The impact of circadian desynchrony on cardiovascular function.

Lead Research Organisation: University of Manchester
Department Name: School of Medical Sciences

Abstract

Organisms on our planet use internal biological clocks anticipate recurring fluctuations in the environment. Dysfunction of the circadian system has a profound impact on human health and wellbeing. For example, chronic shift work is associated with increased incidence of obesity, cardiovascular disease, diabetes, and cancer. We recently revealed that desynchrony between the internal circadian clock and the external light-dark environment has a pronounced effect on cardiac function in mice. This PhD examines why the cardiovascular system is particularly vulnerable to circadian dysfunction, and defines underlying mechanisms involved. Studies will focus on whole animal physiology and incorporate novel genetic and pharmacological techniques to manipulate clock function. This project will advance our understanding of cardiovascular physiology, and provide important new insight into human pathologies associated with circadian disruption and morning susceptibility to sudden cardiac death.
The project reflects the BBSRC 'new ways of working' initiative through our integrative approach to mammalian physiology (from gene to whole animal physiology), tool development (through novel imaging techniques for in vivo analysis of gene expression) and the use of computational approaches to electrophysiological data analyses.
Specifically, the student will gain extensive experience in:
i) The study of whole animal physiology (physiological monitoring, ECG recording, and behavioural assessment; surgical procedures, in vivo models of clock dysfunction, genetic targeting and environmental manipulation).
ii) Ex vivo techniques including the study of cardiac electrophysiology, contractility and pacing, in vitro cell/tissue culture, and molecular techniques.
iii) Computational analyses of electrophysiological data and basic programming.
Therefore, this project represents an excellent training opportunity, employing the latest technologies and contributing vital in vivo training (currently underrepresented) skills to the UK research infrastructure.

Studentship Projects

Project Reference Relationship Related To Start End Student Name
BB/M011208/1 30/09/2015 29/09/2023
1917117 Studentship BB/M011208/1 30/09/2017 29/09/2021 Edward Hayter
 
Description 1. Designed new algorithms for the analysis of longitudinal ECG data in human and mouse.
2. Identified that features of cardiac electrophysiology (eg. pace making, atrioventricular delay) are differentially influenced by circadian clocks in the brain and heart, rendering these features susceptible to misalignment during changes of routine. This is consistent across human and mouse models.
3. Cardiac arrhythmia susceptibility displays a daily rhythm in mice, and circadian clocks in the heart contribute to this rhythm.
Together these reveal vital new understanding about how the circadian system influences cardiac electrophysiology, and has direct relevance to humans.
Exploitation Route Our findings reveal new avenues for follow up research including questions such as:
What is the impact of circadian misalignment of cardiac electrophysiology?
What are the underlying mechanisms coupling the circadian system to cardiac arrhythmias?
Can medial interventions utilise the circadian influence over cardiac electrophysiology to protect against/mitigate risk of arrhythmias in at risk patients?

We are currently investigating some of these avenues of research as part of a new grant from the BBSRC.
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology,Other

 
Description Rhythms in the beat: Circadian Clock Regulation of Cardiac Electrophysiology
Amount £576,764 (GBP)
Funding ID BB/V002651/1 
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 05/2021 
End 05/2024
 
Description Travel grant from Guarantors of Brain
Amount £800 (GBP)
Organisation Guarantors of Brain 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2018 
End 05/2018
 
Title Automated longitudinal human and mouse ECG analysis 
Description A set of MATLAB functions to automatically extract features from collected ECG data from human and mouse. This algorithm is publicly available on Github/Zenodo under the MIT licence (DOI 10.5281/zenodo.4729936). Full details of this algorithm can be found in the associated publication (DOI 10.1038/s41467-021-22788-8). 
Type Of Material Computer model/algorithm 
Year Produced 2021 
Provided To Others? Yes  
Impact This algorithm allowed us to accurately extract ECG features from large amounts of longitudinal data which would not have been possible manually. This data was then used to generate new understanding regarding the circadian control of cardiac electrophysiology. 
URL https://github.com/EdHayter/Hayter-et-al.-ECG-analysis
 
Description Article for Physiology News magazine 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact wrote an article on how the field of circadian rhythms is taught to undergraduates and the public for a news magazine.
Year(s) Of Engagement Activity 2018
URL http://www.physoc.org/magazine-articles/time-to-learn-the-teaching-of-circadian-rhythms/