Hancox, Thomas 
ORCID: 0000-0002-6315-5232
(2024).
An investigation into the circadian regulation of metabolism in mammals in relation to sex, health, and disease.
University of Birmingham.
Ph.D.
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Hancox2024PhD.pdf
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Abstract
Circadian rhythms describe endogenous ~24 h cycles in behaviour and biological processes that are regulated by the circadian system. The circadian system, akin to an internal clock, regulates an organism’s behaviours and biological processes about the day so that they occur at the most optimal time. Over the course of the last decade a new field has emerged applying metabolomic platforms to study the circadian regulation of metabolism in humans. Interest in this field has grown as epidemiological evidence has shown metabolic disorders, such as obesity and type 2 diabetes, are enriched in populations at risk of circadian misalignment e.g., shift workers. This epidemiological evidence is suggestive of a link between the two systems. Prior studies in the field have attempted to characterise circadian metabolite rhythms in healthy populations to better understand the nature of this relationship between the two systems and their co-regulation of one another. In addition, studies simulating shift work and sleep deprivation, which can induce circadian misalignment, have been performed to investigate how these factors disrupt the regulation between these two systems. Studying circadian rhythms in humans requires specialist facilities and demanding protocols that control for external factors that can influence the circadian system and require multiple samples, e.g., blood, to be taken across a >= 24 h time course. As a result, cohorts from circadian studies are often small in number and favour male participants to remove the menstrual cycle, another biological rhythm, as a conflicting variable.
First and foremost, this thesis sought to review the current knowledgebase of this emergent field and identify avenues of future research. Identified gaps in prior research included the aforementioned lack of female representation with no prior human circadian/metabolomics study having investigated a balanced male and female cohort. Further, it was made apparent that there was little diversity in the ultra-high performance liquid chromatography mass spectrometry (UHPLC-MS) assays applied in the field with the vast majority favouring reversed phase assays in positive ion mode.
Second, this thesis acted on the results of the review to apply the most comprehensive untargeted UHPLC-MS study to data, encompassing four assays. These four UHPLC-MS assays were applied to high resolution (2 hourly, 32 h time course) time series samples collected from the largest mixed sex cohort in the field to date, containing 16 males and 16 females. This resulted in the largest list of annotated rhythmic metabolites assembled to date and highlighted lipids; specifically, glycerolipids, fatty acids, and phospholipids, as metabolite classes strongly regulated by the circadian system. Further, it is the first study capable of directly comparing male and female metabolite rhythms as the male and female cohorts were subject to the same experimental design from the point of recruitment through to sample and data analysis. These comparisons facilitated novel observations such as a greater number of rhythmic lipids in females versus male counterparts.
Finally, the data handling and rhythm analysis workflows developed as part of the human circadian study were applied to other time series metabolomic datasets. In this instance to investigate alterations in circadian regulation of metabolism of Huntington’s disease at different ages within a large mammal (sheep) model. Application of the rhythm analysis workflow identified subtle shifts in phospholipid rhythms in sheep with Huntington’s disease relative to controls which appear to progress with age. These perturbations were observed in pre-symptomatic animals and further our understanding of the pathology of Huntington’s disease at this early stage.
| Type of Work: | Thesis (Doctorates > Ph.D.) | ||||||||||||||||||
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| Award Type: | Doctorates > Ph.D. | ||||||||||||||||||
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| Licence: | All rights reserved | ||||||||||||||||||
| College/Faculty: | Colleges > College of Life & Environmental Sciences | ||||||||||||||||||
| School or Department: | School of Biosciences | ||||||||||||||||||
| Funders: | Biotechnology and Biological Sciences Research Council | ||||||||||||||||||
| Subjects: | Q Science > Q Science (General) Q Science > QP Physiology |
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| URI: | http://etheses.bham.ac.uk/id/eprint/14689 |
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