Cardiovascular function around the clock: harnessing protective circadian mechanisms towards smarter design of novel retinoid therapies and lifestyle interventions

About the Project

This exciting project will investigate novel protective cardiac mechanisms and time-of-day circadian information on optimal treatments with the aim of improving cardiovascular health. The student will benefit from multidisciplinary training in a number of cutting-edge research areas from whole body physiology, chronobiology and cardiovascular ageing to pharmacology, synthetic chemistry and data science/modelling.

Heart failure (HF) is one of most significant contributors of mortality globally. Whilst some therapeutic options are available, half of the people die within 5 years of diagnosis, and those diagnosed with end-stage heart failure die within a year. Emerging data has shown that HF in patients is associated with downregulation of retinoic acid (RA) pathway, and that retinoid-based treatments in preclinical models have promising results on cardiovascular outcomes.

Circadian rhythms, a cell-autonomous ~24h time-keeping mechanism, controls many physiological processes such as sleep/wake cycles, drug metabolism and hormones. Many indices of cardiovascular function are regulated by the clock and clock disruption in humans and animals is associated with a number of cardiovascular conditions and adverse outcomes. We have recently gained data showing that circadian rhythms regulate key components of RA pathway in peripheral organs, hence supporting the need for time-scheduled retinoid targeting. This project will provide novel paradigm-shifting knowledge on protective cardiac mechanisms and time-of-day information on optimal treatments with novel synthetic retinoids (provided by our industrial partner) to improve cardiovascular health, which is translationally relevant to patients.

This exciting PhD project will test the two main hypotheses that:

1. Disruption of cardiac clocks leads to altered RA pathway
2. Realigning cardiac clocks is essential for designing effective therapies to improve cardiovascular health.

We will investigate 3 main aims:

1. Identify key biomarkers within RA pathway regulated by the cardiac clocks, and how they change with age
2. Determine how the circadian RA pathway is changed in preclinical models of HF, pathological cardiac hypertrophy and physiological hypertrophy.
3. Test optimal time-of-day treatments for novel retinoids in their ability to boost cardiovascular RA metabolism.

EXPERIMENTAL APPROACHES: We will utilise in vivo preclinical mouse models of ageing and HF containing clock luciferase reporters as well as in vitro culturing of human cardiac cells with serum samples from HF patients. Key laboratory methods include: real-time bioluminescence imaging to monitor clock gene rhythms, histological assessment of tissue/cell physiology, gene/protein expression analyses to determine molecular changes and genome-wide omics profiling approaches to identify time-of-day regulation of target biomarkers. Training will also involve quantitative in silico approaches to model chrono-based retinoid targeting in a human setting and the effects of clock disruption on cardiovascular system and target biomarkers.

RESEARCH ENVIRONMENT: The student will be trained in vibrant multi-user laboratories where they will share stimulating research environment with several PhD students and post-docs from diverse backgrounds. Through the combined expertise of the supervisory team and an industrial partner, the student will benefit from multidisciplinary training in a number of cutting-edge research areas from whole body physiology, chronobiology and cardiovascular ageing to pharmacology, synthetic chemistry and data science/modelling. Throughout their PhD training, the student will be encouraged to take up valuable training opportunities and research exchanges, participate in national/international conferences and attend in-house courses to boost their research skills (e.g. IT, statistics, scientific integrity, ethics, critical thinking, project and time management, networking and teamwork, scientific writing, presentation skills and patient/public involvement).

Supervisors:

Dr Vanja Pekovic-Vaughan - Vanja.Pekovic-Vaughan@liverpool.ac.uk

Dr Sunil Logantha - sunil.logantha@liverpool.ac.uk

Dr Masoud Isanejad - M.Isanejad@liverpool.ac.uk

Prof Paul Chazot - paul.chazot@durham.ac.uk

Please email your CV and cover letter to the primary supervisor along with the project title and reference number, Dr Vanja Pekovic-Vaughan, in the first instance vpv35@liverpool.ac.uk