made by emailing email@example.com with:
· a CV (including contact details of at least two academic (or other relevant) referees);
· a covering letter – clearly stating your first choice project, and optionally 2nd ranked project, as well as including whatever additional information you feel is pertinent to your application; you may wish to indicate, for example, why you are particularly interested in the selected project(s) and at the selected University;
· copies of your relevant undergraduate degree transcripts and certificates;
· a copy of your IELTS or TOEFL English language certificate (where required);
· a copy of your passport (photo page).
A GUIDE TO THE FORMAT REQUIRED FOR THE APPLICATION DOCUMENTS IS AVAILABLE AT https://www.nld-dtp.org.uk/how-apply. Applications not meeting these criteria may be rejected.
In addition to the above items, please email a completed copy of the Additional Details Form (as a Word document) to firstname.lastname@example.org. A blank copy of this form can be found at: https://www.nld-dtp.org.uk/how-apply.
Informal enquiries may be made to email@example.com
The deadline for all applications is 12noon on Monday 9th January 2023.
Open to students worldwide
Cellular mechano-environment regulates the mammary circadian clock. Nature Comm 2017 30 (8):14287
The circadian clock regulates rhythmic activation of the NRF2/glutathione-mediated antioxidant defense pathway to modulate pulmonary fibrosis. 2014 Genes & Development 28 (6): 548-60
Redox responses in skeletal muscle following denervation. Redox Biol 26:101294
The pathopharmacological interplay between vanadium and iron in Parkinsons’s disease models 2020 Int J Mol Sci 14;21(18):6719
PeTTSy: a computational tool for perturbation analysis of complex systems biology models. BMC Bioinformatics. 2016 10;17:124