A mechanistic investigation into the emergent functional dynamics of the HPA axis

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.

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.

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.