MRC Transition Support CDA Jamie Walker
Lead Research Organisation:
UNIVERSITY OF EXETER
Department Name: Mathematics
Abstract
Oscillating activity is ingrained in our physiology, and when these oscillations become disrupted, this can have major consequences for our health. A good example of this is the hypothalamic-pituitary-adrenal (HPA) axis, a vital system in the body controlling the release of 'stress hormones' such as cortisol. Oscillations in these hormones regulate the activity of many important biological functions, and ensure the body is in an ideal state to respond to stress. But stressful experiences early in life, or excessively-large or prolonged periods of stress, can lead to long-lasting disruptions in HPA axis activity, which in turn has consequences for brain function and our physical and mental well-being. The overarching aim of my fellowship is to understand how the HPA axis controls these oscillations in hormone secretion; this information will be critical for understanding how and why these hormone patterns change in disease.
Supported by a Career Development Award (CDA), I am employing quantitative techniques and state-of-the-art experimental approaches to understand how cortisol rhythms are generated. To date, I have investigated how cells in the pituitary gland coordinate the activity of the HPA axis, and have shown how dynamic hormonal signals from the pituitary gland itself are decoded by the adrenal glands to control cortisol secretion. Whilst studying hormone regulation at the level of individual glands provides valuable insight, it tells us little about how the various components of the HPA axis interact with one another to generate oscillating patterns of hormone secretion. Ultimately, it is this 'system-level' oscillating activity that effects our physiology, and it is this system-level activity that becomes disrupted in disease.
Due to unforeseeable factors that have had a significant impact on my research momentum, I have so far been unable to produce these system-level outputs that are the uppermost aim of my CDA, and are critical to secure additional funding in my field. However, based on my significant progress in the pituitary and adrenal aspects of my project, I am confident that with a 2-year Transition Support Award, I will successfully delivery these system-level outputs, which would form the platform I need to develop competitive further funding applications.
Supported by a Career Development Award (CDA), I am employing quantitative techniques and state-of-the-art experimental approaches to understand how cortisol rhythms are generated. To date, I have investigated how cells in the pituitary gland coordinate the activity of the HPA axis, and have shown how dynamic hormonal signals from the pituitary gland itself are decoded by the adrenal glands to control cortisol secretion. Whilst studying hormone regulation at the level of individual glands provides valuable insight, it tells us little about how the various components of the HPA axis interact with one another to generate oscillating patterns of hormone secretion. Ultimately, it is this 'system-level' oscillating activity that effects our physiology, and it is this system-level activity that becomes disrupted in disease.
Due to unforeseeable factors that have had a significant impact on my research momentum, I have so far been unable to produce these system-level outputs that are the uppermost aim of my CDA, and are critical to secure additional funding in my field. However, based on my significant progress in the pituitary and adrenal aspects of my project, I am confident that with a 2-year Transition Support Award, I will successfully delivery these system-level outputs, which would form the platform I need to develop competitive further funding applications.
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, and a critical aspect of its function is an ultradian oscillation in hormone release. These oscillations in blood glucocorticoid 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 glucocorticoid 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 Transition Support award and how they will do so.
Short-term impact (1-2 years)
My research team and direct collaborators will benefit through the further development of my multidisciplinary research laboratory at the University of Exeter that I have established during my CDA. Through my collaborations with other internationally-leading biomedical research laboratories at the Universities of Edinburgh and Bristol, and the Institute of Functional Genomics (IFG), Montpellier, France, I will continue to facilitate knowledge sharing between Exeter and these other institutions.
Through presentations at national and international scientific conferences and publications in academic journals, researchers in the fields of stress, mathematical biology, and basic/clinical neuroendocrinology, as well as the broader international biomedical research community, will benefit from my Transition Support outputs. In particular, the wider research community may use our outputs to guide their own research programmes. For example, many other hormonal systems display rhythms of activity with functional consequences, including systems controlling the secretion of insulin, growth hormone, and sex steroids; the experimental and mathematical modelling approaches we will employ, as well as the data generated using these approaches, will benefit scientists working on these other related (neuro)endocrine systems.
Patients and the general public will also benefit, through the opportunity to attend a public engagement event aimed at members of the public and patients who are affected by stress-related disorders or pathologies of the stress axis. I have already organised one of these events with great success during the course of my CDA, and I plan to organise another public workshop during the period of this Transition Support award.
Other short-term beneficiaries include NC3Rs, who could use my research approach as a case study to illustrate how quantitative methods can help to reduce the number of animals required in research, and the MRC, who could 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.
Medium-term impact (3-10 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 steroid administration that more naturally mimic the body's own production of glucocorticoids, which will improve efficacy and decrease side effects from glucocorticoid administration.
Long-term impact (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.
Short-term impact (1-2 years)
My research team and direct collaborators will benefit through the further development of my multidisciplinary research laboratory at the University of Exeter that I have established during my CDA. Through my collaborations with other internationally-leading biomedical research laboratories at the Universities of Edinburgh and Bristol, and the Institute of Functional Genomics (IFG), Montpellier, France, I will continue to facilitate knowledge sharing between Exeter and these other institutions.
Through presentations at national and international scientific conferences and publications in academic journals, researchers in the fields of stress, mathematical biology, and basic/clinical neuroendocrinology, as well as the broader international biomedical research community, will benefit from my Transition Support outputs. In particular, the wider research community may use our outputs to guide their own research programmes. For example, many other hormonal systems display rhythms of activity with functional consequences, including systems controlling the secretion of insulin, growth hormone, and sex steroids; the experimental and mathematical modelling approaches we will employ, as well as the data generated using these approaches, will benefit scientists working on these other related (neuro)endocrine systems.
Patients and the general public will also benefit, through the opportunity to attend a public engagement event aimed at members of the public and patients who are affected by stress-related disorders or pathologies of the stress axis. I have already organised one of these events with great success during the course of my CDA, and I plan to organise another public workshop during the period of this Transition Support award.
Other short-term beneficiaries include NC3Rs, who could use my research approach as a case study to illustrate how quantitative methods can help to reduce the number of animals required in research, and the MRC, who could 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.
Medium-term impact (3-10 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 steroid administration that more naturally mimic the body's own production of glucocorticoids, which will improve efficacy and decrease side effects from glucocorticoid administration.
Long-term impact (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.
People |
ORCID iD |
| Jamie Walker (Principal Investigator / Fellow) |