Characterising the mechanisms through which the HPA axis maintains homeostasis in health and disease: A multiscale, multidisciplinary approach

The hypothalamic-pituitary-adrenal (HPA) axis dynamically regulates levels of the stress hormone cortisol. This axis is critical for the maintenance of homeostasis, and is the major hormonal system that provides a rapid response and defence against acute stress. Unfortunately, when exposure to stress becomes prolonged, the response of the HPA can become maladaptive and predispose an individual to illness - particularly cardiovascular, metabolic and cognitive dysfunction. There is now an increasing body of evidence that in order to achieve optimal function - from cellular response through to behaviour - oscillating levels of cortisol are required. In complete contrast to the natural state, patients undergoing both hormone replacement and glucocorticoid therapy for inflammatory or malignant disease are typically exposed to constant levels of long-acting synthetic steroids. This pattern of delivery was developed before we understood the importance of glucocorticoid rhythmicity 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 glucocorticoids.

It is therefore very important that we now re-evaluate the therapeutic application of glucocorticoids and to do so it is crucial that we understand the biological mechanisms governing the body's endogenous production of these steroids and further how these cycling levels of hormones help to optimise the body's response to environmental influences and to maintain normal internal regulatory processes. To address these questions, the approach we will pursue is to integrate data obtained from cellular, tissue and whole systems studies through the development of a suite of computational and mathematical models .Using these models we shall probe the data for the likely generators of our experimental observations and to guide the development of new experiments that can validate the predictions of our mathematical models. Given the complexity of the HPA-axis, where dynamic patterns of activity emerge from interactions across many spatial and temporal scales within the system, mathematical models provide a natural suite of tools with which to interrogate our data.

Ultimately we plan to fully integrate our approaches through the development of a hybrid testing approach. This means that we couple part of the system that we wish to study experimentally, with a computational model of the rest of the system. This will enable us to study the specific subcomponent as if it remained part of the whole system. Such an approach will be crucial to appropriately identify the biological mechanisms that give rise to disrupted rhythmicity associated with disease and ageing, since the behaviour of a component of a system in isolation may not be reflective of its behaviour when integrated within the whole system.

This Programme Grant will integrate data obtained from cellular, tissue, whole animal, computational and mathematical models to investigate the biological mechanisms underlying the rhythmic activity of the stress-responsive hypothalamo-pituitary-adrenal (HPA)-axis. The purpose of the Programme is to test the hypothesis that dynamic oscillatory patterns of activity are intrinsic to the HPA axis and are crucial for the stability and reactivity of this critical homeostatic and stress response system. We shall determine how the HPA axis utilises dynamic oscillatory activity - across multiple spatial and temporal domains - to maintain homeostasis and how these activities respond to stress and disease. To address these questions we shall combine our mathematical modelling and in vitro and in vivo expertises, using a variety of techniques including molecular and chromatin biology, cell signalling, systems biology, computational neuroscience and applied nonlinear mathematics. We shall develop novel model-driven hypotheses through a predictive modelling framework - by which we mean an overarching framework that is informed by, and in turns informs, our experimental design. This framework will underpin the construction of a novel hybrid system (where the interaction between computer model and in vivo or in vitro experiment occurs in real time), which will permit experimental design in closer agreement with the natural system as well as reducing the number of animals required for experimental studies. Ultimately our aim is to understand the fundamental mechanisms of CORT rhythmicity so that glucocorticoid therapies can be reevaluated to maximize the therapeutic benefit, whilst minimizing side effects.

There are a number of groups that will benefit from the research, over a number of timescales varying from short-term (< 12 months) to long-term (> 10 years).

Full details of these beneficiaries are provided in our pathway to impact statement and we present a summary of this statement here.

Short-term (0-3 years)

Patient-Groups: We will organize events, via our Outreach Programme, aimed at groups representing patients with hypothalamus-pituitary-adrenal related disorders (including the Addisons Disease Self Help Group, the CAH Support Group the Cushings Syndrome Support Group and the Pituitary Foundation (whose first Chairman was Stafford Lightman). Within these events, that will be organized at least annually, we shall present the latest findings of our research programme and enable the direct input of patients through question and answer sessions with investigators and researchers. These events will be well advertised through our own web-forum, as well as our host organization's Public Engagement Centres.

Medical Research Council: Our proposal satisfies the cross-board highlight notice: Systems Biology for Medicine, and would therefore naturally serve as a case-study for future research programmes within this highlight. We would seek to actively engage with MRC representatives through, for example, their attendance at our regular workshops and outreach activities.

Longer-term (5-8 years)

Clinicians managing hypothalamus-pituitary-adrenal disorders: The proposal offers the potential for a methodological framework that can guide decisions made in clinic, through the development of mathematical models of the generators of clinical observables, and the tools for exploring these mechanisms directly from clinical observables. We will actively engage with clinicians through our workshops and other public understanding of science events organized by our host organizations as part of their commitment to widening the scope of research conducted by them.

Commercial-sector pharmaceuticals: They will be able to plan clinical trials to include data-derived prognostic biomarkers using findings from our Programme to either develop their own generative models or pre-existing ones developed through the Programme. Further, our data should enable the development of novel chronologically discrete methods of drug administration that more naturally mimic the body's own production of glucocorticoids that will improve efficacy and decrease side effects from glucocorticoid administration.

Long-term (> 10 years)

Patients with clinical disorders: Our Programme will ultimately provide the opportunity not only for improved diagnosis of adrenal hypo- and hyperfunction but also for improved therapy both for patients needing glucocorticoid replacement and for patients needing higher dose glucocorticoid therapy for inflammatory or malignant conditions. This will be achieved through the uptake of findings from our Programme by experimental and clinical researchers, and the subsequent translation of these research findings into the clinic.

Health-sector managers and policy makers. A consequence of improving the design for clinical pathways for dynamic disorders using our framework could ultimately result in substantial savings against the costs of treatment. Steroids are one of the most prescribed classes of drug in the UK and consequently reducing side-effects through the more effective delivery of glucocorticoids will ultimately result in financial savings.