1. Reproductive medicine. Emergent dynamics in coupled heterogeneous networks in uterine systems

• Reconstruction of tissue-level electrogenesis in smooth muscle from morphological, biophysical and genomic data. The main purpose is to combine both experimental and mathematical approaches to identify the functions of genes resulting from the expression of various ionic channel proteins in the initiation and conduction of electrical excitations in uterine systems, This will take account of tissue spatial structure and histo-chemistry and chart, in both space and time, proteomic micro-heterogeneity and connectivity patterns.

Aims:

• to assess quantitatively how these patterns determine the origin and propagation of the myometrial action potential (MAP)

• to integrate detailed experimental data into a coherent mathematical and computational platform to develop a predictive tool that enables evaluation of the functional roles of proteins (principally ion channels) of smooth muscle cells and interstitial cells of Cajál (ICC)

• to understand how gestational changes in the expression of ion channels and electrogenic pumps change the myometrium from quiescence to auto-rhythmic excitation; and

• to pioneer a novel genomics-driven mathematical modelling strategy in physiology, which will connect tissue-level physiology with high-throughput molecular data.

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 2. Network inference of energy balance regulation and whole-body metabolic control

Research objectives are:

• to study how control of food intake in mammals adapts to various energy regimes, focussing on the control of gene expression by signal transduction pathways and the resulting change in the electrophysiology of individual neurons and networks

• to develop a whole organism model for neuroendocrine control of nutrient intake, energy balance & growth

• to develop a macrochemical model of dynamics of body composition & its regulation. Manipulating the sugar rearrangement system to manage glucose load in diabetes; and

• to control continuous infusion of insulin in diabetic patients through continuous-time glucose monitoring.

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3. Preganglionic motor neurones

Preganglionic motor neurones are responsible for a number of crucial autonomic responses, in particular the preparation of the body for “fight-or-flight”. They form an extensive, gap-junction network of electrically active cells.

• Computational and mathematical models of the properties of sympatheticneuronal networks have been built using the extensive intracellular patch-clamprecording data generated in the Spanswick lab.

• These demonstrate that these networks have unique properties that are not seen in the more commonly studied chemicalsynapse networks; in particular, they move into a critical “avalanche” state which has unusual and potentially useful computational properties, such as being highly responsive to input signals.

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 4. Analytical platform-technology for the assessment of nitric oxide (NO)/oxidative stress-related metabolites

• This enables trace-level quantification of all major NO metabolites in complex biological matrices spanning from yeast to blood and mammalian cells/tissues, allowing an unparalleled insight into systems-widesignalling processes.

• Additional utilisation of tracer technology will allow us to distinguish between endogenous and exogenous (e.g.nutritional) sources and will put us in a position to become a world-leader in assessing regional and global NO/ Reactive Oxygen Species status of complex organisms in basic and translational studies. Inconjunction with collaborators.

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5. NF-E2-related factor-2 (nrf2) and the anti-stress gene response for good vascular health and healthy ageing.

(BBSRC grants and other support, PI Thornalley)

• Use of a fluorescent nrf2 reporter in vitro to (Funding includes approx. £5m SABR grant, led by Beynon) identify dietary bioactive compounds that provide potent and enduring activation of nrf2 thus activating antioxidant protective genes.
• Custom quantitative gene expression array for screening of health beneficial compounds.
• Mathematical models refined to predict dietary exposure-vascular health benefits.
• Mathematical models refined to healthy ageing benefits.
• Nrf2 activator contents of a some plant lines (rapeseed, tomatoes, broccoli and Rocket salad) foodstuffs rich in bioactives.

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6. Dysfunctional thiamine metabolism and therapy in diabetes

• Increased clearance and tissue-specific deficiency of thiamine in diabetes, link to vascular complications and high dose thiamine therapy.

• Mathematical modelling (physiologicallybased pharmacokinetic models) of thiamine metabolism in diabetes to predict tissuespecific deficiency and correction by high dose therapy.

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