Cardiovascular and Neuromuscular Functions around the Clock: Harnessing Protective Endogenous Mechanisms towards Smarter Design of Novel Therapies and Interventions

Description

Optimal tissue and organ is essential for long-term health and quality of life. One such important regulator within the body is related to circadian rhythms, which control ~24h cycles in many physiological processes such as sleep/wake cycles, physical activity/rest cycles, drug metabolism and hormones. Circadian (24h) rhythms are biological timing mechanisms that keep our body in tune with the external environment and their disruption (as a result of ageing, genetic variation, shift work, high fat diet) is a major risk for developing a number of cardiovascular conditions and adverse cardiovascular events.

Heart failure is one of most significant contributors of mortality globally and 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 many indices of cardiovascular function are regulated by the circadian clock and that clock disruption in humans and animal models is associated with a number of cardiovascular conditions and adverse cardiovascular events including heart attacks and strokes. In addition, frequent complaints of daytime sleepiness, chest plain and fatigue are common among patients with cardiovascular disorders. Moreover, research data has shown that many indices of neuro-muscular function are regulated by the circadian clock and that clock disruption in humans and animal models is associated with a number of neuro-muscular conditions including muscle weakness (sarcopenia), lower back pain (sciatica) and other neuromuscular disorders. Daytime sleepiness, muscle pain and fatigue are common among patients with neuromuscular disorders such as ALS, muscular dystrophy, postpolio syndrome and myasthenia gravis.

This exciting PhD project will test the main hypothesis that disruption of circadian clocks within the cardiovascular system leads to disrupted molecular pathway within the cardiovascular system and that realigning circadian clocks is essential for designing effective therapies for improving cardiovascular health. We will investigate the following three major aims:

1. Identify the key biomarkers regulated by the circadian cardiovascular or neuromuscular systems, and how they change with age.
2. Evaluate how the circadian pathway regulation is changed in preclinical models of heart failure and physiological hypertrophy or sarcopenia and diabetic neuropathy (muscle wasting).
3. Test the optimal time-of-day pharmacological and time-of-day light/diet/exercise regimes in their ability to boost circadian metabolism within the cardiovascular or neuromuscular system.

To investigate molecular changes in the circadian system, we will use tissues/cells from preclinical models of ageing and disease containing clock luciferase reporter as well as human cardiac or muscle cells and blood samples from 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 clock changes and genome-wide omics profiling approaches to identify time-of-day regulation of target biomarkers. We will use light-based interventions and novel drug based drug candidates provided through our Industrial partner. The training will also involve the use of quantitative approaches to model chrono-based drug targeting in a human setting as well as the use of population-based public databases to understand the effects of clock disruption on cardiovascular system and target biomarkers.

This project will be supervised by an interdisciplinary team spanning areas of molecular and cellular biology, circadian physiology/genetics, cardiovascular medicine, neuromuscular medicine, nutrition, pharmacology and synthetic biology, including Dr Vanja Pekovic-Vaughan https://www.liverpool.ac.uk/life-course-and-medical-sciences/staff/vanja-pekovic-vaughan, Dr Sunil Logantha https://www.liverpool.ac.uk/life-course-and-medical-sciences/staff/sunil-jit-logantha, Dr Masoud Isanejad https://www.liverpool.ac.uk/life-course-and-medical-sciences/staff/masoud-isanejad, Prof Paul Chazot https://www.durham.ac.uk/staff/paul-chazot and Prof Andy Whiting (industrial partner https://nevrargenics.com), with an unique opportunity to experience the processes of drug discovery/development in a commercial environment. For any informal queries about the project or application process, please contact the primary supervisor, Dr Vanja Pekovic-Vaughan (vpv35@liv.ac.uk).