A mechanistic investigation into the emergent functional dynamics of the HPA axis
Lead Research Organisation:
UNIVERSITY OF EXETER
Department Name: Mathematics
Abstract
Rhythmic or oscillating activity is everywhere in nature and is absolutely fundamental to our own physiology. Some bodily rhythms are very obvious to us, such as the beating of our heart and our daily sleep-wake cycle, but the vast majority of rhythmic processes inside the body are not so obvious. When these oscillations change in some way or become disrupted, this can have major consequences for our well-being. Examples of this include the emergence of abnormal rhythms in brain activity that can be seen in patients suffering from epilepsy or Parkinson's disease.
Hormonal signalling is governed by rhythmic activity with many hormones following a daily cycle. A good example of this is the vital steroid hormone cortisol, one of the most important hormones that enables us to respond rapidly and appropriately to stressful situations. Cortisol levels are low during periods of rest (sleep) but increase early in the morning to prepare the body for daily activity. In addition to this daily rhythm, we now know that levels of cortisol are actually oscillating much more rapidly every hour or so throughout the day, with larger pulses occurring in the morning.
Recent research has demonstrated that cortisol oscillations are critical for healthy bodily function as they control the activity of many important genes and ensure that the body is in an ideal state to respond to stress. Remarkably, patients undergoing hormone replacement or steroid therapy for inflammatory or malignant disease are typically still being exposed to constant levels of potent, long-acting, synthetic steroids. This pattern of delivery was developed before the importance of cortisol pulsatility became clear, and may well limit efficacy of treatment as well as contribute to the very high levels of side effects associated with the long-term use of synthetic steroids.
Exposure to early-life stress or excessively large or prolonged periods of stress can substantially disrupt cortisol oscillations. This in turn has major consequences for regions of the brain that control our behaviour and also increases susceptibility to many diseases. Given that stress and stress-related illness are rapidly-increasing features of modern society, it is crucial that we gain a deeper understanding of how the body regulates the dynamic pattern of cortisol production. In my research, I am employing mathematical modelling approaches in combination with state-of-the-art experimental technologies to address a number of key questions: How are cortisol rhythms generated? What changes occur in the body that lead to the abnormal rhythms we see in disease? What consequences do these disrupted rhythms have for our physiological and mental well-being? Can abnormal rhythms be "normalised"? Providing answers to these questions will not only transform our understanding of cortisol signalling in both health and disease, but will also be important for developing novel treatment strategies in the clinic that take into account timing of hormone delivery to patients undergoing long-term steroid therapy.
Hormonal signalling is governed by rhythmic activity with many hormones following a daily cycle. A good example of this is the vital steroid hormone cortisol, one of the most important hormones that enables us to respond rapidly and appropriately to stressful situations. Cortisol levels are low during periods of rest (sleep) but increase early in the morning to prepare the body for daily activity. In addition to this daily rhythm, we now know that levels of cortisol are actually oscillating much more rapidly every hour or so throughout the day, with larger pulses occurring in the morning.
Recent research has demonstrated that cortisol oscillations are critical for healthy bodily function as they control the activity of many important genes and ensure that the body is in an ideal state to respond to stress. Remarkably, patients undergoing hormone replacement or steroid therapy for inflammatory or malignant disease are typically still being exposed to constant levels of potent, long-acting, synthetic steroids. This pattern of delivery was developed before the importance of cortisol pulsatility became clear, and may well limit efficacy of treatment as well as contribute to the very high levels of side effects associated with the long-term use of synthetic steroids.
Exposure to early-life stress or excessively large or prolonged periods of stress can substantially disrupt cortisol oscillations. This in turn has major consequences for regions of the brain that control our behaviour and also increases susceptibility to many diseases. Given that stress and stress-related illness are rapidly-increasing features of modern society, it is crucial that we gain a deeper understanding of how the body regulates the dynamic pattern of cortisol production. In my research, I am employing mathematical modelling approaches in combination with state-of-the-art experimental technologies to address a number of key questions: How are cortisol rhythms generated? What changes occur in the body that lead to the abnormal rhythms we see in disease? What consequences do these disrupted rhythms have for our physiological and mental well-being? Can abnormal rhythms be "normalised"? Providing answers to these questions will not only transform our understanding of cortisol signalling in both health and disease, but will also be important for developing novel treatment strategies in the clinic that take into account timing of hormone delivery to patients undergoing long-term steroid therapy.
Technical Summary
The major hormonal system that enables a rapid response to stressors is the hypothalamic-pituitary-adrenal (HPA) axis. This complex neuroendocrine system regulates the secretion of vital glucocorticoid hormones (CORT), and a critical aspect of its function is an ultradian oscillation in hormone release. These oscillations in blood CORT levels are paralleled in the brain; thus neurons throughout the CNS are exposed to this dynamic signal. In hippocampal cells, for example, these rapid changes in CORT levels induce bursts of transcriptional activity and enhance glutamate transmission via non-genomic mechanisms.
Alterations in these oscillations are associated with a wide variety of physiological and pathological conditions, including chronic stress, but the reasons for these dynamic changes are poorly understood. The aim of my research proposal is to characterise the fundamental mechanisms that regulate the ultradian oscillation; and the changes that occur in the oscillation when these mechanisms break down. To achieve this, I will use an integrative approach, combining mathematical modelling with in vitro cellular imaging approaches and in vivo experimental physiology, which will enable me to study the dynamics of the system at multiple scales, and to understand the key mechanism underpinning the oscillatory activity of the system. Elucidating these mechanisms will not only help to realise normal physiological function, but will also help to understand why these dynamics change in disease; leading to the development of, or protection from, pathological consequences.
Alterations in these oscillations are associated with a wide variety of physiological and pathological conditions, including chronic stress, but the reasons for these dynamic changes are poorly understood. The aim of my research proposal is to characterise the fundamental mechanisms that regulate the ultradian oscillation; and the changes that occur in the oscillation when these mechanisms break down. To achieve this, I will use an integrative approach, combining mathematical modelling with in vitro cellular imaging approaches and in vivo experimental physiology, which will enable me to study the dynamics of the system at multiple scales, and to understand the key mechanism underpinning the oscillatory activity of the system. Elucidating these mechanisms will not only help to realise normal physiological function, but will also help to understand why these dynamics change in disease; leading to the development of, or protection from, pathological consequences.
Planned Impact
This Impact Summary contains details of who will benefit from my CDA and how they will do so.
In the short-term (1-5 years):
* My research team and direct collaborators will benefit through the launch of my new multidisciplinary research laboratory at the University of Exeter, which will integrate experimental imaging techniques with mathematical modelling approaches. In collaborating with an internationally leading biomedical research laboratory within the Institute of Functional Genomics (IFG), Montpellier, France, I will also facilitate knowledge sharing between the Universities of Exeter and Bristol and the IFG.
* The broader international biomedical research community will benefit from my CDA through the organisation of an international BioDynamics workshop, which will provide a forum for multidisciplinary presentations, interactions and discussion. They will gain further benefit though the continued development of our own MRC-funded web-based forum (www.bio-dynamics.org), which acts as an online hub connecting the biomedical community, and through me presenting my research findings at national and international conferences, and publishing my work in high-impact biomedical journals.
* Patients and the general public will also benefit, through both access to an online learning 'hub' (www.bio-dynamics.org) that I will continue to run with my collaborators, and the opportunity to attend a Public Understanding Event aimed at members of the public and patients who are affected by stress-related disorders or pathologies of the stress axis.
* Other beneficiaries include NC3Rs, who may be able to use my approach as a case study to illustrate how mathematical approaches can help to reduce the number of animals required in research, and the MRC, who will be able to use my research to highlight the potential of using predictive modelling to understand important questions about physiological regulation. This in turn may encourage more clinical scientists to establish collaborations with theoretical scientists.
In the medium term (5-10 years): clinicians managing HPA disorders may benefit by using my theoretical approaches to guide the decisions made in clinic, for example, through the development of mathematical models of the systems generating clinical observables, and the tools for exploring these mechanisms directly from clinical observables. Commercial-sector pharmaceuticals could also use my research to plan clinical trials to include data-derived prognostic biomarkers using findings from my research to either develop their own generative models, or pre-existing ones that I and others have developed. Further, my experimental data should accelerate the development of novel chronologically discrete methods of drug administration that more naturally mimic the body's own production of glucocorticoids, which will improve efficacy and decrease side effects from glucocorticoid administration.
In the long term (10+ years), my research will have an impact on patients with clinical disorders. I believe that an improved understanding of the mechanisms underlying normal HPA regulation and signalling will provide more rational treatment for patients, resulting in improvements to the health and quality of life of patients, reducing mortality and morbidity. The research contained within my proposal may ultimately provide the opportunity not only for improved diagnosis of adrenal hypo- and hyper-function, but also for improved therapy both for patients needing glucocorticoid replacement and for patients needing higher-dose glucocorticoid therapy for inflammatory or malignant conditions.
In the short-term (1-5 years):
* My research team and direct collaborators will benefit through the launch of my new multidisciplinary research laboratory at the University of Exeter, which will integrate experimental imaging techniques with mathematical modelling approaches. In collaborating with an internationally leading biomedical research laboratory within the Institute of Functional Genomics (IFG), Montpellier, France, I will also facilitate knowledge sharing between the Universities of Exeter and Bristol and the IFG.
* The broader international biomedical research community will benefit from my CDA through the organisation of an international BioDynamics workshop, which will provide a forum for multidisciplinary presentations, interactions and discussion. They will gain further benefit though the continued development of our own MRC-funded web-based forum (www.bio-dynamics.org), which acts as an online hub connecting the biomedical community, and through me presenting my research findings at national and international conferences, and publishing my work in high-impact biomedical journals.
* Patients and the general public will also benefit, through both access to an online learning 'hub' (www.bio-dynamics.org) that I will continue to run with my collaborators, and the opportunity to attend a Public Understanding Event aimed at members of the public and patients who are affected by stress-related disorders or pathologies of the stress axis.
* Other beneficiaries include NC3Rs, who may be able to use my approach as a case study to illustrate how mathematical approaches can help to reduce the number of animals required in research, and the MRC, who will be able to use my research to highlight the potential of using predictive modelling to understand important questions about physiological regulation. This in turn may encourage more clinical scientists to establish collaborations with theoretical scientists.
In the medium term (5-10 years): clinicians managing HPA disorders may benefit by using my theoretical approaches to guide the decisions made in clinic, for example, through the development of mathematical models of the systems generating clinical observables, and the tools for exploring these mechanisms directly from clinical observables. Commercial-sector pharmaceuticals could also use my research to plan clinical trials to include data-derived prognostic biomarkers using findings from my research to either develop their own generative models, or pre-existing ones that I and others have developed. Further, my experimental data should accelerate the development of novel chronologically discrete methods of drug administration that more naturally mimic the body's own production of glucocorticoids, which will improve efficacy and decrease side effects from glucocorticoid administration.
In the long term (10+ years), my research will have an impact on patients with clinical disorders. I believe that an improved understanding of the mechanisms underlying normal HPA regulation and signalling will provide more rational treatment for patients, resulting in improvements to the health and quality of life of patients, reducing mortality and morbidity. The research contained within my proposal may ultimately provide the opportunity not only for improved diagnosis of adrenal hypo- and hyper-function, but also for improved therapy both for patients needing glucocorticoid replacement and for patients needing higher-dose glucocorticoid therapy for inflammatory or malignant conditions.
Organisations
People |
ORCID iD |
Jamie Walker (Principal Investigator / Fellow) |
Publications
Campos P
(2020)
Diving into the brain: deep-brain imaging techniques in conscious animals.
in The Journal of endocrinology
F S
(2018)
Dynamic responses of the adrenal steroidogenic regulatory network
in Yearbook of Paediatric Endocrinology
Galvis D
(2022)
Modelling the dynamic interaction of systemic inflammation and the hypothalamic-pituitary-adrenal (HPA) axis during and after cardiac surgery.
in Journal of the Royal Society, Interface
Marinelli I
(2023)
Circadian distribution of epileptiform discharges in epilepsy: Candidate mechanisms of variability.
in PLoS computational biology
Richards DM
(2020)
Ion channel noise shapes the electrical activity of endocrine cells.
in PLoS computational biology
Romanò N
(2017)
Heterogeneity of Calcium Responses to Secretagogues in Corticotrophs From Male Rats.
in Endocrinology
Smith LIF
(2021)
Activation and expression of endogenous CREB-regulated transcription coactivators (CRTC) 1, 2 and 3 in the rat adrenal gland.
in Journal of neuroendocrinology
Spiga F
(2017)
Dynamic responses of the adrenal steroidogenic regulatory network.
in Proceedings of the National Academy of Sciences of the United States of America
Stirrat LI
(2018)
Pulsatility of glucocorticoid hormones in pregnancy: Changes with gestation and obesity.
in Clinical endocrinology
Tilston TW
(2019)
A Novel Automated System Yields Reproducible Temporal Feeding Patterns in Laboratory Rodents.
in The Journal of nutrition
Description | Transition Support Grant |
Amount | £269,943 (GBP) |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 09/2023 |
End | 09/2024 |
Description | Adrenal dynamics project |
Organisation | University of Exeter |
Department | College of Engineering, Mathematics & Physical Sciences |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | General project planning and discussion. Guidance on mathematical modelling of steroid synthesis and secretion mechanisms in adrenal cells. |
Collaborator Contribution | Mathematical modelling (University of Exeter) and complimentary in vivo experimentation (University of Bristol). |
Impact | Publication in PNAS (doi: 10.1073/pnas.1703779114 ). Multi-disciplinary (mathematics and biology). |
Start Year | 2016 |
Description | Characterising the interplay between cortisol and cytokine dynamics in response to cardiac surgery |
Organisation | University of Bristol |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Providing expert advice on analysis of dynamic hormone/cytonkine data. |
Collaborator Contribution | Clinical partners providing data from patients undergoing heart surgery. Additionally, theoretical partners from the University of Birmingham are providing numerical analysis skills. As part of this we are collaborating with an artist to highlight the ideas behind our research to the general public. |
Impact | Publication in J. R. Soc. Interface (doi: 10.1098/rsif.2021.0925). Multi-disciplinary (mathematics, biology). |
Start Year | 2020 |
Description | Investigating the dynamic relationship between between stress and seizures |
Organisation | University of Birmingham |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Advice on stress physiology, hormone rhythms, and glucocorticoid effects on neuronal function. |
Collaborator Contribution | Mathematical modelling skills and expertise in neural network models. |
Impact | One published research article in PLoS Computation Biology (https://doi.org/10.1371/journal.pcbi.1010508). Multi-disciplinary (mathematics, biology). |
Start Year | 2020 |
Description | Studying the effect of feeding patterns on hormonal dynamics |
Organisation | Cardiff University |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Analysis of dynamic hormonal data using numerical methods. |
Collaborator Contribution | Designing and performing experiments and providing data for analysis. |
Impact | Publication in J Nutr. (doi: 10.1093/jn/nxz116). Multi-disciplinary (mathematics, biology). |
Start Year | 2017 |
Description | The role of channel stochasticity in regulating the electrical activity of endocrine pituitary cells |
Organisation | University of Exeter |
Department | Medical School |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | General scientific guidance. |
Collaborator Contribution | General scientific guidance; mathematical modelling. |
Impact | Publication in PLoS Comput Biol (doi: 10.1371/journal.pcbi.1007769). Multi-disciplinary (mathematics, biology). |
Start Year | 2016 |
Description | Understanding how leak channels control the dynamic activity of endocrine pituitary cells |
Organisation | University of Exeter |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Providing general scientific guidance. |
Collaborator Contribution | Providing general scientific guidance and generating experimental data and mathematical modelling output. |
Impact | No outputs yet. Multi-disciplinary (mathematics and biology). |
Start Year | 2016 |
Description | Understanding links between reproductive and stress systems |
Organisation | King's College London |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Modelling expertise to characterise the dynamic interplay between the stress and reproductive neuroendocrine axes. |
Collaborator Contribution | Providing biological expertise to develop models as well as experimental data to calibrate models; experimental testing of modelling predictions. |
Impact | Publication in Frontiers in Physiology (doi: 10.3389/fphys.2020.598845). Multi-disciplinary (mathematics, biology). |
Start Year | 2019 |
Description | Understanding synergy and heterogeneity in corticotroph calcium responses to CRH and AVP |
Organisation | University of Edinburgh |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Designing and analysing mathematical models of corticotroph cell signalling pathways. |
Collaborator Contribution | Supplying experimental data to calibrate models as well as biological expertise. |
Impact | Publication in Endocrinology (doi: 10.1210/en.2017-00107). Multi-disciplinary (mathematics, biology). |
Start Year | 2016 |
Description | Patient/public-engagement workshop - Hormone Dynamics in Pituitary and Adrenal Disorders |
Form Of Engagement Activity | Participation in an activity, workshop or similar |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Patients, carers and/or patient groups |
Results and Impact | This was a patient/public-engagement workshop that was organised together with the Pituitary Foundation and the Addison's Disease Self-Help Group. The goal was to bring together patients, clinicians, and scientific researchers, and establish a dialogue about the importance of hormone dynamics, how our research contributes to understand this dynamics, and about future research projects aimed at improving and designing novel clinical interventions. |
Year(s) Of Engagement Activity | 2017 |